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  • 1.
    Bazov, Igor
    et al.
    Uppsala University, Uppsala, Sweden.
    Sarkisyan, Daniil
    Uppsala University, Uppsala, Sweden.
    Kononenko, Olga
    Uppsala University, Uppsala, Sweden.
    Watanabe, Hiroyuki
    Uppsala University, Uppsala, Sweden.
    Karpyak, Victor M
    Mayo Clinic College of Medicine, Rochester, USA.
    Yakovleva, Tatiana
    Uppsala University, Uppsala, Sweden.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics2018In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, no 1, article id 122Article in journal (Refereed)
    Abstract [en]

    Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

  • 2.
    Bejerot, Susanne
    et al.
    Örebro University, School of Medical Sciences. Department of Psychiatry, School of Medical Sciences, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hesselmark, Eva
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Solna, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    The Cunningham Panel is an unreliable biological measure2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 49Article in journal (Refereed)
  • 3.
    Bejerot, Susanne
    et al.
    Örebro University, School of Medical Sciences. University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Center for Psychiatry Research, Department of clinical neuroscience, Karolinska Institutet, Solna, Sweden.
    Klang, Albin
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Hesselmark, Eva
    Center for Psychiatry Research, Department of clinical neuroscience, Karolinska Institutet, Solna, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    The Cunningham Panel: concerns remain2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 224Article in journal (Refereed)
    Download full text (pdf)
    The Cunningham Panel: concerns remain
  • 4.
    Carlsson, Torkel
    et al.
    Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; PRIMA Child and Adult Psychiatry, Stockholm, Sweden.
    Rosenqvist, Mina
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry Stockholm, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden; Centre for Ethics, Law, and Mental Health, University of Gothenburg, Gothenburg, Sweden.
    Pan, Pei-Yin
    Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Lundin Remnélius, Karl
    Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Taylor, Mark J.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bölte, Sven
    Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Curtin Autism Research Group, Curtin School of Allied Health, Curtin University, Perth, Western Australia.
    Association of cumulative early medical factors with autism and autistic symptoms in a population-based twin sample2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 73Article in journal (Refereed)
    Abstract [en]

    Although highly heritable, environment also contributes to the etiology of autism spectrum disorder (ASD), with several specific environmental factors previously suggested. A registry-linked population-based twin cohort of 15,701 pairs (586 individuals with an ASD diagnosis), was established within the Child and Adolescent Twin Study in Sweden. Participants were evaluated for autistic symptoms at age 9 using the Autism-Tics, ADHD and other Comorbidities parental interview. A series of binary cut-offs indicated whether participants scored over various ASD symptom percentiles. Three early medical factors previously associated with ASD, beyond familial confounding (low birth weight, congenital malformations and perinatal hypoxia), were summed up creating an individual cumulative exposure load. A series of unconditional logistic regressions between all individuals and conditional regressions within twin pairs were performed for each outcome and exposure level. Between all individuals increasing cumulative early exposure loads were associated with increasing risk of ASD diagnosis (OR 3.33 (95%CI 1.79-6.20) for three exposures) and autistic symptoms (ranging from OR 2.12 (1.57-2.86) for three exposures at the 55th symptom percentile cut-off to OR 3.39 (2.2-5.24) at the 95th). Within twin pairs, the association between three exposures and an ASD diagnosis remained similar, but not statistically significant (OR 2.39 (0.62-9.24)). Having a higher load of early cumulative exposure was consistently associated with autistic symptoms after adjusting for familial confounding and sex (OR 3.45 (1.66-7.15) to OR 7.36 (1.99-27.18)). This study gives support to the cumulative stress hypothesis of ASD, and the dimensional model regarding environmental exposures, after adjustment for familial confounding.

  • 5.
    Fazel, Seena
    et al.
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
    Wolf, Achim
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mallett, Susan
    School of Population and Health Sciences, University of Birmingham, Birmingham, UK.
    Fanshawe, Thomas R.
    Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
    The prediction of suicide in severe mental illness: development and validation of a clinical prediction rule (OxMIS)2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 98Article in journal (Refereed)
    Abstract [en]

