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Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

ABSTRACT: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

SUBMITTER: Wray NR

PROVIDER: S-EPMC5934326 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

Wray Naomi R NR Ripke Stephan S Mattheisen Manuel M Trzaskowski Maciej M Byrne Enda M EM Abdellaoui Abdel A Adams Mark J MJ Agerbo Esben E Air Tracy M TM Andlauer Till M F TMF Bacanu Silviu-Alin SA Bækvad-Hansen Marie M Beekman Aartjan F T AFT Bigdeli Tim B TB Binder Elisabeth B EB Blackwood Douglas R H DRH Bryois Julien J Buttenschøn Henriette N HN Bybjerg-Grauholm Jonas J Cai Na N Castelao Enrique E Christensen Jane Hvarregaard JH Clarke Toni-Kim TK Coleman Jonathan I R JIR Colodro-Conde Lucía L Couvy-Duchesne Baptiste B Craddock Nick N Crawford Gregory E GE Crowley Cheynna A CA Dashti Hassan S HS Davies Gail G Deary Ian J IJ Degenhardt Franziska F Derks Eske M EM Direk Nese N Dolan Conor V CV Dunn Erin C EC Eley Thalia C TC Eriksson Nicholas N Escott-Price Valentina V Kiadeh Farnush Hassan Farhadi FHF Finucane Hilary K HK Forstner Andreas J AJ Frank Josef J Gaspar Héléna A HA Gill Michael M Giusti-Rodríguez Paola P Goes Fernando S FS Gordon Scott D SD Grove Jakob J Hall Lynsey S LS Hannon Eilis E Hansen Christine Søholm CS Hansen Thomas F TF Herms Stefan S Hickie Ian B IB Hoffmann Per P Homuth Georg G Horn Carsten C Hottenga Jouke-Jan JJ Hougaard David M DM Hu Ming M Hyde Craig L CL Ising Marcus M Jansen Rick R Jansen Rick R Jin Fulai F Jorgenson Eric E Knowles James A JA Kohane Isaac S IS Kraft Julia J Kretzschmar Warren W WW Krogh Jesper J Kutalik Zoltán Z Lane Jacqueline M JM Li Yihan Y Li Yun Y Lind Penelope A PA Liu Xiaoxiao X Lu Leina L MacIntyre Donald J DJ MacKinnon Dean F DF Maier Robert M RM Maier Wolfgang W Marchini Jonathan J Mbarek Hamdi H McGrath Patrick P McGuffin Peter P Medland Sarah E SE Mehta Divya D Middeldorp Christel M CM Mihailov Evelin E Milaneschi Yuri Y Milani Lili L Mill Jonathan J Mondimore Francis M FM Montgomery Grant W GW Mostafavi Sara S Mullins Niamh N Nauck Matthias M Ng Bernard B Nivard Michel G MG Nyholt Dale R DR O'Reilly Paul F PF Oskarsson Hogni H Owen Michael J MJ Painter Jodie N JN Pedersen Carsten Bøcker CB Pedersen Marianne Giørtz MG Peterson Roseann E RE Pettersson Erik E Peyrot Wouter J WJ Pistis Giorgio G Posthuma Danielle D Purcell Shaun M SM Quiroz Jorge A JA Qvist Per P Rice John P JP Riley Brien P BP Rivera Margarita M Saeed Mirza Saira S Saxena Richa R Schoevers Robert R Schulte Eva C EC Shen Ling L Shi Jianxin J Shyn Stanley I SI Sigurdsson Engilbert E Sinnamon Grant B C GBC Smit Johannes H JH Smith Daniel J DJ Stefansson Hreinn H Steinberg Stacy S Stockmeier Craig A CA Streit Fabian F Strohmaier Jana J Tansey Katherine E KE Teismann Henning H Teumer Alexander A Thompson Wesley W Thomson Pippa A PA Thorgeirsson Thorgeir E TE Tian Chao C Traylor Matthew M Treutlein Jens J Trubetskoy Vassily V Uitterlinden André G AG Umbricht Daniel D Van der Auwera Sandra S van Hemert Albert M AM Viktorin Alexander A Visscher Peter M PM Wang Yunpeng Y Webb Bradley T BT Weinsheimer Shantel Marie SM Wellmann Jürgen J Willemsen Gonneke G Witt Stephanie H SH Wu Yang Y Xi Hualin S HS Yang Jian J Zhang Futao F Arolt Volker V Baune Bernhard T BT Berger Klaus K Boomsma Dorret I DI Cichon Sven S Dannlowski Udo U de Geus E C J ECJ DePaulo J Raymond JR Domenici Enrico E Domschke Katharina K Esko Tõnu T Grabe Hans J HJ Hamilton Steven P SP Hayward Caroline C Heath Andrew C AC Hinds David A DA Kendler Kenneth S KS Kloiber Stefan S Lewis Glyn G Li Qingqin S QS Lucae Susanne S Madden Pamela F A PFA Magnusson Patrik K PK Martin Nicholas G NG McIntosh Andrew M AM Metspalu Andres A Mors Ole O Mortensen Preben Bo PB Müller-Myhsok Bertram B Nordentoft Merete M Nöthen Markus M MM O'Donovan Michael C MC Paciga Sara A SA Pedersen Nancy L NL Penninx Brenda W J H BWJH Perlis Roy H RH Porteous David J DJ Potash James B JB Preisig Martin M Rietschel Marcella M Schaefer Catherine C Schulze Thomas G TG Smoller Jordan W JW Stefansson Kari K Tiemeier Henning H Uher Rudolf R Völzke Henry H Weissman Myrna M MM Werge Thomas T Winslow Ashley R AR Lewis Cathryn M CM Levinson Douglas F DF Breen Gerome G Børglum Anders D AD Sullivan Patrick F PF

