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Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychology, University of Pennsylvania, Philadelphia, PA, USA.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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2021 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, no 6, p. 2429-2439Article in journal (Refereed) Published
Abstract [en]

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021. Vol. 26, no 6, p. 2429-2439
National Category
Psychiatry
Identifiers
URN: urn:nbn:se:oru:diva-88946DOI: 10.1038/s41380-020-00984-0ISI: 000610020200004PubMedID: 33483693Scopus ID: 2-s2.0-85099857167OAI: oai:DiVA.org:oru-88946DiVA, id: diva2:1522995
Funder
Swedish Foundation for Strategic Research , KF10-0039Swedish Research Council, 2018-02487 2018-02653Swedish Research Council, 538-2013-8864 D0886501Forte, Swedish Research Council for Health, Working Life and Welfare, 2018-00221
Note

Funding Agencies:

Horizon 2020 Program of the European Union (COSYN, RIA) 610307

United States Department of Health & Human Services

National Institutes of Health (NIH) - USA

NIH National Institute of Mental Health (NIMH) U01 MH109528 R01 MH077139 R01MH120170 R01MH119084

US Fulbright grant  

Brain & Behaviour Research Foundation 

Available from: 2021-01-27 Created: 2021-01-27 Last updated: 2021-10-22Bibliographically approved

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