    Assessment of suicide risk in individuals with severe mental illness is currently inconsistent, and based on clinical decision-making with or without tools developed for other purposes. We aimed to develop and validate a predictive model for suicide using data from linked population-based registers in individuals with severe mental illness. A national cohort of 75,158 Swedish individuals aged 15-65 with a diagnosis of severe mental illness (schizophrenia-spectrum disorders, and bipolar disorder) with 574,018 clinical patient episodes between 2001 and 2008, split into development (58,771 patients, 494 suicides) and external validation (16,387 patients, 139 suicides) samples. A multivariable derivation model was developed to determine the strength of pre-specified routinely collected socio-demographic and clinical risk factors, and then tested in external validation. We measured discrimination and calibration for prediction of suicide at 1 year using specified risk cut-offs. A 17-item clinical risk prediction model for suicide was developed and showed moderately good measures of discrimination (c-index 0.71) and calibration. For risk of suicide at 1 year, using a pre-specified 1% cut-off, sensitivity was 55% (95% confidence interval [CI] 47-63%) and specificity was 75% (95% CI 74-75%). Positive and negative predictive values were 2% and 99%, respectively. The model was used to generate a simple freely available web-based probability-based risk calculator (Oxford Mental Illness and Suicide tool or OxMIS) without categorical cut-offs. A scalable prediction score for suicide in individuals with severe mental illness is feasible. If validated in other samples and linked to effective interventions, using a probability score may assist clinical decision-making.

  • 6.
    Garcia-Argibay, Miguel
    et al.
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    du Rietz, Ebba
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lu, Yi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martin, Joanna
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    Haan, Elis
    Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
    Letho, Kelli
    Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
    Bergen, Sarah E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Brikell, Isabell
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    The role of ADHD genetic risk in mid-to-late life somatic health conditions2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 152Article in journal (Refereed)
    Abstract [en]

    Growing evidence suggests that ADHD, an early onset neurodevelopmental disorder, is associated with poor somatic health in adulthood. However, the mechanisms underlying these associations are poorly understood. Here, we tested whether ADHD polygenic risk scores (PRS) are associated with mid-to-late life somatic health in a general population sample. Furthermore, we explored whether potential associations were moderated and mediated by life-course risk factors. We derived ADHD-PRS in 10,645 Swedish twins born between 1911 and 1958. Sixteen cardiometabolic, autoimmune/inflammatory, and neurological health conditions were evaluated using self-report (age range at measure 42-88 years) and clinical diagnoses defined by International Classification of Diseases codes in national registers. We estimated associations of ADHD-PRS with somatic outcomes using generalized estimating equations, and tested moderation and mediation of these associations by four life-course risk factors (education level, body mass index [BMI], tobacco use, alcohol misuse). Results showed that higher ADHD-PRS were associated with increased risk of seven somatic outcomes (heart failure, cerebro- and peripheral vascular disease, obesity, type 1 diabetes, rheumatoid arthritis, and migraine) with odds ratios ranging 1.07 to 1.20. We observed significant mediation effects by education, BMI, tobacco use, and alcohol misuse, primarily for associations of ADHD-PRS with cardiometabolic outcomes. No moderation effects survived multiple testing correction. Our findings suggests that higher ADHD genetic liability confers a modest risk increase for several somatic health problems in mid-to-late life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and appear to be in part mediated by life-course risk factors.

  • 7.
    Ip, Hill F.
    et al.
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Boomsma, Dorret I
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
    Genetic association study of childhood aggression across raters, instruments, and age2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 413Article in journal (Refereed)
    Abstract [en]

    Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

  • 8.
    Isung, Josef
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm.
    Isomura, Kayoko
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Wester, Tomas
    Division of Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Fernández de la Cruz, Lorena
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Sidorchuk, Anna
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Association of chronic and acute inflammation of the mucosa-associated lymphoid tissue with psychiatric disorders and suicidal behavior2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 227Article in journal (Refereed)
    Abstract [en]

    Immune dysregulation due to chronic inflammation is a hypothesized risk factor underlying psychiatric disorders and suicidal behavior. Whether tonsillectomy and acute appendicitis used, respectively, as proxies for chronic and acute inflammation within the mucosa-associated lymphoid tissue (MALT) are associated with psychiatric disorders and suicidal behavior is currently unknown. A birth cohort study was conducted including 3,052,875 individuals born in Sweden between 1973 and 2003. We identified 210,686 individuals ever exposed to tonsillectomy and 86,928 individuals ever exposed to acute appendicitis, as well as 317,214 clusters of siblings discordant for tonsillectomy, and 160,079 sibling clusters discordant for acute appendicitis. Outcomes were an aggregate risk of 'any psychiatric disorder', 'any suicidal behavior', 12 individual psychiatric disorders, suicide attempts and deaths by suicide. Tonsillectomy was associated with increased odds of 'any psychiatric disorder' (adjusted odds ratio [aOR] = 1.39; 95% confidence interval (CI) = 1.38-1.41) and 'any suicidal behavior' (aOR = 1.41; 95% CI = 1.37-1.44), and most individual disorders. Acute appendicitis also increased the odds of 'any psychiatric disorder' and 'any suicidal behavior' (aOR = 1.23; 95% CI = 1.20-1.25, and aOR = 1.32; 95% CI = 1.28-1.37, respectively). Exposure to both tonsillectomy and appendicitis was associated with the highest odds of 'any psychiatric disorder' (aOR = 1.70; 95% CI = 1.59-1.82) and 'any suicidal behavior' (aOR = 1.90; 95% CI = 1.70-2.12). In sibling comparisons, the associations were attenuated but remained significant. We conclude that inflammation within the MALT, particularly when chronic, is robustly associated with a broad range of psychiatric disorders and suicidal behavior.

