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  • 1. Ali, Magdi M. M.
    et al.
    ElGhazali, Gehad
    Montgomery, Scott M.
    Örebro universitet, Hälsoakademin.
    Farouk, Salah E.
    Nasr, Amre
    Noori, Suzan I. A.
    Shamad, Mahdi M.
    Fadlelseed, Omar E.
    Berzins, Klavs
    Fc gamma RIIa (CD32) polymorphism and onchocercal skin disease: implications for the development of severe reactive onchodermatitis (ROD)2007Inngår i: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 77, nr 6, s. 1074-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pathologic manifestations of Onchocerca volvulus infection depend on the interplay between the host and the parasite. A genetic single nucleotide polymorphism in the Fc gamma RIIa gene, resulting in arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses and may influence the clinical variations seen in onchocerciasis. This study investigated the relationship between this polymorphism and disease outcome. Fc gamma RIIa genotyping was performed on clinically characterized onchocerciasis patients (N = 100) and healthy controls (N = 74). Fc gamma RIIa genotype R/R131 frequencies were significantly higher among patients with severe dermatopathology (P < 0.001). Increased risk of developing this form was mostly associated with one tribe (Masalit) (OR = 3.2, 95% CI 1-9.9, P = 0.042). The H131 allele was found to be significantly associated with a reduced risk of having the severe form of the disease (adjusted OR = 0.26, 95% CI = 0.13-0.46, P < 0.001). Our findings suggest that the polymorphism influences the clinical outcome of onchocerciasis.

  • 2.
    Assadi, G.
    et al.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Saleh, R.
    Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Hadizadeh, F.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Vesterlund, L.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Bonfiglio, F.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Törkvist, L.
    Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
    Eriksson, A. S.
    Gatroenterology Unit, Department of Internal Medicine, Sahlgren's University Hospital/Östra, Göteborg, Sweden.
    Harris, H. E.
    Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Sundberg, E.
    Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, M.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
    LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis2016Inngår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 17, nr 4, s. 261-264Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The function of the Laccase domain-containing 1 (LACC1) gene is unknown, but genetic variation at this locus has been reported to consistently affect the risk of Crohn's disease (CD) and leprosy. Recently, a LACC1 missense mutation was found in patients suffering from monogenic forms of CD, but also systemic juvenile idiopathic arthritis. We tested the hypothesis that LACC1 single nucleotide polymorphisms (SNPs), in addition to CD, are associated with juvenile idiopathic arthritis (JIA, non-systemic), and another major form of inflammatory bowel disease, ulcerative colitis (UC). We selected 11 LACC1 tagging SNPs, and tested their effect on disease risk in 3855 Swedish individuals from three case-control cohorts of CD, UC and JIA. We detected false discovery rate corrected significant associations with individual markers in all three cohorts, thereby expanding previous results for CD also to UC and JIA. LACC1's link to several inflammatory diseases suggests a key role in the human immune system and justifies further characterization of its function(s).

  • 3.
    Beck-Nielsen, Signe Sparre
    et al.
    Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
    Mughal, Zulf
    Royal Manchester Children's Hospital, Manchester, UK.
    Haffner, Dieter
    Hannover Medical School, Hannover, Germany.
    Nilsson, Ola
    Örebro universitet, Institutionen för medicinska vetenskaper. Karolinska Institutet, Stockholm, Sweden .
    Levtchenko, Elena
    Katholieke Universiteit Leuven, Leuven, Belgium.
    Ariceta, Gema
    Hospital Universitario Materno-Infantil Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.
    de Lucas Collantes, Carmen
    Hospital Niño Jesús, Madrid, Spain.
    Schnabel, Dirk
    University Children's Hospital of Berlin, Berlin, Germany.
    Jandhyala, Ravi
    Medialis Ltd, Banbury, UK.
    Mäkitie, Outi
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    FGF23 and its role in X-linked hypophosphatemia-related morbidity2019Inngår i: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 14, nr 1, artikkel-id 58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood.

    METHODS: The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH.

    RESULTS: The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations.

    CONCLUSIONS: By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.

  • 4.
    Bento, Celeste
    et al.
    Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal .
    Percy, Melanie J.
    Department of Haematology, Belfast City Hospital, Belfast, United Kingdom .
    Gardie, Betty
    Unité Mixte de Recherche (UMR) 892 Inserm - 6299 CNRS, Université de Nantes, Nantes, France; Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), INSERM U753, Institut de cancérologie Gustave Roussy, Villejuif, France .
    Maia, Tabita Magalhaes
    Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal .
    van Wijk, Richard
    Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, Netherlands .
    Perrotta, Silverio
    Dipartimento della Donna, Del Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, Naples, Italy .
    Della Ragione, Fulvio
    Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy .
    Almeida, Helena
    Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal .
    Rossi, Cedric
    Laboratoire d'Hématologie, Centre Hospitalier Universitaire Dijon, Dijon, France .
    Girodon, Francois
    Laboratoire d'Hématologie, Centre Hospitalier Universitaire Dijon, Dijon, France .
    Åström, Maria
    Region Örebro län. Departments of Medicine and Laboratory Medicine.
    Neumann, Drorit
    Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel .
    Schnittger, Susanne
    Munich Leukemia Laboratory (MLL), Munich, Germany .
    Landin, Britta
    Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden .
    Minkov, Milen
    Department of Hematology/Oncology, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria .
    Randi, Maria Luigia
    Department of Medicine DIMED, University of Padua, Padua, Italy .
    Richard, Stephane
    Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), INSERM U753, Institut de cancérologie Gustave Roussy, Villejuif, France .
    Casadevall, Nicole
    Hôpital Saint Antoine, Paris, France; Assistance Publique-Hôpitaux de Paris, Paris, France; Pierre et Marie Curie University, Paris, France; UMR1009 Institut Gustave Roussy Villejuif, Paris, France .
    Vainchenker, William
    UMR 1009 and GRex, INSERM, Université Paris-Sud, Institut Gustave Roussy, Villejuif, France .
    Rives, Susana
    Department of Pediatric Hematology, Hospital Sant Joan de Déu de Barcelona, University of Barcelona, Barcelona, Spain .
    Hermouet, Sylvie
    Unité Mixte de Recherche (UMR) 892 Inserm - 6299 CNRS, Université de Nantes, Nantes, France .
    Ribeiro, M. Leticia
    Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal .
    McMullin, Mary Frances
    Department of Haematology, CCRCB, Queen's University, Belfast, Northern Ireland, United Kingdom .
    Cario, Holger
    Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany .
    Genetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases2014Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 35, nr 1, s. 15-26Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database.

  • 5.
    Bladen, Catherine L.
    et al.
    Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Medical Research Council, Newcastle Upon Tyne, England.
    Rafferty, Karen
    Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Medical Research Council, Newcastle Upon Tyne, England.
    Straub, Volker
    Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Medical Research Council, Newcastle Upon Tyne, England.
    Monges, Soledad
    Moresco, Angelica
    Hosp Pediat JP Garrahan, Buenos Aires DF, Argentina..
    Dawkins, Hugh
    Department of Health, Office of Population Health Genomics, Perth WA, Australia.
    Roy, Anna
    The Scientific Institute of Public Health (WIV ISP), Brussels, Belgium.
    Chamova, Teodora
    Dept Neurol, Sofia, Med Univ Sofia, Sofia, Bulgaria.
    Guergueltcheva, Velina
    Dept Neurol, Med Univ Sofia, Sofia, Bulgaria.
    Korngut, Lawrence
    Hlth Sci Ctr, Univ Calgary, Calgary AB, Canada.
    Campbell, Craig
    Dept Paediat Clin Neurol Sci & Epidemiol, Univ Western Ontario, London ON, Canada.
    Dai, Yi
    Dept Neurol, Peking Union Med Coll Hosp, Peking Union Med Coll, Beijing , Peoples R China; Chinese Acad Med Sci, Beijing, Peoples R China.
    Barisic, Nina
    Sch Med, Div Paediat Neurol, Univ Hosp Ctr, Univ Zagreb, Zagreb, Croatia.
    Kos, Tea
    Sch Med, Div Paediat Neurol, Univ Hosp Ctr, Univ Zagreb, Zagreb, Croatia.
    Brabec, Petr
    Inst Biostat & Anal, Masaryk Univ, Brno, Czech Republic..
    Rahbek, Jes
    Natl Danish Rehabil Ctr Neuromuscular Dis, Aarhus, Denmark.
    Lahdetie, Jaana
    Cent Hosp, Turku Univ, Turku, Finland.
    Tuffery-Giraud, Sylvie
    Lab Genet Malad Rares, Univ Montpellier I, Montpellier, France; INSERM, Montpellier, France.
    Claustres, Mireille
    Lab Genet Malad Rares, Univ Montpellier I, Montpellier, France; INSERM, Montpellier, France.
    Leturcq, France
    Lab Biochim & Genet Mol, Hop Cochin, Paris, France..
    Ben Yaou, Rabah
    Lab Biochim & Genet Mol, Hop Cochin, Paris, France.
    Walter, Maggie C.
    Dept Neurol, Friedrich Baur Inst, Univ Munich, Munich, Germany.
    Schreiber, Olivia
    Dept Neurol, Friedrich Baur Inst, Univ Munich, Munich, Germany.
    Karcagi, Veronika
    Dept Mol Genet, National Institute of Environmental Health, Budapest, Hungary.
    Herczegfalvi, Agnes
    Dept Mol Genet, National Institute of Environmental Health, Budapest, Hungary.
    Viswanathan, Venkatarman
    Kanchi Kamakoti CHILDS Trust Hosp, Madras, India.
    Bayat, Farhad
    Pasteur Inst Iran, Tehran, Iran.
    Sarmiento, Isis de la Caridad Guerrero
    Pasteur Inst Iran, Tehran, Iran.
    Ambrosini, Anna
    Foundation Telethon Piazza Cavour, Milan, Italy.
    Ceradini, Francesca
    Hosp Pediat JP Garrahan, Buenos Aires DF, Argentina; Parent Project Onlus, Rome, Italy.
    Kimura, En
    Translat Med Ctr, Natl Ctr Neurol & Psychiat Kodaira, Tokyo, Japan.
    van den Bergen, Janneke C.
    Med Ctr, Dept Neurol, Leiden Univ, Leiden, Netherlands.
    Rodrigues, Miriam
    Auckland City Hosp, Auckland, New Zealand.
    Roxburgh, Richard
    Auckland City Hosp, Auckland, New Zealand..
    Lusakowska, Anna
    Warszawa Banacha 1A, Dept Neurol, Warsaw, Poland.
    Oliveira, Jorge
    Ctr Genet Med Jacinto Magalhaes, Oporto, Portugal..
    Santos, Rosario
    Ctr Genet Med Jacinto Magalhaes, Oporto, Portugal..
    Neagu, Elena
    Pediat Neurol Dept, Hosp Al Obregia, Bucharest, Romania..
    Butoianu, Niculina
    Pediat Neurol Dept, Hosp Al Obregia, Bucharest, Romania..
    Artemieva, Svetlana
    Rublevskoe Shosse, Moscow, Russia..
    Rasic, Vedrana Milic
    Clin Child Neurol & Psychiat, Belgrade, Serbia..
    Posada, Manuel
    Inst Rare Dis Res, Inst Hlth Carlos III, Madrid, Spain.
    Palau, Francesc
    Unit Genet, Hosp La Fe, Valencia, Spain..
    Lindvall, Björn
    Region Örebro län.
    Bloetzer, Clemens
    Paediat Neurol & Neurorehabil Unit, Univ Lausanne Hosp, Lausanne, Switzerland..
    Karaduman, Ayse
    Fac Hlth Sci, Dept Physiotherapy & Rehabil, Hacettepe Univ, Ankara, Turkey..
    Topaloglu, Haluk
    Fac Hlth Sci, Dept Physiotherapy & Rehabil, Hacettepe Univ, Ankara, Turkey..
    Inal, Serap
    Dept Neurol, PTR Unit, Istanbul Univ, Fac Med, Istanbul, Turkey..
    Oflazer, Piraye
    Dept Neurol, PTR Unit, Istanbul Univ, Fac Med, Istanbul, Turkey..
    Stringer, Angela
    Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle upon Tyne, United Kingdom; Division of Paediatric Neurology, University Hospital Centre Zagreb (KBC Zagreb), University of Zagreb Medical School, Zagreb, Croatia; Act Duchenne, Epictr, London, England..
    Shatillo, Andriy V.
    Inst Neurol Psychiat & Narcol NAMS, Kharkov, Ukraine..
    Martin, Ann S.
    DuchenneConnect, Hackensack NJ, USA.
    Peay, Holly
    DuchenneConnect, Hackensack NJ, USA.
    Flanigan, Kevin M.
    Ohio State Univ, Columbus OH, USA.;Nationwide Childrens Hosp, Columbus OH, USA.
    Salgado, David
    Fac Med Timone INSERM, UMR S910, Aix Marseille Univ, Marseille, France; Australian Regenerat Med Inst, EMBL Australia, Monash Univ, Clayton Vic, Australia.
    von Rekowski, Brigitta
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne, England..
    Lynn, Stephen
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne, England..
    Heslop, Emma
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne, England..
    Gainotti, Sabina
    Annali dell'Istituto Superiore di Sanità, Natl Ctr Rare Dis, Rome, Italy.
    Taruscio, Domenica
    Annali dell'Istituto Superiore di Sanità, Natl Ctr Rare Dis, Rome, Italy.
    Kirschner, Jan
    Univ Med Ctr, Freiburg, Germany..
    Verschuuren, Jan
    Dept Neurol, ZA, Leiden Univ, Med Ctr, Leiden, Netherlands.
    Bushby, Kate
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne, England..
    Beroud, Christophe
    Fac Med Timone, INSERM, UMR S910, Aix Marseille Univ, Marseille, France..
    Lochmueller, Hanns
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne , England..
    The TREAT-NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia2013Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, nr 11, s. 1449-1457Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence<5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

