Genetic variation in the Major Histocompatibility Complex and association with depression
Genetic variation in the Major Histocompatibility Complex and association with depression
Abstract BackgroundThe prevalence of depression is higher in individuals suffering from autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Epidemiological findings point to a bi-directional relationship - that depression increases the risk of developing an autoimmune disease, and vice-versa. Shared genetic etiology is a plausible explanation for the overlap between depression and autoimmune diseases. In this study we tested whether genetic variation in the Major Histocompatibility Complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. MethodWe fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). In the 26 PGC-MDD studies, cases met a lifetime diagnosis of MDD, determined by a structured diagnostic interview. In the UKB, cases and controls were identified from an online mental health questionnaire. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants in each study and performed an inverse-variance weighted meta-analysis across the PGC-MDD and UKB samples, applying both a conservative region-wide significance threshold (3.9-e6) and a candidate threshold (1.6e-4). ResultsNo HLA alleles or C4 haplotypes were associated with depression at the conservative threshold in the PGC, UKB or meta-analysis. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold in the meta-analysis. Under the conservative threshold, 70 SNPs were detected in the UKB and 143 SNPs were detected in the meta-analysis, mirroring previous findings from highly powered GWAS of depression. DiscussionWe found no evidence that HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia, confer risk for depression. These results indicate that autoimmune diseases and depression do not share common risk loci of moderate or large effect in the MHC.
Milaneschi Yuri、Potash James B、Smoller Jordan W、Sullivan Patrick F、Buttensch?n Henriette N、Colodro-Conde Luc¨aa、Forstner Andreas J、Coleman Jonathan R I、Breen Gerome、Jones Ian、Jones Lisa A、Kutalik Zolt¨￠n、Lewis Glyn、McGuffin Peter、McIntosh Andrew M、M¨1ller-Myhsok Bertram、Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium、Blackwood Douglas H R、Hamilton Steven P、Purves Kirstin L、Knowles James A、O?ˉReilly Paul F、Hanscombe Ken B、Tiemeier Henning、Preisig Martin、Mors Ole、Pedersen Nancy L、Shi Jianxin、Lind Penelope A、Shyn Stanley I、Uher Rudolf、Air Tracy M、Grabe Hans J、Euesden Jack、Glanville Kylie P、Weissman Myrna M、Geus Eco JC de、Direk Nese、Auwera Sandra Van der、Boomsma Dorret I、Andlauer Till F M、Mostafavi Sara、Binder Elisabeth B、Penninx Brenda WJH、Baune Bernhard T、Streit Fabian、Lucae Susanne、Dunn Erin C、Levinson Douglas F、Ripke Stephan、Choi Shing Wan、Magnusson Patrik K、Dannlowski Udo、Lewis Cathryn M
Department of Psychiatry, Amsterdam UMC, Vrije Universiteit AmsterdamPsychiatry, University of IowaDepartment of Psychiatry, Massachusetts General Hospital||Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad InstituteDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet||Genetics, University of North Carolina at Chapel Hill||Psychiatry, University of North Carolina at Chapel HillNIDO | Danmark, Regional Hospital West Jutland||iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric ResearchGenetics and Computational Biology, QIMR Berghofer Medical Research InstituteDepartment of Psychiatry (UPK), University of Basel||Human Genomics Research Group, Department of Biomedicine, University of Basel||Institute of Human Genetics, University of Bonn||Life&Brain Center, Department of Genomics, University of BonnSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King?ˉs College London||NIHR Biomedical Research Centre, South London and Maudsley NHS Trust, King?ˉs College LondonSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King?ˉs College London||NIHR Biomedical Research Centre, South London and Maudsley NHS Trust, King?ˉs College LondonMRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff UniversityDepartment of Psychological Medicine, University of WorcesterInstitute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne||Swiss Institute of BioinformaticsDivision of Psychiatry, University College LondonSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King?