  • 9.
    Kanina, Aleksandra
    et al.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health Services, Akershus University Hospital, Lørenskog, Norway; Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.
    Taylor, Mark J.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martini, Miriam I.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundberg, Frida E.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
    Rosenqvist, Mina A.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Association between cumulative psychosocial adversity in the family and ADHD and autism: a family-based cohort study2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 282Article in journal (Refereed)
    Abstract [en]

    Cumulative exposure to psychosocial adversity at an early age has been shown to be a risk factor for attention-deficit hyperactivity disorder (ADHD) and autism that often co-occur. However, it is not clear if this association reflects a causal effect or familial confounding. We aimed to assess whether cumulative psychosocial adversity in the family increases the risk for ADHD and autism in offspring while accounting for unmeasured familial confounding. We used a population-based cohort of 1,877,901 individuals born in Sweden between 1990 and 2009. Participants were followed from the age of 3 until 2013, with a median follow up time of 13.8 years. We created a cumulative index based on 7 psychosocial adversity factors. We used Cox regression to estimate the hazard ratios (HRs) relating neurodevelopmental conditions to cumulative psychosocial adversity. To address familial confounding, the analyses were repeated in groups of relatives of different kinship: siblings and half-siblings and cousins. A dose-response relationship was observed between cumulative exposure to psychosocial adversity and ADHD at a general population level (covariate adjusted HRs (aHRs) with 95% confidence intervals ranged from 1.55 [one adversity; 1.53-1.58] to 2.65 [ ≥ 4 adversities; 1.98-3.54]). No clear dose-response relation was seen for autism (aHRs ranged from 1.04 [.59-1.84] to 1.37 [1.30-1.45]). HRs of ADHD and autism decreased with increasing level of kinship in the analysis of relatives. Cumulative exposure to psychosocial adversity was associated with both ADHD and autism in the general population, these associations were partly explained by unmeasured familial confounding between relatives. This highlights the need for using family-based designs in studies of psychosocial adversity and ADHD and autism.

  • 10.
    Kastrati, G.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Rosén, J.
    Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Fredrikson, M.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Chen, X.
    Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences.
    Jensen, K. B.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Åhs, F.
    Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Genetic influences on central and peripheral nervous system activity during fear conditioning2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 95Article in journal (Refereed)
    Abstract [en]

    Fear conditioning is an evolutionarily conserved type of learning serving as a model for the acquisition of situationally induced anxiety. Brain function supporting fear conditioning may be genetically influenced, which in part could explain genetic susceptibility for anxiety following stress exposure. Using a classical twin design and functional magnetic resonance imaging, we evaluated genetic influences (h2) on brain activity and standard autonomic measures during fear conditioning. We found an additive genetic influence on mean brain activation (h2 = 0.34) and autonomic responses (h2 = 0.24) during fear learning. The experiment also allowed estimation of the genetic influence on brain activation during safety learning (h2 = 0.55). The mean safety, but not fear, related brain activation was genetically correlated with autonomic responses. We conclude that fear and safety learning processes, both involved in anxiety development, are moderately genetically influenced as expressed both in the brain and the body.

  • 11.
    Kowalec, Kaarina
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; College of Pharmacy, University of Manitoba, Winnipeg, MN, Canada.
    Lu, Yi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Song, Jie
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Dalman, Christina
    Department of Global Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
    Hultman, Christina M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Icahn School of Medicine, Department of Psychiatry, Mt Sinai Hospital, New York, NY, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sullivan, Patrick F.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    The association between family history and genomic burden with schizophrenia mortality: a Swedish population-based register and genetic sample study2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 163Article in journal (Refereed)
    Abstract [en]

    Individuals with schizophrenia (SCZ) have a 2-3-fold higher risk of mortality than the general population. Heritability of mortality in psychiatric disorders has been proposed; however, few have investigated SCZ family history and genetic variation, with all-cause and specific causes of death. We aimed to identify correlates of SCZ mortality using genetic epidemiological and genetic modelling in two samples: a Swedish national population sample and a genotyped subsample. In the Swedish national population sample followed from the first SCZ treatment contact until emigration, death or end of the follow-up, we investigated a standardised measure of SCZ family history. In a subgroup with comprehensive genetic data, we investigated the impact of common and rare genetic variation. Cox proportional hazards regression was used to estimate the association between various factors and mortality (all and specific causes). A total of 13727 SCZ cases fulfilled criteria for the population-based analyses (1268 deaths, 9.2%). The genomic subset contained 4991 cases (1353 deaths, 27.1%). Somatic mutations associated with clonal hematopoiesis with unknown drivers were associated with all-cause mortality (HR 1.77, 95% CI: 1.26-2.49). No other heritable measures were associated with all-cause mortality nor with any specific causes of death. Future studies in larger, comparable cohorts are warranted to further understand the association between hereditary measures and mortality in SCZ.