  • 6.
    Bogl, Leonie H.
    et al.
    Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
    Tuvblad, Catherine
    Örebro universitet, Institutionen för juridik, psykologi och socialt arbete. Department of Psychology, University of Southern California, Los Angeles CA, United States.
    Kaprio, Jaakko
    Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
    Does the sex of one's co-twin affect height and BMI in adulthood?: A study of dizygotic adult twins from 31 cohorts2017Inngår i: Biology of Sex Differences, ISSN 2042-6410, Vol. 8, nr 1, artikkel-id 14Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The comparison of traits in twins from opposite-sex (OS) and same-sex (SS) dizygotic twin pairs is considered a proxy measure of prenatal hormone exposure. To examine possible prenatal hormonal influences on anthropometric traits, we compared mean height, body mass index (BMI), and the prevalence of being overweight or obese between men and women from OS and SS dizygotic twin pairs.

    Methods: The data were derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) database, and included 68,494 SS and 53,808 OS dizygotic twin individuals above the age of 20 years from 31 twin cohorts representing 19 countries. Zygosity was determined by questionnaires or DNA genotyping depending on the study. Multiple regression and logistic regression models adjusted for cohort, age, and birth year with the twin type as a predictor were carried out to compare height and BMI in twins from OS pairs with those from SS pairs and to calculate the adjusted odds ratios and 95% confidence intervals for being overweight or obese.

    Results: OS females were, on average, 0.31 cm (95% confidence interval (CI) 0.20, 0.41) taller than SS females. OS males were also, on average, taller than SS males, but this difference was only 0.14 cm (95% CI 0.02, 0.27). Mean BMI and the prevalence of overweight or obesity did not differ between males and females from SS and OS twin pairs. The statistically significant differences between OS and SS twins for height were small and appeared to reflect our large sample size rather than meaningful differences of public health relevance.

    Conclusions: We found no evidence to support the hypothesis that prenatal hormonal exposure or postnatal socialization (i.e., having grown up with a twin of the opposite sex) has a major impact on height and BMI in adulthood.

  • 7.
    Bruder, Carl E. G.
    et al.
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Hirvelä, Carina
    Department of Otorhinolaryngology and Head and Neck Surgery, Uppsala University Hospital, Uppsala, Sweden.
    Tapia-Paez, Isabel
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Fransson, Ingegerd
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Segraves, Richard
    Department of Laboratory Medicine, UCSF Cancer Center, San Fancisco, USA.
    Hamilton, Greg
    Department of Laboratory Medicine, UCSF Cancer Center, San Fancisco, USA.
    Zhang, Xiao Xiao
    Department of Laboratory Medicine, UCSF Cancer Center, San Fancisco, USA.
    Evans, D. Gareth
    Department of Medical Genetics, St Mary Hospital, Manchester, UK.
    Wallace, Andrew J.
    Department of Medical Genetics, St Mary Hospital, Manchester, UK.
    Baser, Michael E.
    Los Angeles, USA.
    Zucman-Rossi, Jessica
    Laboratorie de Geneticque des Tumeurs, Paris, France.
    Hergersberg, Martin
    Institute of Medical Genetics, University of Zürich, Zürich, Switzerland.
    Boltshauser, Eugene
    Division of Pediatric Neurology, Children Hospital, Zürich, Switzerland .
    Papi, Laura
    Medical Genetics Unit, Department of Physiopathology, University of Florence, Florence, Italy.
    Rouleau, Guy A.
    Centre for Research in Neuroscience, Montreal General Hospital, Quebec, Canada.
    Poptodorov, George
    Department of Neurosurgery, University Hospital, Sofia, Bulgaria.
    Jordanova, Albena
    Laboratory of Molecular Pathology, Sofia, Bulgaria.
    Rask-Andersen, Helge
    Department of Otorhinolaryngology and Head and Neck Surgery, Uppsala University Hospital, Uppsala, Sweden.
    Kluwe, Lan
    Department of Neurology, Klinikum Nord Ochenzoll, Hamburg, Germany.
    Mautner, Victor
    Department of Neurology, Klinikum Nord Ochenzoll, Hamburg, Germany.
    Sainio, Markku
    Department of Pathology, University of Helsinki, Haartman Institute, Helsinki, Finland.
    Hung, Gene
    House Ear Institute, Los Angeles, USA.
    Mathiesen, Tiit
    Department of Neurosurgery, Karolinska Hospital, Stockholm, Sweden.
    Möller, Claes
    Department of Audiology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Pulst, Stefan M.
    Division of Neurology, Cedars-Sinai Medical Center, Los Angeles USA.
    Harder, Henrik
    Department of Otorhinolaryngology, Linköping University Hospital, Linköping, Sweden.
    Heiberg, Arvid
    Department of Medical Genetics, Rikshospitalet, Oslo, Norway.
    Honda, Mariko
    Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.
    Niimura, Michihito
    Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.
    Sahlén, Sigrid
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Blennow, Elisabeth
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Albertson, Donna G.
    Cancer Research Institute, UCSF Cancer Center, San Francisco, USA.
    Pinkel, David
    Department of Laboratory Medicine, UCSF Cancer Center, San Fancisco, USA.
    Dumanski, Jan P.
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden; Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University Hospital, Uppsala, Sweden.
    High resolution deletion analysis of conctitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH2001Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 10, nr 3, s. 271-282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CON methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.

  • 8.
    Böttiger, Anna K.
    et al.
    Örebro universitet, Hälsoakademin.
    Hurtig-Wennlöf, Anita
    Örebro universitet, Hälsoakademin.
    Sjöström, Michael
    Yngve, Agneta
    Nilsson, Torbjörn K.
    Örebro universitet, Hälsoakademin.
    Association of total plasma homocysteine with methylenetetrahydrofolate reductase genotypes 677C>T, 1298A>C, and 1793G>A and the corresponding haplotypes in Swedish children and adolescents2007Inngår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 19, nr 4, s. 659-665Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We studied 692 Swedish children and adolescents (aged 9-10 or 15-16 years, respectively), in order to evaluate the effect of the methylenetetrahydrofolate reductase (MTHFR) 677C>T, 1298A>C, and 1793G>A polymorphisms on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing technology. The MTHFR 677C>T polymorphism was associated with increased tHcy concentrations in both the children and the adolescents (P<0.001 for both age groups) in both genders. The effect of MTHFR 1298A>C was studied separately in subjects with the 677CC and 677CT genotypes, and the 1298C allele was found to be associated with higher tHcy levels both when children were stratified according to 677C>T genotypes, and when using haplotype analyses and diplotype reconstructions. The 1793A allele was in complete linkage disequilibrium with the 1298C allele. It was still possible to show that the 1793A allele was associated with lower tHcy levels, statistically significant in the adolescents. In conclusion, a haplotype-based approach was slightly superior in explaining the genetic interaction on tHcy plasma levels in children and adolescents than a simple genotype based approach (R2 adj 0.44 vs. 0.40). The major genetic impact on tHcy concentrations is attributable to the MTHFR 677C>T polymorphism. The common 1298A>C polymorphism had a minor elevating effect on tHcy, whereas the 1793G>A polymorphism had a lowering effect on tHcy.

