Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

被引：546

作者：

O'Dushlaine, Colm ^{[1
,2
]}

Rossin, Lizzy ^{[2
]}

Lee, Phil H. ^{[3
]}

Duncan, Laramie ^{[2
,4
,5
]}

Parikshak, Neelroop N. ^{[6
]}

Newhouse, Stephen ^{[7
,8
]}

Ripke, Stephan ^{[2
,4
,5
]}

Neale, Benjamin M. ^{[2
,4
,5
]}

Purcell, Shaun M. ^{[2
,4
,5
,9
]}

Posthuma, Danielle ^{[10
,11
]}

Nurnberger, John I. ^{[12
,13
]}

Lee, S. Hong ^{[14
]}

Faraone, Stephen V. ^{[15
,16
]}

Perlis, Roy H. ^{[2
,3
]}

Mowry, Bryan J. ^{[14
,17
]}

Thapar, Anita ^{[18
,19
]}

Goddard, Michael E. ^{[20
,21
]}

Witte, John S. ^{[22
]}

Absher, Devin ^{[23
]}

Agartz, Ingrid ^{[24
,25
]}

Akil, Huda ^{[26
]}

Amin, Farooq ^{[27
]}

Andreassen, Ole A. ^{[24
,28
]}

Anjorin, Adebayo ^{[29
]}

Anney, Richard ^{[30
]}

Anttila, Verneri ^{[2
]}

Arking, Dan E. ^{[31
]}

Asherson, Philip ^{[7
]}

Azevedo, Maria H. ^{[32
]}

Backlund, Lena ^{[33
]}

Badner, Judith A. ^{[34
]}

Bailey, Anthony J. ^{[35
]}

Banaschewski, Tobias ^{[36
]}

Barchas, Jack D. ^{[37
]}

Barnes, Michael R. ^{[38
]}

Barrett, Thomas B. ^{[39
]}

Bass, Nicholas ^{[29
]}

Battaglia, Agatino ^{[40
]}

Bauer, Michael ^{[41
]}

Bayes, Monica ^{[42
]}

Bellivier, Frank ^{[43
,44
]}

Bergen, Sarah E. ^{[3
,4
,5
,45
]}

Berrettini, Wade ^{[46
]}

Betancur, Catalina ^{[47
,48
]}

Bettecken, Thomas ^{[49
]}

Biederman, Joseph ^{[50
,51
]}

Binder, Elisabeth B. ^{[49
]}

Black, Donald W. ^{[52
]}

Blackwood, Douglas H. R. ^{[53
]}

Bloss, Cinnamon S. ^{[54
,55
]}

机构：

[1] Regeneron Pharmaceut Inc, Regeneron Genet Ctr, Tarrytown, NY 10591 USA

[2] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA

[3] Massachusetts Gen Hosp, Psychiat & Neurodevelopmental Genet Unit, Boston, MA 02114 USA

[4] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[5] Harvard Univ, Sch Med, Boston, MA 02115 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Program Neurobehav Genet, Los Angeles, CA 90095 USA

[7] Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, MRC, London, England

[8] NIHR, Biomed Res Ctr Mental Hlth, South London & Maudsley NHS Trust & Inst Psychiat, London, England

[9] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Gen, New York, NY USA

[10] Vrije Univ Amsterdam, Dept Funct Gen, Amsterdam, Netherlands

[11] Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands

[12] Indiana Univ, Sch Med, Inst Psychiat Res, Indianapolis, IN 46202 USA

[13] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[14] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

[15] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA

[16] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA

[17] Queensland Ctr Mental Hlth Res, Wacol, Qld, Australia

[18] Cardiff Univ, Sch Med, MRC, Ctr Neuropsychiat Genet & Gen, Cardiff CF10 3AX, S Glam, Wales

[19] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales

[20] Dept Environm & Primary Ind Victoria, Biosci Res Div, Melbourne, Vic, Australia

[21] Univ Melbourne, Fac Land & Environm, Melbourne, Vic, Australia

[22] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[23] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[24] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Psychosis Res, Oslo, Norway

[25] Diakonhjemmet Hosp Oslo, Dept Res, Oslo, Norway

[26] Univ Michigan, Mol & Behav Neurosci Inst, Mol Psychiat Lab, Ann Arbor, MI 48109 USA

[27] Emory Univ, Atlanta Vet Affairs Med Ctr, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA

[28] Oslo Univ Hosp, Div Mental Hlth & Addict, N-0450 Oslo, Norway

[29] UCL, Mental Hlth Sci Unit, London, England

[30] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland

[31] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA

[32] Univ Coimbra, Fac Med, Coimbra, Portugal

[33] Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden

[34] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA

[35] Univ British Columbia, Dept Psychiat, Vancouver, BC V5Z 1M9, Canada

[36] Heidelberg Univ, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherary, Mannheim, Germany

[37] Cornell Univ, Weill Med Coll, Dept Psychiat, New York, NY 10021 USA

[38] GlaxoSmithKline, London, England

[39] Portland VA Med Ctr, Portland, OR USA

[40] Stella Maris Inst Child & Adolescent Neuropsychia, Pisa, Italy

[41] Carl Gustav Carus Univ Hosp, Dept Psychiat & Psychotherapy, Dresden, Germany

[42] CNAG, PCB, Barcelona, Spain

[43] INSERM, U955, Creteil, France

[44] ENBREC Grp, Fdn FondaMental, Creteil, France

[45] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[46] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA

[47] INSERM, U952, Paris, France

[48] Univ Paris 06, Paris, France

[49] Max Planck Inst Psychiat, D-80804 Munich, Germany

[50] Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol & ADHD, Boston, MA 02114 USA

来源：

NATURE NEUROSCIENCE | 2015年 / 18卷 / 02期

关键词：

DE-NOVO MUTATIONS; METHYLATION; SCHIZOPHRENIA;

D O I：

10.1038/nn.3922

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

引用

页码：199 / 209

页数：11

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