  • 12.
    Kuzmin, A.
    et al.
    Karolinska Institute, Stockholm, Sweden; Stockholms Läns Landsting Stockholm, Sweden.
    Chefer, V.
    U.S. Department of Health and Human Services, Baltimore, MD, USA.
    Bazov, Igor
    Uppsala University, Uppsala, Sweden.
    Meis, J.
    U.S. Department of Health and Human Services, Baltimore, MD, USA.
    Ögren, S. O.
    Karolinska Institute, Stockholm, Sweden.
    Shippenberg, T.
    U.S. Department of Health and Human Services, Baltimore, MD, USA.
    Bakalkin, G.
    Uppsala University, Uppsala, Sweden.
    Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment2013In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 3, no 10, article id e310Article in journal (Refereed)
    Abstract [en]

    The dynorphin opioid peptides control glutamate neurotransmission in the hippocampus. Alcohol-induced dysregulation of this circuit may lead to impairments in spatial learning and memory. This study examines whether changes in the hippocampal dynorphin and glutamate systems are related, and contribute to impairment of spatial learning and memory in a rat model of cognitive deficit associated with alcohol binge drinking. Hippocampal dynorphins (radioimmunoassay) and glutamate (in vivo microdialysis) were analyzed in Wistar rats exposed to repeated moderate-dose ethanol bouts that impair spatial learning and memory in the Water Maze Task (WMT). The highly selective, long-acting κ-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was administered systemically or into the hippocampal CA3 region to test a role of dynorphins in alcohol-induced dysregulations in glutamate neurotransmission and behavior in the WMT. The ethanol treatment impaired learning and memory, upregulated dynorphins and increased glutamate overflow in the CA3 region. Administration of nor-BNI after cessation of ethanol exposure reversed ethanol-induced changes in glutamate neurotransmission in animals exposed to ethanol and normalized their performance in the WMT. The findings suggest that impairments of spatial learning and memory by binge-like ethanol exposure are mediated through the KOR activation by upregulated dynorphins resulting in elevation in glutamate levels. Selective KOR antagonists may correct alcohol-induced pathological processes, thus representing a novel pharmacotherapy for treating of ethanol-related cognitive deficits.

  • 13.
    Månsson, Kristoffer N. T.
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychology, Stockholm University, Stockholm, Sweden; Department of Psychology, Uppsala University, Uppsala, Sweden.
    Lindqvist, Daniel
    Department of Clinical Sciences Lund, Psychiatry, Lund University, Lund.
    Yang, Liu L.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Svanborg, Cecilia
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Isung, Josef
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Nilsonne, Gustav
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stress Research Institute, Stockholm University, Stockholm, Sweden.
    Bergman Nordgren, Lise
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    El Alaoui, Samir
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Hedman-Lagerlöf, Erik
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kraepelien, Martin
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Högström, Jens
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Andersson, Gerhard
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
    Boraxbekk, Carl-Johan
    Centre for Demographic and Ageing Research, Umeå University, Umeå, Sweden; Center for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark.
    Fischer, Håkan
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Lavebratt, Catharina
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Wolkowitz, Owen M.
    Department of Psychiatry, University of California, San Francisco, CA, USA.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Improvement in indices of cellular protection after psychological treatment for social anxiety disorder2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 340Article in journal (Refereed)
    Abstract [en]

    Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen's d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety. 

  • 14.
    O'Gorman, A.
    et al.
    Department of Psychiatry, Royal College of Surgeons in Ireland (RCSI), Beaumont Hospital, Dublin, Ireland; Institute of Food and Health, UCD School of Agriculture and Food Science, University College Dublin (UCD) Belfield, Dublin, Ireland.
    Suvitaival, T.
    Steno Diabetes Center, Gentofte, Denmark.
    Ahonen, L.
    Steno Diabetes Center, Gentofte, Denmark.
    Cannon, M.
    Department of Psychiatry, Royal College of Surgeons in Ireland (RCSI), Beaumont Hospital, Dublin, Ireland.
    Zammit, S.
    Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK; Centre for Academic Mental Health, School of Social & Community Medicine, University of Bristol, Bristol, UK.
    Lewis, G.
    Division of Psychiatry, University College London, London, UK.
    Roche, H. M.
    Nutrigenomics Research Group, UCD Conway Institute/UCD Institute of Food & Health, School of Public Health, Physiotherapy & Sports Science, University College Dublin (UCD) Belfield, Dublin, Ireland.
    Mattila, I.
    Steno Diabetes Center, Gentofte, Denmark.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. Steno Diabetes Center, Gentofte, Denmark.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Brennan, L.
    Institute of Food and Health, UCD School of Agriculture and Food Science, University College Dublin (UCD) Belfield, Dublin, Ireland.
    Cotter, D. R.
    Department of Psychiatry, Beaumont Hospital, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Identification of a plasma signature of psychotic disorder in children and adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, article id e1240Article in journal (Refereed)
    Abstract [en]