  • 9.
    Böttiger, Anna K.
    et al.
    Örebro universitet, Hälsoakademin.
    Nilsson, Torbjörn K.
    Henriquez, Patricia
    Serra-Majem, Lluis
    Plasma homocysteine and MTHFR genotypes and haplotypes: gene-nutrient interactions in the Canary Islands Nutrition Study (ENCA)Manuskript (Annet (populærvitenskap, debatt, mm))
  • 10.
    Ellinghaus, David
    et al.
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Jostins, Luke
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    Spain, Sarah L.
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    Cortes, Adrian
    Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    Bethune, Jörn
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Han, Buhm
    Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
    Park, Yu Rang
    Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
    Raychaudhuri, Soumya
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge MA, United States; Division of Genetics, Brigham and Women's Hospital, Boston MA, United States; Division of Rheumatology, Brigham and Women's Hospital, Boston MA, United States.
    Pouget, Jennie G.
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
    Hübenthal, Matthias
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Folseraas, Trine
    Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Cancer Medicine,Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
    Wang, Yunpeng
    Department of Neurosciences, University of California, San Diego, USA.
    Esko, Tonu
    Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Boston Children's Hospital, Cambridge MA, USA; Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge MA, USA.
    Metspalu, Andres
    Estonian Genome Center, University of Tartu, Tartu, Estonia.
    Westra, Harm-Jan
    Program in Medical and Population Genetics, Broad Institute of mit and Harvard, Cambridge MA, United States; Division of Genetics, Brigham and Women's Hospital, Boston MA, United States; Division of Rheumatology, Brigham and Women's Hospital, Boston MA, United States; Department of Medicine, Harvard Medical School, Boston MA, United States.
    Franke, Lude
    University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, the Netherlands.
    Pers, Tune H.
    Program in Medical and Population Genetics, Broad Institute of mit and Harvard, Cambridge MA, United States; Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge MA, United States; Novo Nordisk Foundation, Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
    Weersma, Rinse K.
    Department of Gastroenterology and Hepatology, University Medical Center, University of Groningen, Groningen, the Netherlands.
    Collij, Valerie
    Department of Gastroenterology and Hepatology, University Medical Center, University of Groningen, Groningen, the Netherlands.
    D'Amato, Mauro
    Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioCruces Health Research Institute, Basque Foundation for Science (Ikerbasque), Bilbao, Spain.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Jensen, Anders Boeck
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Lieb, Wolfgang
    Institute of Epidemiology, University Hospital Schleswig-Holstein, Kiel, Germany; PopGen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany.
    Degenhardt, Franziska
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    Forstner, Andreas J.
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    Hofmann, Andrea
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    The International IBD Genetics Consortium, (IIBDGC)
    International Genetics of Ankylosing Spondylitis Consortium, (IGAS)
    International PSC Study Group, (IPSCSG)
    Genetic Analysis of Psoriasis Consortium, (GAPC)
    Psoriasis Association Genetics Extension, (PAGE)
    Schreiber, Stefan
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    Mrowietz, Ulrich
    Department of Dermatology, University Hospital Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
    Juran, Brian D.
    Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester MN, USA.
    Lazaridis, Konstantinos N.
    Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester MN, USA.
    Brunak, Søren
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Dale, Anders M.
    Department of Neurosciences, University of California, San Diego, USA; Department of Radiology, University of California, San Diego, USA.
    Trembath, Richard C.
    Division of Genetics and Molecular Medicine, King's College London, London, UK.
    Weidinger, Stephan
    Department of Dermatology, University Hospital Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
    Weichenthal, Michael
    Department of Dermatology, University Hospital Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
    Ellinghaus, Eva
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Elder, James T.
    Department of Dermatology, University of Michigan, Ann Arbor, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, USA.
    Barker, Jonathan N. W. N.
    St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK.
    Andreassen, Ole A.
    NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway.
    McGovern, Dermot P.
    F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, USA; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
    Karlsen, Tom H.
    Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Cancer Medicine,Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
    Barrett, Jeffrey C.
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    Parkes, Miles
    Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
    Brown, Matthew A.
    University of Queensland Diamantina Institute, Translational Research Institute, Brisbane QLD, Australia; Institute of Health and Biomedical Innovation (IHBI), Translational Research Institute, Queensland University of Technology (QUT), Brisbane QLD, Australia .
    Franke, Andre
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci2016Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, nr 5, s. 510-518Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

  • 11.
    Engström, Karolina
    et al.
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Vánky, Farkas
    Department of Cardiothoracic and Vascular Surgery and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Rehnberg, Malin
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Trinks, Cecilia
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Jonasson, Jon
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Green, Anna
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Laboratory Medicine.
    Gunnarsson, Cecilia
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Novel SMAD3 p.Arg386Thr genetic variant co-segregating with thoracic aortic aneurysm and dissection2020Inngår i: Molecular Genetics & Genomic Medicine, ISSN 2324-9269, artikkel-id e1089Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Pathogenic variants in the SMAD3 gene affecting the TGF-beta/SMAD3 signaling pathway with aortic vessel involvement cause Loeys-Dietz syndrome 3, also known as aneurysms-osteoarthritis syndrome.

    Methods: Description of clinical history of a family in Sweden using clinical data, DNA sequencing, bioinformatics, and pedigree analysis.

    Results: We report a novel SMAD3 variant, initially classified as a genetic variant of uncertain clinical significance (VUS), and later found to be co-segregating with aortic dissection in the family. The index patient presented with a dissecting aneurysm of the aorta including the ascending, descending, and abdominal parts. Genotype analysis revealed a heterozygous missense SMAD3 variant: NM_005902.3(SMAD3): c.11576G > C (p.Arg386Thr). The same variant was also identified in a 30 years old formalin-fixed paraffin-embedded block of tissue from a second cousin, who died at 26 years of age from a dissecting aneurysm of the aorta.

    Conclusion: A "variant of uncertain significance" according to the ACMG guidelines has always a scope for reappraisal. Genetic counselling to relatives, and the offering of surveillance service is important to families with aortic aneurysm disease. The report also highlight the potential use of FFPE analysis from deceased relatives to help in the interpretation of variants.

  • 12.
    Faraone, Stephen V.
    et al.
    Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Genetics of attention deficit hyperactivity disorder2019Inngår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 24, nr 4, s. 562-575Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies show that ADHD runs in families. ADHD's high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD's heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD's heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.

  • 13.
    Farkas, Sanja A.
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Vymetalkova, Veronika
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
    Vodickova, Ludmila
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine, Charles University, Pilsen, Czech Republic.
    Vodicka, Pavel
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
    Nilsson, Torbjörn K.
    Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
    DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/beta-catenin signaling pathway genes2014Inngår i: Epigenomics, ISSN 1750-1911, Vol. 6, nr 2, s. 179-191Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: The onset and progression of colorectal cancer (CRC) involves a cascade of genetic and/or epigenetic events. The aim of the present study was to address the DNA methylation status of genes relevant in colorectal carcinogenesis and its progression, such as genes frequently mutated in CRC, genes involved in the DNA repair and Wnt signaling pathway.

    Material & methods: We analyzed methylation status in totally 160 genes in 12 paired colorectal tumors and adjacent healthy mucosal tissues using the Illumina Infinium Human Methylation 450 BeadChip.

    Results: We found significantly aberrant methylation in 23 genes (NEIL1, NEIL3, DCLRE1C, NHEJ1, GTF2H5, CCNH, CTNNB1, DKK2, DKK3, FZD5 LRP5, TLE3, WNT2, WNT3A, WNT6, TCF7L1, CASP8, EDNRB1, GPC6, KIAA1804, MYO1B, SMAD2 and TTN). External validation by mRNA expression showed a good agreement between hypermethylation in cancer and down-regulated mRNA expression of the genes EDNRB1, GPC6 and SMAD2, and between hypomethylation and up-regulated mRNA expression of the CASP8 and DCLRE1C genes.

    Conclusion: Aberrant methylation of the DCLRE1C and GPC6 genes are presented here for the first time and are therefore of special interest for further validation as novel candidate biomarker genes in CRC, and merit further validation with specific assays.

  • 14.
    Fransén, Karin
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Franzén, Petra
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Magnuson, Anders
    Örebro University Hospital, Örebro, Sweden.
    Elmabsout, Ali
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Nyhlin, Nils
    Region Örebro län.
    Wickbom, Anna
    Örebro University Hospital, Örebro, Sweden.
    Curman, Bengt
    Örebro University Hospital, Örebro, Sweden.
    Törkvist, Leif
    Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, Mauro
    Karolinska University Hospital, Stockholm, Sweden.
    Bohr, Johan
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län.
    Tysk, Curt
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län.
    Sirsjö, Allan
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för läkarutbildning. Region Örebro län.
    Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's disease2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 8, s. e72739-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.

  • 15.
    Gkourogianni, Alexandra
    et al.
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institute and University Hospital, Stockholm, Sweden.
    Andrade, Anenisia C.
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institute and University Hospital, Stockholm, Sweden.
    Jonsson, Björn-Anders
    Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden.
    Segerlund, Emma
    Department of Pediatrics, Sunderby Hospital, Sunderby, Sweden.
    Werner-Sperker, Antje
    Department of Pediatrics, Sunderby Hospital, Sunderby, Sweden.
    Horemuzova, Eva
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm.
    Dahlgren, Jovanna
    Göteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
    Burstedt, Magnus
    Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden.
    Nilsson, Ola
    Örebro universitet, Institutionen för medicinska vetenskaper. Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institute and University Hospital, Stockholm, Sweden; University Hospital, Örebro, Sweden.
    Pre and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment2020Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: To explore the phenotype and response to growth hormone in patients with heterozygous-mutations in the insulin-like growth factor I receptor gene (IGF1R).

    METHODS: Children with short-stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analyzed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation dependent probe amplification analysis.

    RESULTS: In two families, a novel heterozygous non-synonymous missense IGF1R variant was identified. In family 1, c.3364G>T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G>A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26 - 0.60) and 0.64 (range: 0.32 - 0.86) after 1 and 2 years of treatment, respectively.

    CONCLUSION: Our study presents two heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.

  • 16.
    Götz, Alexandra
    et al.
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tyynismaa, Henna
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Euro, Liliya
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Ellonen, Pekka
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Ojala, Tiina
    Department of Pediatric Cardiology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Hämäläinen, Riikka H
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tommiska, Johanna
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland g.
    Raivio, Taneli
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Karikoski, Riitta
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tammela, Outi
    Pediatric Research Centre, Tampere University Hospital, Tampere, Finland.
    Simola, Kalle O J
    Genetics Outpatient Clinic, Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Paetau, Anders
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tyni, Tiina
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Pediatric Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Suomalainen, Anu
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy2011Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, nr 5, s. 635-642Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.

  • 17.
    Harris, Simon R.
    et al.
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Clarke, Ian N.
    Molecular Microbiology Group, Southampton General Hospital, University Medical School, Southampton, United Kingdom.
    Seth-Smith, Helena M. B.
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Solomon, Anthony W.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Cutcliffe, Lesley T.
    Molecular Microbiology Group, Southampton General Hospital, University Medical School, Southampton, United Kingdom.
    Marsh, Peter
    Health Protection Agency, Public Health Laboratory Southampton, Southampton General Hospital, Southampton, United Kingdom.
    Skilton, Rachel J.
    Molecular Microbiology Group, Southampton General Hospital, University Medical School, Southampton, United Kingdom.
    Holland, Martin J.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Mabey, David
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Peeling, Rosanna W.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Lewis, David A.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Sexually Transmitted Infections Reference Centre, National Health Laboratory Service, National Institute for Communicable Diseases, Johannesburg, South Africa; Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Spratt, Brian G.
    Department of Infectious Disease Epidemiology, St. Mary's Hospital Campus, Imperial College, London, United Kingdom.
    Unemo, Magnus
    Region Örebro län. Department of Laboratory Medicine and Clinical Microbiology, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden.
    Persson, Kenneth
    Department of Laboratory Medicine, Clinical Microbiology, Malmö University Hospital, Malmö, Sweden.
    Bjartling, Carina
    Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Malmö University Hospital, Malmö, Sweden.
    Brunham, Robert
    British Columbia Centre for Disease Control, Vancouver BC, Canada.
    de Vries, Henry J. C.
    Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; Sexually Transmitted Infections Outpatient Clinic, Infectious Diseases Cluster, Public Health Service Amsterdam, Amsterdam, Netherlands; Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
    Morré, Servaas A.
    Department of Medical Microbiology of Infection Prevention, Laboratory of Immunogenetics, Vrije University Medical Center, Amsterdam, Netherlands; Department of Genetics and Cell Biology, Institute of Public Health Genomics, University of Maastricht, Maastricht, Netherlands.
    Speksnijder, Arjen
    Geneeskundige en Gezondheidsdienst (GGD), Amsterdam, The Netherlands.
    Bébéar, Cecile M.
    Unité Sous Contrat (USC) Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Université de Bordeaux, Bordeaux, France; USC Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Institut National de la Recherche Agronomique, Bordeaux, France.
    Clerc, Maite
    Unité Sous Contrat (USC) Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Université de Bordeaux, Bordeaux, France; USC Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Institut National de la Recherche Agronomique, Bordeaux, France.
    de Barbeyrac, Bertille
    Unité Sous Contrat (USC) Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Université de Bordeaux, Bordeaux, France; USC Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Institut National de la Recherche Agronomique, Bordeaux, France.
    Parkhill, Julian
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Thomson, Nicholas R.
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Whole-genome analysis of diverse Chlamydia trachomatis strains identifies phylogenetic relationships masked by current clinical typing2012Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, nr 4, s. 413-419Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chlamydia trachomatis is responsible for both trachoma and sexually transmitted infections, causing substantial morbidity and economic cost globally. Despite this, our knowledge of its population and evolutionary genetics is limited. Here we present a detailed phylogeny based on whole-genome sequencing of representative strains of C. trachomatis from both trachoma and lymphogranuloma venereum (LGV) biovars from temporally and geographically diverse sources. Our analysis shows that predicting phylogenetic structure using ompA, which is traditionally used to classify Chlamydia, is misleading because extensive recombination in this region masks any true relationships present. We show that in many instances, ompA is a chimera that can be exchanged in part or as a whole both within and between biovars. We also provide evidence for exchange of, and recombination within, the cryptic plasmid, which is another key diagnostic target. We used our phylogenetic framework to show how genetic exchange has manifested itself in ocular, urogenital and LGV C. trachomatis strains, including the epidemic LGV serotype L2b.