ˉs College LondonDivision of Psychiatry, University of Edinburgh||Centre for Cognitive Ageing and Cognitive Epidemiology, University of EdinburghDepartment of Translational Research in Psychiatry, Max Planck Institute of Psychiatry||Munich Cluster for Systems Neurology (SyNergy)||University of LiverpoolConsortium members listed in supplementary materialDivision of Psychiatry, University of EdinburghPsychiatry, Kaiser Permanente Northern CaliforniaSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King?ˉs College LondonPsychiatry & The Behavioral Sciences, University of Southern CaliforniaSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King?ˉs College LondonDepartment of Medical & Molecular Genetics, King?ˉs College LondonEpidemiology, Erasmus MC, Rotterdam||Child and Adolescent Psychiatry, Erasmus MC||Psychiatry, Erasmus MCDepartment of Psychiatry, University Hospital of LausanneiPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research||Psychosis Research Unit, Aarhus University HospitalDepartment of Medical Epidemiology and Biostatistics, Karolinska InstitutetDivision of Cancer Epidemiology and Genetics, National Cancer InstituteGenetics and Computational Biology, QIMR Berghofer Medical Research InstituteBehavioral Health Services, Kaiser Permanente WashingtonPsychiatry, Dalhousie UniversityDiscipline of Psychiatry, Adelaide Medical School, University of AdelaideDepartment of Psychiatry and Psychotherapy, University Medicine GreifswaldSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King?ˉs College LondonSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King?ˉs College LondonDivision of Epidemiology, New York State Psychiatric Institute||Psychiatry, Columbia University College of Physicians and SurgeonsDept of Biological Psychology & EMGO+ Institute for Health and Care Research, Vrije Universiteit Amsterdam||Amsterdam Public Health Institute, Vrije Universiteit Medical CenterEpidemiology, Erasmus MC, Rotterdam||Psychiatry, Dokuz Eylul University School Of MedicineDepartment of Psychiatry and Psychotherapy, University Medicine GreifswaldDept of Biological Psychology & EMGO+ Institute for Health and Care Research, Vrije Universiteit AmsterdamDepartment of Translational Research in Psychiatry, Max Planck Institute of Psychiatry||Munich Cluster for Systems Neurology (SyNergy)Medical Genetics, University of British Columbia||Statistics, University of British ColumbiaDepartment of Translational Research in Psychiatry, Max Planck Institute of Psychiatry||Department of Psychiatry and Behavioral Sciences, Emory University School of MedicineDepartment of Psychiatry, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Psychiatry, Melbourne Medical School, University of MelbourneDepartment of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg UniversityMax Planck Institute of PsychiatryDepartment of Psychiatry, Massachusetts General Hospital||Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad InstitutePsychiatry & Behavioral Sciences, Stanford UniversityAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Department of Psychiatry and Psychotherapy, Universit?tsmedizin Berlin Campus Charit¨| Mitte||Medical and Population Genetics, Broad InstituteSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King?ˉs College LondonDepartment of Medical Epidemiology and Biostatistics, Karolinska InstitutetDepartment of Psychiatry, University of M¨1nster, M¨1nster, Nordrhein-WestfalenSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King?ˉs College London||NIHR Biomedical Research Centre, South London and Maudsley NHS Trust, King?ˉs College London
基础医学神经病学、精神病学遗传学
Milaneschi Yuri,Potash James B,Smoller Jordan W,Sullivan Patrick F,Buttensch?n Henriette N,Colodro-Conde Luc¨aa,Forstner Andreas J,Coleman Jonathan R I,Breen Gerome,Jones Ian,Jones Lisa A,Kutalik Zolt¨￠n,Lewis Glyn,McGuffin Peter,McIntosh Andrew M,M¨1ller-Myhsok Bertram,Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium,Blackwood Douglas H R,Hamilton Steven P,Purves Kirstin L,Knowles James A,O?ˉReilly Paul F,Hanscombe Ken B,Tiemeier Henning,Preisig Martin,Mors Ole,Pedersen Nancy L,Shi Jianxin,Lind Penelope A,Shyn Stanley I,Uher Rudolf,Air Tracy M,Grabe Hans J,Euesden Jack,Glanville Kylie P,Weissman Myrna M,Geus Eco JC de,Direk Nese,Auwera Sandra Van der,Boomsma Dorret I,Andlauer Till F M,Mostafavi Sara,Binder Elisabeth B,Penninx Brenda WJH,Baune Bernhard T,Streit Fabian,Lucae Susanne,Dunn Erin C,Levinson Douglas F,Ripke Stephan,Choi Shing Wan,Magnusson Patrik K,Dannlowski Udo,Lewis Cathryn M.Genetic variation in the Major Histocompatibility Complex and association with depression[EB/OL].(2025-03-28)[2025-08-03].https://www.biorxiv.org/content/10.1101/469023.点此复制
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