    The identification of an early biomarker of psychotic disorder is important as early treatment is associated with improved patient outcome. Metabolomic and lipidomic approaches in combination with multivariate statistical analysis were applied to identify plasma alterations in children (age 11) (38 cases vs 67 controls) and adolescents (age 18) (36 cases vs 117 controls) preceeding or coincident with the development of psychotic disorder (PD) at age 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC). Overall, 179 lipids were identified at age 11, with 32 found to be significantly altered between the control and PD groups. Following correction for multiple comparisons, 8 of these lipids remained significant (lysophosphatidlycholines (LPCs) LPC(18: 1), LPC(18: 2), LPC(20: 3); phosphatidlycholines (PCs) PC(32: 2; PC(34: 2), PC(36: 4), PC(0-34-3) and sphingomyelin (SM) SM(d18: 1/24: 0)), all of which were elevated in the PD group. At age 18, 23 lipids were significantly different between the control and PD groups, although none remained significant following correction for multiple comparisons. In conclusion, the findings indicate that the lipidome is altered in the blood during childhood, long before the development of psychotic disorder. LPCs in particular are elevated in those who develop PD, indicating inflammatory abnormalities and altered phospholipid metabolism. These findings were not found at age 18, suggesting there may be ongoing alterations in the pathophysiological processes from prodrome to onset of PD.

  • 15.
    O'Reilly, Lauren M.
    et al.
    Indiana University, Bloomington IN, USA.
    Kuja-Halkola, Ralf
    Karolinska Institutet, Solna, Sweden.
    Rickert, Martin E.
    Indiana University, Bloomington IN, USA.
    Class, Quetzal A
    University of Illinois, Chicago IL, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Karolinska Institutet, Solna, Sweden.
    Lichtenstein, Paul
    Karolinska Institutet, Solna, Sweden.
    D'Onofrio, Brian M.
    Indiana University, Bloomington IN, USA; Karolinska Institutet, Solna, Sweden.
    The intergenerational transmission of suicidal behavior: an offspring of siblings study2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1, article id 173Article in journal (Refereed)
    Abstract [en]

    We examined the extent to which genetic factors shared across generations, measured covariates, and environmental factors associated with parental suicidal behavior (suicide attempt or suicide) account for the association between parental and offspring suicidal behavior. We used a Swedish cohort of 2,762,883 offspring born 1973-2001. We conducted two sets of analyses with offspring of half- and full-siblings: (1) quantitative behavior genetic models analyzing maternal suicidal behavior and (2) fixed-effects Cox proportional hazard models analyzing maternal and paternal suicidal behavior. The analyses also adjusted for numerous measured covariates (e.g., parental severe mental illness). Quantitative behavior genetic analyses found that 29.2% (95% confidence interval [CI], 5.29, 53.12%) of the intergenerational association was due to environmental factors associated with exposure to maternal suicidal behavior, with the remainder due to genetic factors. Statistical adjustment for parental behavioral health problems partially attenuated the environmental association; however, the results were no longer statistically significant. Cox hazard models similarly found that offspring were at a 2.74-fold increased risk [95% CI, 2.67, 2.83]) of suicidal behavior if their mothers attempted/died by suicide. After adjustment for familial factors and measured covariates, associations attenuated but remained elevated for offspring of discordant half-siblings (HR, 1.57 [95% CI, 1.45, 1.71]) and full-siblings (HR, 1.62 [95% CI, 1.57, 1.67]). Cox hazard models demonstrated a similar pattern between paternal and offspring suicidal behavior. This study found that the intergenerational transmission of suicidal behavior is largely due to shared genetic factors, as well as factors associated with parental behavioral health problems and environmental factors associated with parental suicidal behavior.