Nature genetics 20180426 5

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved ...[more]

PMID: 29700475

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Project description:ImportanceAlcohol dependence (AD) and major depression (MD) are leading causes of disability that often co-occur. Genetic epidemiologic data have shown that AD and MD share a common possible genetic cause. The molecular nature of this shared genetic basis is poorly understood.ObjectivesTo detect genetic risk variants for comorbid AD and MD and to determine whether polygenic risk alleles are shared with neuropsychiatric traits or subcortical brain volumes.Design, setting, and participantsThis genome-wide association study analyzed criterion counts of comorbid AD and MD in African American and European American data sets collected as part of the Yale-Penn study of the genetics of drug and alcohol dependence from February 14, 1999, to January 13, 2015. After excluding participants never exposed to alcohol or with missing information for any diagnostic criterion, genome-wide association studies were performed on 2 samples (the Yale-Penn 1 and Yale-Penn 2 samples) totaling 4653 African American participants and 3169 European American participants (analyzed separately). Tests were performed to determine whether polygenic risk scores derived from potentially related traits in European American participants could be used to estimate comorbid AD and MD.Main outcomes and measuresComorbid criterion counts (ranging from 0 to 14) for AD (7 criteria) and MD (9 criteria, scaled to 7) as defined by the DSM-IV.ResultsOf the 7822 participants (3342 women and 4480 men; mean [SD] age, 40.1 [10.7] years), the median comorbid criterion count was 6.2 (interquartile range, 2.3-10.9). Under the linear regression model, rs139438618 at the semaphorin 3A (SEMA3A [OMIM 603961]) locus was significantly associated with AD and MD comorbidity in African American participants in the Yale-Penn 1 sample (β = 0.89; 95% CI, 0.57-1.20; P = 2.76 × 10-8). In the independent Yale-Penn 2 sample, the association was also significant (β = 0.83; 95% CI, 0.39-1.28; P = 2.06 × 10-4). Meta-analysis of the 2 samples yielded a more robust association (β = 0.87; 95% CI, 0.61-1.12; P = 2.41 × 10-11). There was no significant association identified in European American participants. Analyses of polygenic risk scores showed that individuals with a higher risk of neuroticism (β = 1.01; 95% CI, 0.50-1.52) or depressive symptoms (β = 0.87; 95% CI, 0.32-1.42) and a lower level of subjective well-being (β = -0.94; 95% CI, -1.46 to -0.42) and educational attainment (β = -1.00, 95% CI, -1.57 to -0.44) had a higher level of AD and MD comorbidity, while larger intracranial (β = 1.07; 95% CI, 0.50 to 1.64) and smaller putamen volumes (β = -1.16; 95% CI, -1.86 to -0.46) were associated with higher risks of AD and MD comorbidity.Conclusions and relevanceSEMA3A variation is significantly and replicably associated with comorbid AD and MD in African American participants. Analyses of polygenic risk scores identified pleiotropy with neuropsychiatric traits and brain volumes. Further studies are warranted to understand the biological and genetic mechanisms of this comorbidity, which could facilitate development of medications and other treatments for comorbid AD and MD.

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Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

Publications

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

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