  • 18.
    Heap, Graham A.
    et al.
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England; Precis Med, Univ Exeter, Exeter, England.
    Weedon, Michael N.
    Precision medicine, Exeter Medical School, University of Exeter, Exeter, England.
    Bewshea, Claire M.
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England; Precision Med Exeter, Univ Exeter, Exeter, England.
    Singh, Abhey
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England.
    Chen, Mian
    Oxford Transplant Ctr, Royal Devon & Exeter Hosp, Oxford, England.
    Satchwel, Jack B.
    Oxford Transplant Ctr, Oxford Univ Hosp Natl Hlth Serv NHS Trust, Oxford, England.
    Vivian, Julian P.
    Sch Biomed Sci, Dept Biochem & Mol Biol, Monash Univ, Clayton Vic, Australia.
    So, Kenji
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England.
    Dubois, Patrick C.
    Dept Gastroenterol, Kings Coll Hosp, London, England.
    Andrews, Jane M.
    Dept Gastroenterol, IBD Serv, Adelaide SA, Australia; Royal Adelaide Hosp, Univ Adelaide, Adelaide SA, Australia.
    Annese, Vito
    Div Gastroenterol, Azienda Osped, Univ Careggi, Florence, Italy.
    Bampton, Peter
    Flinders Med Ctr, Flinders Univ South Australia, Adelaide SA, Australia.
    Barnardo, Martin
    Oxford Transplant Ctr, Oxford Univ Hosp Natl Hlth Serv NHS Trust, Oxford, England.
    Bell, Sally
    Dept Gastroenterol, St Vincent Hosp, Fitzroy Vic, Australia.
    Cole, Andy
    Royal Derby Hosp, Derby, England.
    Connor, Susan J.
    Dept Gastroenterol & Hepatol, Liverpool Hosp, Sydney NSW, Australia.
    Creed, Tom
    Joint Clin Res Unit, Univ Hosp Bristol NHS Fdn Trust, Bristol, England.
    Cummings, Fraser R.
    Dept Gastroenterol, Univ Hosp Southampton NHS Fdn Trust, Southampton, England.
    D'Amato, Mauro
    Dept Biosci & Nutr, Karolinska Inst, Stockholm, Sweden.
    Daneshmend, Tawfique K.
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England.
    Fedorak, Richard N.
    Div Gastroenterol, Univ Alberta, Edmonton AB, Canada.
    Florin, Timothy H.
    Sch Med, Univ Queensland, South Brisbane Qld, Australia.
    Gaya, Daniel R.
    Gastroenterol Unit, Glasgow Royal Infirm, Glasgow, UK.
    Greig, Emma
    Dept Gastroenterol, Taunton & Somerset NHS Fdn Trust, Taunton, England.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för läkarutbildning. Region Örebro län. Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hart, Alisa
    Dept Med, St Marks Hosp, London, England; Acad Inst, North West London Hosp NHS Trust, London, England.
    Irving, Peter M.
    Dept Gastroenterol, Guys & St Thomas NHS Fdn Trust, London, England.
    Jones, Gareth
    Dept Gastroenterol, Western Gen Hosp, Edinburgh, UK.
    Karban, Amir
    Dept Gastroenterol, Rambam Med Ctr, Haifa, Israel.
    Lawrance, Ian C.
    Ctr Inflammatory Bowel Dis, Fremantle Hosp, Univ Western Australia, Fremantle WA, Australia.
    Lee, James C.
    Dept Gastroenterol, Cambridge Univ Hosp NHS Trust, Cambridge, England.
    Lees, Charlie
    Dept Gastroenterol, Western Gen Hosp, Edinburgh, UK.
    Lev-Tzion, Raffi
    Paediatr Gastroenterol & Nutr Unit, Shaare Zedek Med Ctr, Jerusalem, Israel.
    Lindsay, James
    Dept Gastroenterol, Barts & London NHS Trust, London, England.
    Mansfield, John
    Dept Gastroenterol, Newcastle Univ Hosp NHS Trust, Newcastle NSW, Australia.
    Mawdsley, Joel
    Dept Gastroenterol, West Middlesex Univ Hosp NHS Trust, Isleworth, England.
    Mazhar, Zia
    Dept Gastroenterol, Basildon & Thurrock Hosp NHS Trust, Basildon, England.
    Parkes, Miles
    Dept Gastroenterol, Cambridge Univ Hosp NHS Trust, Cambridge, England.
    Parnell, Kirstie
    Precision Med Exeter, Univ Exeter, Exeter, England.
    Orchard, Timothy R.
    Dept Med, Imperial Coll Healthcare NHS, London, England.
    Radford-Smith, Graham
    Dept Gastroenterol, Royal Brisbane & Womens Hosp, Brisbane Qld, Australia; IBD Grp, Queensland Inst Med Res, Brisbane Qld, Australia; Sch Med, Univ Queensland, Brisbane Qld, Australia.
    Russell, Richard K.
    Dept Paediat Gastroenterol, Yorkhill Hosp, Glasgow, UK.
    Reffitt, David
    Dept Gastroenterol, Lewisham & Greenwich NHS Trust, London, England.
    Satsangi, Jack
    Dept Gastroenterol, Western Gen Hosp, Edinburgh, UK.
    Silverberg, Mark S.
    Zane Cohen Ctr Digest Dis, Inflammatory Bowel Dis Grp, Mt Sinai Hosp, Toronto ON, Canada.
    Sturniolo, Giacomo C.
    Univ Padua, Padua, Italy.
    Tremelling, Mark
    Dept Gastroenterol, Norfolk & Norwich Hosp NHS Trust, Norwich, England.
    Tsianos, Epameinondas V.
    Fac Med, Div Internal Med 1, Univ Ioannina, Ioannina, Greece; Fac Med, Div Gastroenterol, Univ Ioannina, Ioannina, Greece.
    van Heel, David A.
    Barts & London Sch Med & Dent, Blizard Inst, Queen Mary Univ, London, England.
    Walsh, Alissa
    Dept Gastroenterol, St Vincents Hosp, Sydney NSW, Australia.
    Watermeyer, Gill
    Gastrointestinal Clin, Groote Schuur Hosp, Cape Town, South Africa.
    Weersma, Rinse K.
    Dept Gastroenterol & Hepatol, Univ Med Ctr, Groningen, Netherlands; Univ Groningen, Groningen, Netherlands.
    Zeissig, Sebastian
    Dept Internal Med, Univ Med Ctr Schleswig Holstein, Kiel, Germany.
    Rossjohn, Jamie
    Sch Biomed Sci, Dept Biochem & Mol Biol, Monash Univ, Clayton Vic, Australia.
    Holden, Arthur L.
    Int Serious Adverse Events Consortium, Chicago IL, USA.
    Ahmad, Tariq
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England; Precision Med, Univ Exeter, Exeter, England.
    HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, nr 10, s. 1131-1134Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the H LA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

  • 19.
    Hong, Eva
    et al.
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Thulin Hedberg, Sara
    Region Örebro län. Dept Lab Med, Natl Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Abad, Raquel
    Reference Lab Meningococci, Inst Hlth Carlos III, Madrid, Spain.
    Fazio, Cecilia
    Dept Infect Parasites & Immune Mediated Dis, Ist Super Sanita, Rome, Italy.
    Enriquez, Rocio
    Reference Lab Meningococci, Inst Hlth Carlos III, Madrid, Spain.
    Deghmane, Ala-Eddine
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Jolley, Keith A.
    Oxford University, Oxford, England.
    Stefanelli, Paola
    Dept Infect Parasites & Immune Mediated Dis, Ist Super Sanita, Rome, Italy.
    Unemo, Magnus
    Region Örebro län. Dept Lab Med, Natl Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Vazquez, Julio A.
    Reference Lab Meningococci, Inst Hlth Carlos III, Madrid, Spain.
    Veyrier, Frederic J.
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Taha, Muhamed-Kheir
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Target Gene Sequencing To Define the Susceptibility of Neisseria meningitidis to Ciprofloxacin2013Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, nr 4, s. 1961-1964Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Meningococcal gyrA gene sequence data, MICs, and mouse infection were used to define the ciprofloxacin breakpoint for Neisseria meningitidis. Residue T91 or D95 of GyrA was altered in all meningococcal isolates with MICs of >= 0.064 mu g/ml but not among isolates with MICs of <= 0.032 mu g/ml. Experimental infection of ciprofloxacin-treated mice showed slower bacterial clearance when GyrA was altered. These data suggest a MIC of >= 0.064 mu g/ml as the ciprofloxacin breakpoint for meningococci and argue for the molecular detection of ciprofloxacin resistance.

  • 20.
    Huang, Hailiang
    et al.
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Broad Institute of MIT and Harvard, Cambridge MA, United States.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Gastroenterology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Barrett, Jeffrey C.
    Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
    Fine-mapping inflammatory bowel disease loci to single-variant resolution2017Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 547, nr 7662, s. 173-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

  • 21.
    Hur, Yoon-Mi
    et al.
    Department of Education, Mokpo National University, Jeonnam, South Korea.
    Bogl, Leonie H.
    Department of Public Health, University of Helsinki, Helsinki, Finland.
    Ordoñana, Juan R.
    Department of Human Anatomy and Psychobiology and Murcia Institute for Biomedical Research (IMIB-ARRIXACA), University of Murcia, Murcia, Spain.
    Taylor, Jeanette
    Department of Psychology, Florida State University, Tallahassee, FL, USA.
    Hart, Sara A.
    Department of Psychology, Florida State University, Tallahassee, FL, USA.
    Tuvblad, Catherine
    Örebro universitet, Institutionen för juridik, psykologi och socialt arbete.
    Ystrom, Eivind
    PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway; Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.
    Dalgård, Christine
    Department of Public Health, Environmental Medicine, and Danish Twin Registry, University of Southern Denmark, Odense, Denmark.
    Skytthe, Axel
    Department of Public Health, and Danish Twin Registry, University of Southern Denmark, Odense, Denmark.
    Willemsen, Gonneke
    Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
    Twin Family Registries Worldwide: An Important Resource for Scientific Research2019Inngår i: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 22, nr 6, s. 427-437Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Much progress has been made in twin research since our last special issue on twin registries (Hur, Y.-M., & Craig, J. M. (2013). Twin Research and Human Genetics, 16, 1-12.). This special issue provides an update on the state of twin family registries around the world. This issue includes 61 papers on twin family registries from 25 countries, of which 3 describe consortia based on collaborations of several twin family registries. The articles included in this issue discuss the establishment and maintenance of twin registries, recruitment strategies, methods of zygosity assessment, research aims and major findings from twin family cohorts, as well as other important topics related to twin studies. The papers amount to approximately 1.3 million monozygotic, dizygotic twins and higher order multiples and their family members who participate in twin studies around the world. Nine new twin family registries have been established across the world since our last issue, which demonstrates that twin registers are increasingly important in studies of the determinants and correlates of complex traits from disease susceptibility to healthy development.