  • 16.
    Orešič, Matej
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Herukka, S-K.
    Department of Neurology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Sysi-Aho, M.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, I.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppänan-Laakso, T.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Julkunen, V.
    Department of Neurology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Gopalacharyulu, P. V.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hallikainen, M.
    Department of Neurology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Koikkalainen, J.
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Kivipelto, M.
    Aging Research Center, Karolinska Institute, Stockholm, Sweden.
    Helisalmi, S.
    Department of Neurology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Lötjönen, J.
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Soininen, H.
    Department of Neurology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
    Metabolome in progression to Alzheimer's disease2011In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 1, article id e57Article in journal (Refereed)
    Abstract [en]

    Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimer's disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues.

  • 17.
    Polderman, T. J. C.
    et al.
    Department of Functional Genomics, Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije University, Amsterdam, The Netherlands.
    Hoekstra, R. A.
    Department of Life, Health and Chemical Sciences, Faculty of Science, The Open University, Milton Keynes, UK.
    Posthuma, D.
    Department of Functional Genomics, Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije University Amsterdam, The Netherlands.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    The co-occurrence of autistic and ADHD dimensions in adults: an etiological study in 17,770 twins2014In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 4, article id e435Article in journal (Refereed)
    Abstract [en]

    Autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) often occur together. To obtain more insight in potential causes for the co-occurrence, this study examined the genetic and environmental etiology of the association between specific ASD and ADHD disorder dimensions. Self-reported data on ASD dimensions social and communication difficulties (ASDsc), and repetitive and restricted behavior and interests (ASDr), and ADHD dimensions inattention (IA), and hyperactivity/impulsivity (HI) were assessed in a community sample of 17,770 adult Swedish twins. Phenotypic, genetic and environmental associations between disorder dimensions were examined in a multivariate model, accounting for sex differences. ASDr showed the strongest associations with IA and HI in both sexes (r(p) 0.33 to 0.40). ASDsc also correlated moderately with IA (females r(p) 0.29 and males r(p) 0.35) but only modestly with HI (females r(p) 0.17 and males r(p) 0.20). Genetic correlations ranged from 0.22 to 0.64 and were strongest between ASDr and IA and HI. Sex differences were virtually absent. The ASDr dimension (reflecting restricted, repetitive and stereotyped patterns of behavior, interests and activities) showed the strongest association with dimensions of ADHD, on a phenotypic, genetic and environmental level. This study opens new avenues for molecular genetic research. As our findings demonstrated that genetic overlap between disorders is dimension-specific, future gene-finding studies on psychiatric comorbidity should focus on carefully selected genetically related dimensions of disorders.

  • 18.
    Risal, Sanjiv
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Manti, Maria
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Lu, Haojiang
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Fornes, Romina
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Benrick, Anna
    Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; School of Health Sciences, University of Skövde, Skövde, Sweden.
    Deng, Qiaolin
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Cesta, Carolyn E.
    Department of Medicine, Solna, Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.
    Rosenqvist, Mina A.
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Stener-Victorin, Elisabet
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 45Article in journal (Refereed)
    Abstract [en]

    If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F3) in the androgenized lineage. In contrast, following the male germline, F3 male offspring (mF3) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F3 females in the androgenized lineage and eight genes in the obese lineage. In mF3 male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F1 and F2 offspring in the female germline did not develop anxiety-like behavior, while the F2 male offspring (mF2) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.

  • 19.
    Sariaslan, A.
    et al.
    Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fazel, S.
    Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
    D'Onofrio, B. M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Långström, N.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bergen, S. E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Schizophrenia and subsequent neighborhood deprivation: revisiting the social drift hypothesis using population, twin and molecular genetic data2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, article id e796Article in journal (Refereed)
    Abstract [en]

    Neighborhood influences in the etiology of schizophrenia have been emphasized in a number of systematic reviews, but causality remains uncertain. To test the social drift hypothesis, we used three complementary genetically informed Swedish cohorts. First, we used nationwide Swedish data on approximately 760 000 full- and half-sibling pairs born between 1951 and 1974 and quantitative genetic models to study genetic and environmental influences on the overlap between schizophrenia in young adulthood and subsequent residence in socioeconomically deprived neighborhoods. Schizophrenia diagnoses were ascertained using the National Patient Registry. Second, we tested the overlap between childhood psychotic experiences and neighborhood deprivation in early adulthood in the longitudinal Twin Study of Child and Adolescent Development (TCHAD; n=2960). Third, we investigated to what extent polygenic risk scores for schizophrenia predicted residence in deprived neighborhoods during late adulthood using the TwinGene sample (n=6796). Sibling data suggested that living in deprived neighborhoods was substantially heritable; 65% (95% confidence interval (95% CI): 60-71%) of the variance was attributed to genetic influences. Although the correlation between schizophrenia and neighborhood deprivation was moderate in magnitude (r=0.22; 95% CI: 0.20-0.24), it was entirely explained by genetic influences. We replicated these findings in the TCHAD sample. Moreover, the association between polygenic risk for schizophrenia and neighborhood deprivation was statistically significant (R(2)=0.15%, P=0.002). Our findings are primarily consistent with a genetic selection interpretation where genetic liability for schizophrenia also predicts subsequent residence in socioeconomically deprived neighborhoods. Previous studies may have overemphasized the relative importance of environmental influences in the social drift of schizophrenia patients. Clinical and policy interventions will therefore benefit from the future identification of potentially causal pathways between different dimensions of cognitive functions and socioeconomic trajectories derived from studies adopting family-based research designs.

