Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

被引：141

作者：

Power, Robert A. ^{[1
]}

Tansey, Katherine E. ^{[2
]}

Buttenschon, Henriette Normolle ^{[3
]}

Cohen-Woods, Sarah ^{[4
]}

Bigdeli, Tim ^{[5
]}

Hall, Lynsey S.

Kutalik, Zoltn ^{[6
]}

Lee, S. Hong ^{[7
,8
]}

Ripke, Stephan ^{[9
,10
,11
,12
]}

Steinberg, Stacy ^{[13
]}

Teumer, Alexander ^{[14
]}

Viktorin, Alexander ^{[15
]}

Wray, Naomi R. ^{[7
]}

Arolt, Volker ^{[16
]}

Baune, Bernard T. ^{[4
]}

Boomsma, Dorret I. ^{[17
]}

Borglum, Anders D.

Byrne, Enda M. ^{[7
]}

Castelao, Enrique

Craddock, Nick ^{[2
]}

Craig, Ian W. ^{[1
]}

Dannlowski, Udo ^{[16
,20
,21
]}

Deary, Ian J. ^{[22
,23
]}

Degenhardt, Franziska ^{[24
]}

Forstner, Andreas J. ^{[24
]}

Gordon, Scott D. ^{[25
]}

Grabe, Hans J. ^{[26
]}

Grove, Jakob ^{[3
,19
]}

Hamilton, Steven P. ^{[27
]}

Hayward, Caroline ^{[28
]}

Heath, Andrew C. ^{[29
]}

Hocking, Lynne J. ^{[30
]}

Homuth, Georg ^{[31
]}

Hottenga, Jouke J. ^{[17
,18
]}

Kloiber, Stefan ^{[32
]}

Krogh, Jesper ^{[33
]}

Landen, Mikael ^{[15
]}

Lang, Maren ^{[34
,35
]}

Levinson, Douglas F. ^{[36
]}

Lichtenstein, Paul ^{[15
]}

Lucae, Susanne ^{[32
]}

MacIntyre, Donald J. ^{[28
]}

Madden, Pamela ^{[29
]}

Magnusson, Patrik K. E. ^{[15
]}

Martin, Nicholas G. ^{[25
]}

McIntosh, Andrew M. ^{[22
]}

Middeldorp, Christel M. ^{[17
,18
]}

Milaneschi, Yuri ^{[37
]}

Montgomery, Grant W. ^{[25
]}

Mors, Ole ^{[3
,38
]}

机构：

[1] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England

[2] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, Med Res Council,Ctr Neuropsychiatr Genet & Genom, Cardiff, S Glam, Wales

[3] Aarhus Univ, Dept Clin Med, Translat Neuropsychiatry Unit HNB, Initiat Integrat Psychiat Res,iPSYCH, Aarhus, Denmark

[4] Univ Adelaide, Sch Med, Discipline Psychiat, Adelaide, SA, Australia

[5] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA

[6] Univ Vaudois, Ctr Hosp, Inst Social & Prevent Med, Lausanne, Switzerland

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

[8] Univ New England, Sch Environm & Rural Sci, Armidale, NSW, Australia

[9] Massachusetts Inst Technol & Harvard, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA

[10] Massachusetts Gen Hosp, Analyt & Translational Genet Unit, Boston, MA 02114 USA

[11] Harvard Med Sch, Boston, MA 02114 USA

[12] Charite, Dept Psychiat & Psychotherapy, Berlin, Germany

[13] deCODE Genet, Reykjavik, Iceland

[14] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[15] Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden

[16] Univ Munster, Dept Psychiat & Psychotherapy, Munster, Germany

[17] Vrije Univ, Inst Hlth & Care Res & Neurosci Campus Amsterdam, EMGO, Amsterdam, Netherlands

[18] Aarhus Univ, ISEQ, Dept Biomed, Aarhus, Denmark

[19] Aarhus Univ, ISEQ, Ctr Integrat Sequencing, Aarhus, Denmark

[20] Univ Lausanne Hosp, Lausanne, Switzerland

[21] Univ Marburg, Dept Psychiat, Marburg, Germany

[22] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[23] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland

[24] Univ Bonn, Life & Brain Ctr, Dept Genom, Inst Human Genet, Bonn, Germany

[25] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[26] Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany

[27] Univ Edinburgh, Kaiser Permanente San Francisco Med Ctr, Dept Psychiat, San Francisco, CA USA

[28] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh, Midlothian, Scotland

[29] Washington Univ St Louis, Dept Psychiat, St Louis, MO USA

[30] Univ Aberdeen, Div Appl Hlth Sci, Aberdeen, Scotland

[31] Univ Greifswald, Interfaculty Inst Genet & Funct Genom, Greifswald, Germany

[32] Max Planck Inst Psychiat, Munich, Germany

[33] Univ Copenhagen, Mental Hlth Serv Capital Reg, Mental Hlth Ctr Copenhagen, Copenhagen, Denmark

[34] Univ Gothenburg, Inst Neuroscience & Physiol, Gothenburg, Sweden

[35] Heidelberg Univ, Fac Med, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany

[36] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA USA

[37] Vrije Univ Med Ctr, EMGO Inst Hlth & Care Res & Neuro Sci Campus Amst, Dept Psychiat, Amsterdam, Netherlands

[38] Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark

[39] Munich Cluster Syst Neurol, Munich, Germany

[40] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England

[41] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia

[42] Therapeia, Reykjavik, Iceland

[43] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland

[44] Florida Atlantic Univ, Charles E Schmidt Coll Med, Boca Raton, FL USA

[45] Univ Iowa, Dept Psychiat, Coll Med, Iowa City, IA USA

[46] Univ Granada, Ctr Invest Biomed Red Salud Mental, Granada, Spain

[47] Univ Granada, Hospit Univ Granada, Inst Invest Biosanitaria ibs, Granada, Spain

[48] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA

[49] Grp Hlth, Dept Psychiat, Seattle, WA USA

[50] Univ Iceland, Fac Med, Reykjavik, Iceland

来源：

BIOLOGICAL PSYCHIATRY | 2017年 / 81卷 / 04期

基金：

瑞典研究理事会; 英国医学研究理事会; 美国国家卫生研究院; 澳大利亚研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金; 瑞士国家科学基金会;

关键词：

Age at onset; GWAS; Heterogeneity; Major depressive disorder; Polygenic scoring; Stratification; HAN CHINESE WOMEN; FAMILY-HISTORY; TWIN; MORTALITY; DISEASE; RISK; EPIDEMIOLOGY; PREDICTOR; GENOTYPE; REGISTRY;

D O I：

10.1016/j.biopsych.2016.05.010

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 x 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult-and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.

引用

页码：325 / 335

页数：11

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