  • 22.
    Huyghe, Jeroen R.
    et al.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium; StatUA Statistics Center, University of Antwerp, Antwerp, Belgium.
    Hannula, Samuli
    Institute of Clinical Medicine, Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Van Laer, Lut
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Van Eyken, Els
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Institute of Clinical Medicine, Department of Otorhinolaryngology, University of Oulu, Oulu, Finland; Department of Clinical and Experimental Medicine/Technical Audiology, Linköping University, Linköping, Sweden.
    Aikio, Pekka
    Thule Institute, University of Oulu, Oulu, Finland.
    Sorri, Martti
    Institute of Clinical Medicine, Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Huentelman, Matthew J.
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, USA.
    Van Camp, Guy
    Department of Medical Genetics, University of Antwerp,Antwerp, Belgium.
    A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies2011Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, nr 3, s. 347-352Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise F(ST) statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, F(ST) was smallest for the comparison with the Russians (F(ST)=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations.

  • 23.
    Huyghe, Jeroen R.
    et al.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Hannula, Samuli
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Van Laer, Lut
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Van Eyken, Els
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Lysholm-Bernacchi, Alana
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, USA.
    Aikio, Pekka
    Thule Institute, University of Oulu, Oulu, Finland.
    Stephan, Dietrich A.
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, USA.
    Sorri, Martti
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Huentelman, Matthew J.
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, USA.
    Van Camp, Guy
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Genome-wide SNP analysis reveals no gain in power for association studies of common variants in the Finnish Saami2010Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, nr 5, s. 569-574Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Saami from Fennoscandia are believed to represent an ancient, genetically isolated population with no evidence of population expansion. Theoretical work has indicated that under this demographic scenario, extensive linkage disequilibrium (LD) is generated by genetic drift. Therefore, it has been suggested that the Saami would be particularly suited for genetic association studies, offering a substantial power advantage and allowing more economic study designs. However, no study has yet assessed this claim. As part of a GWAS for a complex trait, we evaluated the relative power for association studies of common variants in the Finnish Saami. LD patterns in the Saami were very similar to those in the non-African HapMap reference panels. Haplotype diversity was reduced and, on average, levels of LD were higher in the Saami as compared with those in the HapMap panels. However, using a 'hidden' SNP approach we show that this does not translate into a power gain in association studies. Contrary to earlier claims, we show that for a given set of common SNPs, genomic coverage attained in the Saami is similar to that in the non-African HapMap panels. Nevertheless, the reduced haplotype diversity could potentially facilitate gene identification, especially if multiple rare variants play a role in disease etiology. Our results further indicate that the HapMap is a useful resource for genetic studies in the Saami.

  • 24.
    Huyghe, Jeroen R.
    et al.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Van Laer, Lut
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Hendrickx, Jan-Jaap
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium; Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Demeester, Kelly
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Topsakal, Vedat
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Kunst, Sylvia
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Manninen, Minna
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Jensen, Mona
    Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
    Bonaconsa, Amanda
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Mazzoli, Manuela
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Baur, Manuela
    Department of Otorhinolaryngology, University of Tübingen, Tübingen, Germany.
    Hannula, Samuli
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Espeso, Angeles
    Welsh Hearing Institute, Cardiff University, Cardiff, UK.
    Van Eyken, Els
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Flaquer, Antonia
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
    Becker, Christian
    Cologne Center for Genomics (CCG) and Institute for Genetics, University of Cologne, Cologne, Germany.
    Stephens, Dafydd
    Welsh Hearing Institute, Cardiff University, Cardiff, UK.
    Sorri, Martti
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Orzan, Eva
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Bille, Michael
    Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
    Parving, Agnete
    Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
    Pyykkö, Ilmari
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Cremers, Cor W. R. J.
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Kremer, Hannie
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, NL-6500 HB Nijmegen, the Netherlands; Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
    Van de Heyning, Paul H.
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Wienker, Thomas F.
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
    Nürnberg, Peter
    Cologne Center for Genomics (CCG) and Institute for Genetics, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, D-50674Cologne, Germany.
    Pfister, Markus
    Department of Otorhinolaryngology, University of Tübingen, Tübingen, Germany.
    Van Camp, Guy
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait2008Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 83, nr 3, s. 401-407Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Age-related hearing impairment (ARHI), or presbycusis, is a very common multifactorial disorder. Despite the knowledge that genetics play an important role in the etiology of human ARHI as revealed by heritability studies, to date, its precise genetic determinants remain elusive. Here we report the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were detected. Linkage analysis identified a linkage peak on 8q24.13-q24.22 for a trait correlated to audiogram shape. The signal reached genome-wide significance, as assessed by simulations. This finding represents the first locus for an ARHI trait.

  • 25.
    Isaksson, Helena S.
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Farkas, Sanja A.
    Örebro universitet, Institutionen för hälsovetenskaper. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Müller, Patrick
    Affymetrix core facility at Novum, BEA, Karolinska Institute, Huddinge, Sweden.
    Gustafsson, Dan
    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Nilsson, Torbjörn, K.
    Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
    Whole genome microarray expression analysis in blood leucocytes identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia2018Inngår i: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 191, nr 2, s. 240-251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A child, 2 years with the "hypercalprotectinemia with hyperzincemia" clinical syndrome presented with atypical symptoms and signs, notably persistent fever of around 38°C, thrombocythaemia of >700 x 10(9) /L, and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analyzed whole-genome mRNA expression by the Affymetrix HG U133 PLUS 2.0 array on three occasions 3 to 5 months apart. Major upregulation was demonstrated for the JAK/STAT pathway including in particular CD177, S100A8, S100A9, and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors, and activators, accounting for the febrile apathic state; and the HMBG1 gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic workup of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.

  • 26.
    Johansson, Magnus
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Frelin, Lars
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Maravelia, Panagiota
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Asghar, Naveed
    Melik, Wessam
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Caro-Perez, Noelia
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Pasetto, Anna
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahlen, Gustaf
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sallberg, Matti
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Immunogenicity of a New Flaviviral-Based DNA Launched Suicidal Replicon for Protective Vaccination Against Hepatitis C2019Inngår i: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 27, nr 4, s. 139-139Artikkel i tidsskrift (Annet vitenskapelig)
  • 27.
    Jonsson, Lina
    et al.
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Anckarsäter, Henrik
    Departments of Forensic Psychiatry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.
    Zettergren, Anna
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Westberg, Lars
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Walum, Hasse
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Departments of Forensic Psychiatry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden; Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; RandD Unit, Swedish Prison and Probation Service, Gothenburg, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Melke, Jonas
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Association between ASMT and autistic-like traits in children from a Swedish nationwide cohort2014Inngår i: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 24, nr 1, s. 21-27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Individuals with autism spectrum disorders often show low levels of melatonin, and it has been suggested that this decrease may be because of the low activity of the acetylserotonin O-methyltransferase (ASMT), the last enzyme in the melatonin-synthesis pathway. Also, genetic variants in ASMT have been associated with autism, as well as with low ASMT activity and melatonin levels, suggesting that the low ASMT activity observed in autism may partly be because of variations within the ASMT gene. In this study, we present a symptom-based approach to investigate possible associations between ASMT and autistic-like traits in the general population. To this end, continuous measures of autistic-like traits were assessed in a nationally representative twin cohort (n=1771) from Sweden and six single nucleotide polymorphisms (SNPs), and a duplication of exons 2-8 in ASMT were genotyped. Our results show a nominally significant association, in girls, between one single nucleotide polymorphism (rs5949028) in the last intron of ASMT and social interaction impairments. No significant association, however, was observed with traits related to language impairment or restricted and repetitive behavior. In conclusion, our results support the possible involvement of the ASMT gene in autism spectrum disorders, and our finding that only one of the three traits shows association suggests that genetic research may benefit from adopting a symptom-specific approach to identify genes involved in autism psychopathology.

  • 28.
    Jostins, Luke
    et al.
    Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Halfvarson, Jonas
    Region Örebro län. Örebro universitet, Institutionen för medicinska vetenskaper.
    Cho, Judy H.
    Department of Genetics, Yale School of Medicine, New Haven CT, United States; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven CT, United States.
    Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease2012Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, nr 7422, s. 119-124Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

  • 29.
    Jørgenrud, Benedicte
    et al.
    Hormone Laboratory, Oslo University Hospital, Oslo, Norway; Hormone Laboratory, Aker Hospital, Oslo, Norway; Division of Women and Children's Health, Department of Pediatric Research, Oslo University Hospital, Oslo, Norway.
    Jalanko, Mikko
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Heliö, Tiina
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Jääskeläinen, Pertti
    Heart Center, Kuopio University Hospital, Kuopio, Finland.
    Laine, Mika
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Nieminen, Markku S
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Laakso, Markku
    Department of Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Kuusisto, Johanna
    University of Eastern Finland, Kuopio, Finland; Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
    The Metabolome in Finnish Carriers of the MYBPC3-Q1061X Mutation for Hypertrophic Cardiomyopathy2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 8, artikkel-id e0134184Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the metabolome to the echocardiographic parameters.

    METHODS AND RESULTS: 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation.

    CONCLUSIONS: Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle.

  • 30.
    Kaas, A.
    et al.
    Department of Paediatrics, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
    Pfleger, C.
    Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine University, Düsseldorf, Germany.
    Kharagjitsingh, A. V.
    Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
    Schloot, N .C.
    Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine University, Düsseldorf, Germany; Medical Faculty, Department of Metabolic Diseases, University of Düsseldorf, Düsseldorf, Germany .
    Hansen, L.
    Department of Paediatrics, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
    Buschard, K.
    Bartholin Institute, Rigshospitalet, Copenhagen, Denmark.
    Koeleman, B. P. C.
    Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
    Roep, B. O.
    Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
    Mortensen, H. B.
    Department of Paediatrics, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
    Alizadeh, B. Z.
    Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
    Association between age, IL-10, IFN gamma, stimulated C-peptide and disease progression in children with newly diagnosed Type 1 diabetes2012Inngår i: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 29, nr 6, s. 734-741Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: The relation of disease progression and age, serum interleukin 10 (IL-10) and interferon gamma (IFNγ) and their genetic correlates were studied in paediatric patients with newly diagnosed Type 1 diabetes.

    METHODS: Two hundred and twenty-seven patients from the Hvidoere Study Group were classified in four different progression groups as assessed by change in stimulated C-peptide from 1 to 6 months. CA repeat variants of the IL-10 and IFNγ gene were genotyped and serum levels of IL-10 and IFNγ were measured at 1, 6 and 12 months.

    RESULTS: IL-10 decreased (P < 0.001) by 7.7% (1 month), 10.4% (6 months) and 8.6% (12 months) per year increase in age of child, while a twofold higher C-peptide concentration at 1 month (p = 0.06), 6 months (P = 0.0003) and 12 months (P = 0.02) was associated with 9.7%, 18.6% and 9.7% lower IL-10 levels, independent of each other. IL-10 concentrations did not associate with the disease progression groups. By contrast, IFNγ concentrations differed between the four progression groups at 6 and 12 months (P = 0.02 and P = 0.01, respectively); patients with rapid progressing disease had the highest levels at both time points. Distribution of IL-10 and IFNγ genotypes was equal among patients from the progression groups.