  • 20.
    Strom, Nora I.
    et al.
    Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Sweden; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
    Smit, Dirk J. A.
    Department of Psychiatry, Amsterdam University Medical Centers, Amsterdam, The Netherlands; Amsterdam Neuroscience, Amsterdam, The Netherlands.
    Silzer, Talisa
    Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada.
    Iyegbe, Conrad
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, England; Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, USA.
    Burton, Christie L.
    Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada.
    Pool, René
    Department of Biological Psychology, Vrije Universiteit, Amsterdam, Netherlands.
    Lemire, Mathieu
    Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada.
    Crowley, James J.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Sweden; Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, USA.
    Hottenga, Jouke-Jan
    Netherlands Twin Register, Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
    Ivanov, Volen Z.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Magnusson, Patrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Sweden.
    Schachar, Russell J.
    Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada.
    Wu, Hei Man
    Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, USA.
    Meier, Sandra M.
    Department of Psychiatry, Dalhousie University, Halifax, NS, Canada; Community Health & Epidemiology, Dalhousie University, NS, Dalhousie, Canada.
    Crosbie, Jennifer
    Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada.
    Arnold, Paul D.
    The Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
    Mattheisen, Manuel
    Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada; Community Health & Epidemiology, Dalhousie University, NS, Dalhousie, Canada.
    Boomsma, Dorret I.
    Netherlands Twin Register, Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands; Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands .
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Sweden.
    Cath, Danielle
    Rijksuniversiteit Groningen and Department of Psychiatry, University Medical Center Groningen, Groningen, Netherlands; Department of specialized training, Drenthe Mental Health Care Institute, Assen, The Netherlands.
    Meta-analysis of genome-wide association studies of hoarding symptoms in 27,537 individuals2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 479Article in journal (Refereed)
    Abstract [en]

    Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27,537 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we report heritability estimates for the twin-cohorts between 26-48%, and a SNP-heritability of 11% for an unrelated sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a "gene discovery zone". To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples.

  • 21.
    Suvitaival, T.
    et al.
    Steno Diabetes Center, Gentofte, Denmark.
    Mantere, O.
    Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, McGill University, Montréal QC, Canada; Bipolar Disorders Clinic, Douglas Mental Health University Institute, Montréal QC, Canada.
    Kieseppä, T.
    Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, Helsinki University, Helsinki, Finland; Department of Psychiatry, Helsinki University Hospital, Helsinki, Finland.
    Mattila, I.
    Steno Diabetes Center, Gentofte, Denmark.
    Pöhö, P.
    Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. Steno Diabetes Center, Gentofte, Denmark.
    Suvisaari, J.
    Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Orešič, M.
    Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
    Serum metabolite profile associates with the development of metabolic co-morbidities in first-episode psychosis2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, no 11, article id e951Article in journal (Refereed)
    Abstract [en]

    Psychotic patients are at high risk for developing obesity, metabolic syndrome and type 2 diabetes. These metabolic co-morbidities are hypothesized to be related to both treatment side effects as well as to metabolic changes occurring during the psychosis. Earlier metabolomics studies have shown that blood metabolite levels are predictive of insulin resistance and type 2 diabetes in the general population as well as sensitive to the effects of antipsychotics. In this study, we aimed to identify the metabolite profiles predicting future weight gain and other metabolic abnormalities in psychotic patients. We applied comprehensive metabolomics to investigate serum metabolite profiles in a prospective study setting in 36 first-episode psychosis patients during the first year of the antipsychotic treatment and 19 controls. While corroborating several earlier findings when comparing cases and controls and the effects of the antipsychotic medication, we also found that prospective weight gain in psychotic patients was associated with increased levels of triacylglycerols with low carbon number and double-bond count at baseline, that is, lipids known to be associated with increased liver fat. Our study suggests that metabolite profiles may be used to identify the psychotic patients most vulnerable to develop metabolic co-morbidities, and may point to a pharmacological approach to counteract the antipsychotic-induced weight gain.