    CONCLUSION: IL-10 serum levels associate inversely with age and C-peptide. As age and C-peptide also associate, a triangular association is proposed. Genetic influence on IL-10 production seems to be masked by distinct disease mechanisms. Increased serum IFNγ concentrations associate with rapid disease progression. Functional genetic variants do not associate with a single progression pattern group, implying that disease processes override genetically predisposed cytokine production.

  • 31. Kaminsky, Zachary A.
    et al.
    Tang, Thomas
    Wang, Sun-Chong
    Ptak, Carolyn
    Oh, Gabriel H. T.
    Wong, Albert H. C.
    Feldcamp, Laura A.
    Virtanen, Carl
    Halfvarson, Jonas
    Tysk, Curt
    Örebro universitet, Hälsoakademin.
    McRae, Allan F.
    Visscher, Peter M.
    Montgomery, Grant W.
    Gottesman, Irving I.
    Martin, Nicholas G.
    Petronis, Art
    DNA methylation profiles in monozygotic and dizygotic twins2009Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, nr 2, s. 240-245Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of approximately 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 x 10(-294)). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.

  • 32. Karypidis, A.-H.
    et al.
    Olsson, M.
    Andersson, Swen-Olof
    Örebro universitet, Hälsoakademin.
    Rane, A.
    Ekström, L.
    Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate2008Inngår i: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 8, nr 2, s. 147-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metabolism of androgens includes glucuronidation, the major pathway of steroid elimination in several steroid target tissues. Glucuronidation is catalysed by UDP-glucuronosyltransferases (UGTs). UGT2B17 has been shown to be particularly active against androgens and is highly abundant in the prostate. Recently, we discovered that deletion of the UGT2B17 gene is associated with low or undetectable urinary testosterone levels. Here, we determined the phenotypic outcome of the deletion by quantifying the UGT2B17 mRNA expression in normal prostate tissues in individuals with different genotypes. Additionally, the frequency of UGT2B17 deletion polymorphism was studied in a Swedish population-based case–control study including 176 patients diagnosed with prostate cancer and 161 controls. We found that the individuals homozygous for the insertion allele expressed 30 times more UGT2B17 mRNA in prostate tissue than the heterozygotes. Carriers of the deletion allele had a significantly increased risk of prostate cancer (OR=2.07; 95% CI=1.32–3.25). In conclusion, these results show the UGT2B17 deletion polymorphism is associated with prostate cancer risk. 

  • 33.
    Kuja-Halkola, Ralf
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, United States.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Maternal smoking during pregnancy and adverse outcomes in offspring: genetic and environmental sources of covariance2014Inngår i: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 44, nr 5, s. 456-467Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Maternal smoking during pregnancy (SDP) has been associated with several psychiatric outcomes in the offspring; studies have questioned whether the associations are causal, however. We analyzed all children born in Sweden between 1983 and 2009 to investigate the effect of SDP on multiple indicators of adverse outcomes in three areas: pregnancy outcomes (birth weight, preterm birth and being born small for gestational age), long-term cognitive abilities (low academic achievement and general cognitive ability) and externalizing behaviors (criminal conviction, violent criminal conviction and drug misuse). SDP was associated with all outcomes. Within-family analyses of the pregnancy outcomes were consistent with a causal interpretation as the associations persisted when siblings discordant for SDP were compared. For the cognitive and externalizing outcomes, the results were not consistent with causal effects; when comparing differentially exposed siblings none of the associations remained significant. In quantitative genetic models genetic factors explained the majority of the associations between SDP and cognitive and externalizing outcomes. The results suggest that the associations between SDP in mothers and cognition and externalizing behaviors in their offspring is primarily due to genetic effects that influence the behaviors in both generations.

  • 34.
    Kurland, Lisa
    et al.
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Liljedahl, Ulrika
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Karlsson, Julia
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Kahan, Thomas
    Division of Medicine, Karolinska Institute Danderyd Hospital, Stockholm, Sweden.
    Malmqvist, Karin
    Division of Medicine, Karolinska Institute Danderyd Hospital, Stockholm, Sweden.
    Melhus, Håkan
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Syvänen, Ann Christine
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Lind, Lars
    AstraZeneca R&D, Mölndal, Sweden.
    Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial.2004Inngår i: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 17, nr 1, s. 8-13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is important for the development of hypertension, and several antihypertensive drugs target this system. Our aim was to determine whether specific single nucleotide polymorphisms (SNPs) in RAAS genes were related to the blood pressure (BP) lowering effect of antihypertensive treatment.

    METHODS: Patients with mild to moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta(1)-adrenergic receptor blocker atenolol (n = 49) as monotherapy. A microarray-based minisequencing system was used to genotype 30 SNPs in seven genes in the RAAS. These polymorphisms were related to the antihypertensive response after 12 weeks treatment.

    RESULTS: The BP reductions were similar in the atenolol and the irbesartan groups. Presence of the angiotensinogen (AGT) -6A allele or the AGT 235T allele were both associated with the most pronounced systolic BP response to atenolol treatment (P =.001 when -6 AA+AG was compared with GG and P =.008 for presence of the 235T variant compared with 235 MM).

    CONCLUSIONS: We found that SNPs in the angiotensinogen gene were associated with the BP lowering response to atenolol. This study is limited by a relatively small sample size, and the results should therefore be viewed as preliminary. Despite this limitation, these results illustrate the potential of using SNP genotyping as a pharmacogenetic tool in antihypertensive treatment.

  • 35.
    Kurland, Lisa
    et al.
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Melhus, Håkan
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Karlsson, Julia
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Kahan, Thomas
    Division of Internal Medicine, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Malmqvist, Karin
    Division of Internal Medicine, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Öhman, Peter
    Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden.
    Nyström, Fredrik
    Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden.
    Hägg, Anders
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Lind, Lars
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial2002Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 20, nr 4, s. 657-663Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Our aim was to determine if gene polymorphisms in the renin-angiotensin-aldosterone system (RAAS) were related to the degree of change in left ventricular hypertrophy (LVH) during antihypertensive treatment.

    METHODS AND RESULTS: Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months. The angiotensinogen T174M and M235T, the angiotensin-converting enzyme I/D, the AT1-receptor A1166C and the aldosterone synthase (CYP11B2) -344 C/T polymorphisms were analysed and related to the change in left ventricular mass (LVM). Patients with the angiotensinogen 174 TM genotype treated with irbesartan responded with the greatest reduction in LVM (-23 +/- 31SD g/m2 for TM and +0.5 +/- 18 g/m2 for TT, P = 0.005), independent of blood pressure reduction. Both the angiotensinogen 235 T-allele (P = 0.02) and the AT1-receptor 1166 AC genotype responded with the greatest reduction in LVM when treated with irbesartan (-0.1 +/- 19 g/m2 for AA and -18 +/- 30 g/m2 for AC, P = 0.02), independent of blood pressure reduction. These polymorphisms were not associated with the change in LVM during treatment with atenolol.

    DISCUSSION: The angiotensinogen T174M and M235T and the AT1-receptor A1166C polymorphisms were related to the change in LVH during antihypertensive treatment with an AT1-receptor antagonist; of these angiotensinogen T174M was the most powerful. This highlights the role of the RAAS for left ventricular hypertrophy and the potential of pharmacogenetics as a tool for guidance of antihypertensive therapy.

  • 36.
    Laanpere, Margit
    et al.
    Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
    Altmäe, Signe
    Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Department of Clinical Science, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden; Department of Obstetrics and Gynaecology, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden.
    Stavreus- Evers, Anneli
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Nilsson, Torbjörn
    Department of Clinical Chemistry, Örebro University Hospital, Örebro, Sweden.
    Yngve, Agneta
    Unit for Public Health Nutrition, Department of Biosciences at Novum, Karolinska Institute, Stockholm, Sweden.
    Salumets, Andrej
    Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Department of Obstetrics and Gynaecology, University of Tartu, Tartu, Estonia.
    Folate-mediated one-carbon metabolism and its effect on female fertility and pregnancy viability2010Inngår i: Nutrition reviews, ISSN 0029-6643, E-ISSN 1753-4887, Vol. 68, nr 2, s. 99-113Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This review summarizes current knowledge of the effect of folate-mediated one-carbon metabolism and related genetic variants on female fertility and pregnancy viability. Insufficient folate status disrupts DNA methylation and integrity and increases blood homocysteine levels. Elevated levels of follicular fluid homocysteine correlate with oocyte immaturity and poor early embryo quality, while methylenetetrahydrofolate reductase (MTHFR) gene variants are associated with lower ovarian reserves, diminished response to follicular stimulation, and reduced chance of live birth after in vitro fertilization. Embryos carrying multiple MTHFR variants appear to have a selective disadvantage; however, the heterozygousMTHFR 677CT genotype in the mother and fetus provides the greatest chance for a viable pregnancy and live birth, possibly due to a favorable balance in folate cofactor distribution between methyl donor and nucleotide synthesis. The results of previous studies clearly emphasize that imbalances in folate metabolism and related gene variants may impair female fecundity as well as compromise implantation and the chance of a live birth.

  • 37. Labayen, Idoia
    et al.
    Ortega, Francisco B.
    Sjöström, Michael
    Nilsson, Torbjörn K.
    Örebro universitet, Hälsoakademin.
    Olsson, Lovisa A.
    Örebro universitet, Hälsoakademin.
    Ruiz, Jonatan R.
    Association of common variants of UCP2 gene with low-grade inflammation in Swedish children and adolescents: the European Youth Heart Study2009Inngår i: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 66, nr 3, s. 350-354Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We examined the associations of two functional variants 866G>A and DEL/INS polymorphisms of UCP2 gene with low-grade inflammatory proteins (C-reactive protein, fibrinogen, complement C3 [C3], and complement C4 [C4]) in 131 children (52.7% boys, aged 9.5 +/- 0.4 y) and 118 adolescents (44.1% males, aged 15.5 +/- 0.4 y) selected from the European Youth Heart Study. Differences in inflammatory markers among the genotype variants of the two UCP2 gene polymorphisms were analyzed after adjusting for sex, age, pubertal stage, fitness, and fatness. The results showed that fibrinogen, C3, and C4 were higher in GG carriers than in subjects carrying the A allele of the 866G>A polymorphism of the UCP2 gene (UCP2 -866G>A) polymorphism (all p < 0.05). The DEL/DEL genotype of 45nt deletion/insertion variant polymorphism of the UCP2 gene (UCP2 DEL/INS) was associated with higher C3 (p < 0.05) than DEL/INS and INS/INS genotypes. This study provides evidence of a role of UCP2 -866G>A in modifying low-grade inflammatory state in apparently healthy children and adolescents. Given the implication of complement factors on atherosclerosis process, these results contribute to explain the reduced cardiovascular risk associated with the A allele of the UCP2 -866G>A polymorphism.

  • 38.
    Laurila, Pirkka-Pekka
    et al.
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
    Surakka, Ida
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Sarin, Antti-Pekka
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland.
    Söderlund, Sanni
    Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
    Naukkarinen, Jussi
    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Tang, Jing
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Kettunen, Johannes
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Mirel, Daniel B
    Program in Medical and Population Genetics, Broad Institute, Cambridge MA, United States.
    Soronen, Jarkko
    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Lehtimäki, Terho
    Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland.
    Ruokonen, Aimo
    Institute of Diagnostics, University of Oulu, Oulu, Finland.
    Ehnholm, Christian
    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Eriksson, Johan G.
    Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Vasa Central Hospital, Vasa, FinlandM; Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Salomaa, Veikko
    Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Jula, Antti
    Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Raitakari, Olli T
    Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Clinical Physiology, University of Turku, Turku University Hospital, Turku, Finland.
    Järvelin, Marjo-Riitta
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Institute of Health Sciences, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland.
    Palotie, Aarno
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland; Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom; Program in Medical and Population Genetics, Broad Institute, Cambridge MA, United States.
    Peltonen, Leena
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Jauhiainen, Matti
    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Taskinen, Marja-Riitta
    Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
    Ripatti, Samuli
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland; Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
    Genomic, transcriptomic, and lipidomic profiling highlights the role of inflammation in individuals with low high-density lipoprotein cholesterol2013Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 33, nr 4, s. 847-857Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Low high-density lipoprotein cholesterol (HDL-C) is associated with cardiometabolic pathologies. In this study, we investigate the biological pathways and individual genes behind low HDL-C by integrating results from 3 high-throughput data sources: adipose tissue transcriptomics, HDL lipidomics, and dense marker genotypes from Finnish individuals with low or high HDL-C (n=450).

    APPROACH AND RESULTS: In the pathway analysis of genetic data, we demonstrate that genetic variants within inflammatory pathways were enriched among low HDL-C associated single-nucleotide polymorphisms, and the expression of these pathways upregulated in the adipose tissue of low HDL-C subjects. The lipidomic analysis highlighted the change in HDL particle quality toward putatively more inflammatory and less vasoprotective state in subjects with low HDL-C, as evidenced by their decreased antioxidative plasmalogen contents. We show that the focal point of these inflammatory pathways seems to be the HLA region with its low HDL-associated alleles also associating with more abundant local transcript levels in adipose tissue, increased plasma vascular cell adhesion molecule 1 (VCAM1) levels, and decreased HDL particle plasmalogen contents, markers of adipose tissue inflammation, vascular inflammation, and HDL antioxidative potential, respectively. In a population-based look-up of the inflammatory pathway single-nucleotide polymorphisms in a large Finnish cohorts (n=11 211), no association of the HLA region was detected for HDL-C as quantitative trait, but with extreme HDL-C phenotypes, implying the presence of low or high HDL genes in addition to the population-genomewide association studies-identified HDL genes.

    CONCLUSIONS: Our study highlights the role of inflammation with a genetic component in subjects with low HDL-C and identifies novel cis-expression quantitative trait loci (cis-eQTL) variants in HLA region to be associated with low HDL-C.

  • 39.
    Liljedahl, Ulrika
    et al.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Kahan, Thomas
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Malmqvist, Karin
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Melhus, Håkan
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Syvänen, Ann-Christine
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Lind, Lars
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Astra Zeneca R&D, Mölndal, Sweden.
    Kurland, Lisa
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Single nucleotide polymorphisms predict the change in left ventricular mass in response to antihypertensive treatment2004Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 22, nr 12, s. 2321-2328Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Our aim was to determine whether the change in left ventricular (LV) mass in response to antihypertensive treatment could be predicted by multivariate analysis of single nucleotide polymorphisms (SNPs) in candidate genes reflecting pathways likely to be involved in blood pressure control.

    METHODS: Patients with mild to moderate primary hypertension and LV hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta1 adrenoreceptor blocker atenolol (n = 49). A microarray-based minisequencing system was used for genotyping 74 SNPs in 25 genes. These genotypes were related to the change in LV mass index by echocardiography, after 12 weeks treatment as monotherapy, using stepwise multiple regression analysis.

    RESULTS: The blood pressure reductions were similar and significant in both treatment groups. Two SNPs in two separate genes (the angiotensinogen T1198C polymorphism, corresponding to the M235T variant and the apolipoprotein B G10108A polymorphism) for those treated with irbesartan, and the adrenoreceptor alpha2A A1817G for those treated with atenolol, significantly predicted the change in LV mass. The predictive power of these SNPs was independent of the degree of blood pressure reduction.

    CONCLUSION: SNPs in the angiotensinogen, apolipoprotein B, and the alpha2 adrenoreceptor gene predicted the change in LV mass during antihypertensive therapy. These results illustrate the potential of using microarray-based technology for SNP genotyping in predicting individual drug responses.

  • 40.
    Liljedahl, Ulrika
    et al.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Karlsson, Julia
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Melhus, Håkan
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Kurland, Lisa
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Lindersson, Marie
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Kahan, Thomas
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Nyström, Fredrik
    Department of Medicosurgical Gastroenterology, Endocrinology and Metabolism, University Hospital of Linköping, Linköping, Sweden.
    Lind, Lars
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Astra Zeneca R&D, Mölndal, Sweden.
    Syvänen, Ann-Christine
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    A microarray minisequencing system for pharmacogenetic profiling of antihypertensive drug response2003Inngår i: Pharmacogenetics, ISSN 0960-314X, E-ISSN 1473-561X, Vol. 13, nr 1, s. 7-17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We aimed to develop a microarray genotyping system for multiplex analysis of a panel of single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in blood pressure regulation, and to apply this system in a pilot study demonstrating its feasibility in the pharmacogenetics of hypertension. A panel of 74 SNPs in 25 genes involved in blood pressure regulation was selected from the SNP databases, and genotyped in DNA samples of 97 hypertensive patients. The patients had been randomized to double-blind treatment with either the angiotensin II type 1 receptor blocker irbesartan or the beta 1-adrenergic receptor blocker atenolol. Genotyping was performed using a microarray based DNA polymerase assisted 'minisequencing' single nucleotide primer extension assay with fluorescence detection. The observed genotypes were related to the blood pressure reduction using stepwise multiple regression analysis. The allele frequencies of the selected SNPs were determined in the Swedish population. The established microarray-based genotyping system was validated and allowed unequivocal multiplex genotyping of the panel of 74 SNPs in every patient. Almost 7200 SNP genotypes were generated in the study. Profiles of four or five SNP-genotypes that may be useful as predictors of blood pressure reduction after antihypertensive treatment were identified. Our results highlight the potential of microarray-based technology for SNP genotyping in pharmacogenetics.

  • 41.
    Liljedahl, Ulrika
    et al.
    Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
    Lind, Lars
    Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden; Astra Zeneca Research & Development Mölndal, Mölndal, Sweden.
    Kurland, Lisa
    Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
    Berglund, Lars
    Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden.
    Kahan, Thomas
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Syvänen, Ann-Christine
    Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
    Single nucleotide polymorphisms in the apolipoprotein B and low density lipoprotein receptor genes affect response to antihypertensive treatment2004Inngår i: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 4, nr 1, artikkel-id 16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Dyslipidemia has been associated with hypertension. The present study explored if polymorphisms in genes encoding proteins in lipid metabolism could be used as predictors for the individual response to antihypertensive treatment.

    METHODS: Ten single nucleotide polymorphisms (SNP) in genes related to lipid metabolism were analysed by a microarray based minisequencing system in DNA samples from ninety-seven hypertensive subjects randomised to treatment with either 150 mg of the angiotensin II type 1 receptor blocker irbesartan or 50 mg of the beta1-adrenergic receptor blocker atenolol for twelve weeks.

    RESULTS: The reduction in blood pressure was similar in both treatment groups. The SNP C711T in the apolipoprotein B gene was associated with the blood pressure response to irbesartan with an average reduction of 19 mmHg in the individuals carrying the C-allele, but not to atenolol. The C16730T polymorphism in the low density lipoprotein receptor gene predicted the change in systolic blood pressure in the atenolol group with an average reduction of 14 mmHg in the individuals carrying the C-allele.

    CONCLUSIONS: Polymorphisms in genes encoding proteins in the lipid metabolism are associated with the response to antihypertensive treatment in a drug specific pattern. These results highlight the potential use of pharmacogenetics as a guide for individualised antihypertensive treatment, and also the role of lipids in blood pressure control.

  • 42.
    Lindberg, Eva
    et al.
    Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Möller, Claes
    Örebro universitet, Institutionen för medicinska vetenskaper. The Swedish Institute for Disability Research, Örebro University, Örebro, Sweden.
    Kere, Juha
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Stem Cells and Metabolism Research Program, University of Helsinki, and Folkhälsan Research Center, Helsinki, Finland.
    Wedenoja, Satu
    Stem Cells and Metabolism Research Program, University of Helsinki, and Folkhälsan Research Center, Helsinki, Finland; Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Anderzen-Carlsson, Agneta
    Örebro universitet, Institutionen för hälsovetenskaper. Region Örebro län. The Swedish Institute for Disability Research, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Congenital chloride diarrhea and Pendred syndrome: case report of siblings with two rare recessive disorders of SLC26 family genes2020Inngår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 21, nr 1, artikkel-id 79Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness.

    CASE PRESENTATION: We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD.

    CONCLUSIONS: Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.

  • 43.
    Liu, Yangfan P.
    et al.
    Center for Human Disease Modeling, Duke University School of Medicine, Durham NC, USA.
    Bosch, Danielle G. M.
    Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
    Siemiatkowska, Anna M.
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
    Dahl Rendtorff, Nanna
    Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, ICMM, University of Copenhagen, Copenhagen, Denmark; Department of Audiology, Bispebjerg Hospital and Rigshospitalet, Copenhagen, Denmark.
    Boonstra, F. Nienke
    Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
    Möller, Claes
    Örebro universitet, Institutionen för hälsovetenskaper. Region Örebro län. Audiological Research Centre, Örebro University Hospital, Örebro, Sweden.
    Tranebjaerg, Lisbeth
    Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine ICMM, University of Copenhagen, Copenhagen, Denmark; Department of Audiology, Bispebjerg Hospital and Rigshospitalet, Copenhagen, Denmark.
    Katsanis, Nicholas
    Center for Human Disease Modeling, Duke University School of Medicine, Durham NC, USA.
    Cremers, Frans P. M.
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
    Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy2017Inngår i: Ophthalmic Genetics, ISSN 1381-6810, E-ISSN 1744-5094, Vol. 38, nr 2, s. 127-132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype.

    Materials and methods: In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy, whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity.

    Results: Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Gln2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum.

    Conclusions: We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology.

  • 44.
    Lui, Julian C.
    et al.
    National Institutes of Health, .
    Barnes, Kevin M.
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Dong, Lijin
    Genetic Engineering Core, National Eye Institute, National Institutes of Health, Bethesda MD, USA.
    Yue, Shanna
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Graber, Evan
    Division of Pediatric Endocrinology and Diabetes, Ichan School of Medicine at Mount Sinai, New York NY, USA.
    Rapaport, Robert
    Division of Pediatric Endocrinology and Diabetes, Ichan School of Medicine at Mount Sinai, New York NY, USA.
    Dauber, Andrew
    Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Nilsson, Ola
    Örebro universitet, Institutionen för medicinska vetenskaper. Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA; Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; Örebro University Hosptial, Örebro, Sweden.
    Baron, Jeffrey
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Ezh2 mutations found in the Weaver overgrowth syndrome cause a partial loss of H3K27 histone methyltransferase activity2018Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, nr 4, s. 1470-1478Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in EZH2, a histone methyltransferase responsible for H3K27 trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome.

    Objective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome either cause a gain of function or a partial loss of function.

    Design: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos.

    Results: A de novo missense EZH2 mutation (c.1876G>A (p.Val626Met)) was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality while heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation.