  • 22.
    Tate, Ashley E.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Akingbuwa, Wonuola A.
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Amsterdam Public Health Research Institute, Amsterdam University Medical Centres, Amsterdam, the Netherlands.
    Karlsson, Robert
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Hottenga, Jouke-Jan
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
    Pool, René
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Amsterdam Public Health Research Institute, Amsterdam University Medical Centres, Amsterdam, the Netherlands.
    Boman, Magnus
    Division of Software and Computer Systems, School of Electrical Engineering and Computer Science KTH, Stockholm, Sweden; Department of Learning, Informatics, Management and Ethics, Karolinska Institute, Solna, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Lundström, Sebastian
    Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Gothenburg, Sweden; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden .
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    Middeldorp, Christel M.
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Child Health Research Centre, the University of Queensland, Brisbane, QLD, Australia; Child and Youth Mental Health Service, Children’s Health Queensland Hospital and Health Services, Brisbane, QLD, Australia .
    Bartels, Meike
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
    A genetically informed prediction model for suicidal and aggressive behaviour in teens2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 488Article in journal (Refereed)
    Abstract [en]

    Suicidal and aggressive behaviours cause significant personal and societal burden. As risk factors associated with these behaviours frequently overlap, combined approaches in predicting the behaviours may be useful in identifying those at risk for either. The current study aimed to create a model that predicted if individuals will exhibit suicidal behaviour, aggressive behaviour, both, or neither in late adolescence. A sample of 5,974 twins from the Child and Adolescent Twin Study in Sweden (CATSS) was broken down into a training (80%), tune (10%) and test (10%) set. The Netherlands Twin Register (NTR; N = 2702) was used for external validation. Our longitudinal data featured genetic, environmental, and psychosocial predictors derived from parental and self-report data. A stacked ensemble model was created which contained a gradient boosted machine, random forest, elastic net, and neural network. Model performance was transferable between CATSS and NTR (macro area under the receiver operating characteristic curve (AUC) [95% CI] AUCCATSS(test set) = 0.709 (0.671-0.747); AUCNTR = 0.685 (0.656-0.715), suggesting model generalisability across Northern Europe. The notable exception is suicidal behaviours in the NTR, which was no better than chance. The 25 highest scoring variable importance scores for the gradient boosted machines and random forest models included self-reported psychiatric symptoms in mid-adolescence, sex, and polygenic scores for psychiatric traits. The model's performance is comparable to current prediction models that use clinical interviews and is not yet suitable for clinical use. Moreover, genetic variables may have a role to play in predictive models of adolescent psychopathology.

  • 23.
    Zayats, T
    et al.
    K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
    Jacobsen, K K
    K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
    Kleppe, R
    K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
    Jacob, C P
    Section of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition Center of Mental Health, University of Wurzburg, Würzburg, Germany.
    Kittel-Schneider, S
    Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
    Ribasés, M
    Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain.
    Ramos-Quiroga, J A
    Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain; Departments of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
    Richarte, V
    Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain; Departments of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
    Casas, M
    Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain; Departments of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
    Mota, N R
    Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
    Grevet, E H
    Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
    Klein, M
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
    Corominas, J
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Ophtalmology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
    Bralten, J
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
    Galesloot, T
    Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
    Vasquez, A A
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
    Herms, S
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, Bonn, Germany; Department of Biomedicine, University of Basel, Basel, Switzerland.
    Forstner, A J
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, Bonn, Germany.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Breen, G
    NIHR BRC for Mental Health, Institute of Psychiatry, Psychology and Neuroscience and SLaM NHS Trust, King's College London, London, UK; MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
    Asherson, P
    NIHR BRC for Mental Health, Institute of Psychiatry, Psychology and Neuroscience and SLaM NHS Trust, King's College London, London, UK; MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
    Gross-Lesch, S
    Section of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition Center of Mental Health, University of Wurzburg, Würzburg, Germany.
    Lesch, K P
    Section of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition Center of Mental Health, University of Wurzburg, Würzburg, Germany.
    Cichon, S
    Department of Genomics, Life and Brain Center, Bonn, Germany; Department of Biomedicine, University of Basel, Basel, Switzerland; Institute of Neuroscience and Medicine, Structural and Functional Organization of the Brain (INM-1), Research Center Juelich, Juelich, Germany.
    Gabrielsen, M B
    K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
    Holmen, O L
    K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
    Bau, C H D
    Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
    Buitelaar, J
    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
    Kiemeney, L
    Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
    Faraone, S V
    K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse NY, USA.
    Cormand, B
    Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación BiomédicaAnchor en Red de Enfermedades Raras, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain; Institut de Recerca Pediàtrica HosAnchorpital Sant Joan de Déu, Barcelona, Spain.
    Franke, B
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
    Reif, A
    Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
    Haavik, J
    K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
    Johansson, S
    K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Clinical Science, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Exome chip analyses in adult attention deficit hyperactivity disorder2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, no 10, article id e923Article in journal (Refereed)
    Abstract [en]

    Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.

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