    Conclusion: We generated a mouse model with the same mutation as our patient and found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.

  • 45.
    Luningham, Justin M.
    et al.
    Department of Psychology, University of Notre Dame, Notre Dame IN, United States; School of Public Health, Georgia State University, Atlanta GA, United States.
    McArtor, Daniel B.
    Department of Psychology, University of Notre Dame, Notre Dame IN, United States.
    Hendriks, Anne M.
    Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Faculty of Behavioural and Movement Sciences, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
    van Beijsterveldt, Catharina E. M.
    Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Faculty of Behavioural and Movement Sciences, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundstrom, Sebastian
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Orebro Univ, Sch Med Sci, Orebro, Sweden..
    Bartels, Meike
    Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Faculty of Behavioural and Movement Sciences, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands.
    Boomsma, Dorret, I
    Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Faculty of Behavioural and Movement Sciences, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands.
    Lubke, Gitta H.
    Department of Psychology, University of Notre Dame, Notre Dame IN, United States.
    Data Integration Methods for Phenotype Harmonization in Multi-Cohort Genome-Wide Association Studies With Behavioral Outcomes2019Inngår i: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 10, artikkel-id 1227Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Parallel meta-analysis is a popular approach for increasing the power to detect genetic effects in genome-wide association studies across multiple cohorts. Consortia studying the genetics of behavioral phenotypes are oftentimes faced with systematic differences in phenotype measurement across cohorts, introducing heterogeneity into the meta-analysis and reducing statistical power. This study investigated integrative data analysis (IDA) as an approach for jointly modeling the phenotype across multiple datasets. We put forth a bi-factor integration model (BFIM) that provides a single common phenotype score and accounts for sources of study-specific variability in the phenotype. In order to capitalize on this modeling strategy, a phenotype reference panel was utilized as a supplemental sample with complete data on all behavioral measures. A simulation study showed that a mega-analysis of genetic variant effects in a BFIM were more powerful than meta-analysis of genetic effects on a cohort-specific sum score of items. Saving the factor scores from the BFIM and using those as the outcome in meta-analysis was also more powerful than the sum score in most simulation conditions, but a small degree of bias was introduced by this approach. The reference panel was necessary to realize these power gains. An empirical demonstration used the BFIM to harmonize aggression scores in 9-year old children across the Netherlands Twin Register and the Child and Adolescent Twin Study in Sweden, providing a template for application of the BFIM to a range of different phenotypes. A supplemental data collection in the Netherlands Twin Register served as a reference panel for phenotype modeling across both cohorts. Our results indicate that model-based harmonization for the study of complex traits is a useful step within genetic consortia.

  • 46.
    Luukkonen, Panu K.
    et al.
    Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland; Yale School of Medicine, Yale University, New Haven, Connecticut, USA.
    Tukiainen, Taru
    Institute for Molecular Medicine Finland, Helsinki, Finland.
    Juuti, Anne
    Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Sammalkorpi, Henna
    Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Haridas, P. A. Nidhina
    Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Niemelä, Onni
    Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Tampere, Finland.
    Arola, Johanna
    Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Orho-Melander, Marju
    Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Hakkarainen, Antti
    Department of Radiology, HUS Medical Imaging Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Espoo, Finland.
    Kovanen, Petri T.
    Wihuri Research Institute, Helsinki, Finland.
    Dwivedi, Om
    Institute for Molecular Medicine Finland, Helsinki, Finland.
    Groop, Leif
    Institute for Molecular Medicine Finland, Helsinki, Finland; Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Hodson, Leanne
    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
    Gastaldelli, Amalia
    Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche, Pisa, Italy.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Yki-Järvinen, Hannele
    Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease2020Inngår i: JCI Insight, ISSN 2379-3708, Vol. 5, nr 5, artikkel-id 132158Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Carriers of the hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [DNL] and adipose tissue lipolysis [ATL] using 2H2O and 2H-glycerol) and insulin sensitivity using 3H-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, DNL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.

  • 47.
    Malm, Eva
    et al.
    Department of Ophthalmology, Skåne University Hospital, Lund, Sweden.
    Ponjavic, Vesna
    Department of Ophthalmology, Skåne University Hospital, Lund, Sweden.
    Möller, Claes
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Audiology, Swedish Institute of Disability Research, Örebro University Hospital, Örebro, Sweden.
    Kimberling, William J.
    Department of Ophthalmology and Visual Science, Iowa University Carver School of Medicine, Iowa City IA, United States; Usher Syndrome Center, BoysTown National Research Hospital, Omaha NE, United States.
    Andréasson, Sten
    Department of Ophthalmology, Skåne University Hospital, Lund, Sweden.
    Phenotypes in defined genotypes including siblings with Usher syndrome2011Inngår i: Ophthalmic Genetics, ISSN 1381-6810, E-ISSN 1744-5094, Vol. 32, nr 2, s. 65-74Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To characterize visual function in defined genotypes including siblings with Usher syndrome.

    METHODS: Thirteen patients with phenotypically different subtypes of Usher syndrome, including 3 families with affected siblings, were selected. Genetic analysis and ophthalmological examinations including visual fields, full-field electroretinography (ERG), multifocal electroretinography (mf ERG), and optical coherence tomography (OCT) were assessed. The patients' degree of visual handicap was evaluated by a questionnaire (ADL).

    RESULTS: Twelve of thirteen patients were genotyped as Usher 1B, 1D, 1F, 2A, 2C or 3A. In 12 of 13 patients examined with ERG the 30 Hz flickering light response revealed remaining cone function. In 3 of the patients with Usher type 1 mf ERG demonstrated a specific pattern, with a sharp distinction between the area with reduced function and the central area with remaining macular function and normal peak time. OCT demonstrated loss of foveal depression with distortion of the foveal architecture in the macula in all patients. The foveal thickness ranged from 159 to 384 µm and was not correlated to retinal function. Three siblings shared the same mutation for Usher 2C but in contrast to previous reports regarding this genotype, 1 of them diverged in phenotype with substantially normal visual fields, almost normal OCT and mf ERG findings, and only moderately reduced rod and cone function according to ERG.

    CONCLUSIONS: Evaluation of visual function comprising both the severity of the rod cone degeneration and the function in the macular region confirm phenotypical heterogeneity within siblings and between different genotypes of Usher syndrome.

  • 48.
    Martin, Joanna
    et al.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
    Tammimies, Kristiina
    Center of Neurodevelopmental Disorders at Karolinska Institutet (KIND), Department of Women's and Children's Health, Karolinska Institutet and Center for Psychiatry Research, Stockholm, Sweden.
    Karlsson, Robert
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lu, Yi
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Magnusson, Patrik K. E.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Copy number variation and neuropsychiatric problems in females and males in the general population2019Inngår i: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 180, nr 6, s. 341-350Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neurodevelopmental problems (NPs) are more common in males, whereas anxiety and depression are more common in females. Rare copy number variants (CNVs) have been implicated in neurodevelopmental disorders. The aim of this study was to characterize the relationship between rare CNVs with NPs, anxiety, and depression in a childhood population sample, as well as to examine sex-specific effects. We analyzed a sample of N = 12,982 children, of whom 5.3% had narrowly defined NPs (clinically diagnosed), 20.9% had broadly defined NPs (based on validated screening measures, but no diagnosis), and 3.0% had clinically diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorized by size (100-500 kb or > 500 kb), type, and putative relevance to NPs. We tested for association of CNV categories with outcomes and examined sex-specific effects. Medium deletions (OR[CI] = 1.18[1.05-1.33], p = .0053) and large duplications (OR[CI] = 1.45[1.19-1.75], p = .00017) were associated with broadly defined NPs. Large deletions (OR[CI] = 1.85[1.14-3.01], p = .013) were associated with narrowly defined NPs. There were no significant sex differences in CNV burden in individuals with NPs. Although CNVs were not associated with anxiety/depression in the whole sample, in individuals diagnosed with these disorders, females were more likely to have large CNVs (OR[CI] = 3.75[1.45-9.68], p = .0064). Rare CNVs are associated with both narrowly and broadly defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex-specific phenotypic effects.

  • 49.
    Momozawa, Yukihide
    et al.
    Unit of Animal Genomics, WELBIO, GIGA-R, Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium; Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Gastroenterology.
    Zhao, Hongyu
    Department of Biostatistics, School of Public Health, Yale University, New Haven CT, United States.
    IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes2018Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikkel-id 2427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by similar to 9720 regulatory modules, of which similar to 3000 operate in multiple tissues and similar to 970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that >= 10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

  • 50.
    Momozawa, Yukihide
    et al.
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    Mni, Myriam
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    Nakamura, Kayo
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    Coppieters, Wouter
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    Almer, Sven
    Inst Mol & Klin Med IMK, Div Gastroenterol & Hepatol, Linköpings Univ, Linköping, Sweden .
    Amininejad, Leila
    Dept Gastroenterol, Erasme Hosp, Univ Libre Brussels, Brussels, Belgium .
    Cleynen, Isabelle
    Dept Pathophysiol, Gastroenterol Sect, Catholic Univ Louvain, Louvain, Belgium.
    Colombel, Jean-Frédéric
    Registre MICI Nord Quest France EPIMAD, Hop Calmette, Lille, France.
    de Rijk, Peter
    Dept Mol Genet, Univ Antwerp VIB, Antwerp, Belgium.
    Dewit, Olivier
    Dept Gastroenterol, Clin Univ St Luc, Catholic Univ Louvain, Brussels, Belgium.
    Finkel, Yigael
    Dept Gastroenterol, Karolinska Childrens Hosp, Stockholm, Sweden.
    Gassull, Miquel A.
    Dept Gastroenterol, Hosp Badalona Germans Trias & Pujol, Badalona, Spain.
    Goossens, Dirk
    Dept Mol Genet, Univ Antwerp VIB, Antwerp, Belgium.
    Laukens, Debby
    Dept Gastroenterol, Univ Hosp, Univ Ghent, Ghent, Belgium.
    Lémann, Marc
    AP HP, Dept Gastroenterol, Hop St Louis, Univ Paris 07, Paris, France.
    Libioulle, Cécile
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    O'Morain, Colm
    Adelaide & Meath Hosp, Dublin, Ireland.
    Reenaers, Catherine
    Fac Med, Univ Liege B34, Liege, Belgium.
    Rutgeerts, Paul
    Dept Pathophysiol, Gastroenterol Sect, Catholic Univ Louvain, Louvain, Belgium.
    Tysk, Curt
    Örebro universitet, Hälsoakademin.
    Zelenika, Diana
    Ctr Natl Genotypage, Evry, France.
    Lathrop, Mark
    Ctr Natl Genotypage, Evry, France.
    Del-Favero, Jurgen
    Dept Mol Genet, Univ Antwerp VIB, Antwerp, Belgium .
    Hugot, Jean-Pierre
    INSERM, U843, Hop Robert Debre, IParis, France.
    de Vos, Martine
    Dept Gastroenterol,Univ Hosp, Univ Ghent, Ghent, Belgium.
    Franchimont, Denis
    Dept Gastroenterol, Erasme Hosp, Univ Libre Brussels, Brussels, Belgium.
    Vermeire, Severine
    Dept Pathophysiol, Gastroenterol Sect, Catholic Univ Louvain, Louvain, Belgium.
    Louis, Edouard
    Fac Med, Univ Liege B34, Liege, Belgium.
    Georges, Michel
    Fac Med, Univ Liege B34, Liege, Belgium.
    Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease2011Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, nr 1, s. 43-47Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.

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