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.23andMe; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Language: English. Date Revised: 20210327. Date Created: 20180428. Date Completed: 20190424. Update Code: 20220301. Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't. Journal ID: 9216904. Publication Model: Print-Electronic. Cited Medium: Internet. NLM ISO Abbr: Nat Genet. PubMed Central ID: PMC5934326. Linked References: Kessler, R. C. & Bromet, E. J. The epidemiology of depression across cultures. Annu. Rev. Public Health 34, 119–138 (2013). (PMID: 23514317410046110.1146/annurev-publhealth-031912-114409); Judd, L. L. The clinical course of unipolar major depressive disorders. Arch. Gen. Psychiatry 54, 989–991 (1997). (PMID: 936665410.1001/archpsyc.1997.01830230015002); Lopez, A. D., Mathers, C. 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Subset: MEDLINE; Grant Information: U01 MH085520 United States MH NIMH NIH HHS; P50 CA097007 United States CA NCI NIH HHS; U01 MH046276 United States MH NIMH NIH HHS; MC_QA137853 United Kingdom MRC_ Medical Research Council; MR/K026992/1 United Kingdom MRC_ Medical Research Council; R01 MH067257 United States MH NIMH NIH HHS; R01 MH059587 United States MH NIMH NIH HHS; MC_PC_U127561128 United Kingdom MRC_ Medical Research Council; R01 MH059586 United States MH IMH NIH HHS; P50 CA093459 United States CA NCI NIH HHS; U01 MH109528 United States MH NIMH NIH HHS; R01 MH060879 United States MH NIMH NIH HHS; R01 MH061675 United States MH NIMH NIH HHS; MC_UU_00007/10 United Kingdom MRC_ Medical Research Council; MR/N015746/1 United Kingdom MRC_ Medical Research Council; R01 CA133996 United States CA NCI NIH HHS; T32 HL007901 United States HL NHLBI NIH HHS; R01 ES011740 United States ES NIEHS NIH HHS; U01 MH079469 United States MH NIMH NIH HHS; R01 MH060870 United States MH NIMH NIH HHS; R01 MH081800 United States MH NIMH NIH HHS; R01 DA034076 United States DA NIDA NIH HHS; R01 MH059571 United States MH NIMH NIH HHS; G0200243 United Kingdom MRC_ Medical Research Council; R01 MH059565 United States MH NIMH NIH HHS; U01 MH109536 United States MH NIMH NIH HHS; U01 MH079470 United States MH NIMH NIH HHS; R01 HG009658 United States HG NHGRI NIH HHS; U01 MH109532 United States MH NIMH NIH HHS; R01 MH059566 United States MH NIMH NIH HHS; K01 MH109772 United States MH NIMH NIH HHS; U01 MH094421 United States MH NIMH NIH HHS; P30 GM103328 United States GM NIGMS NIH HHS; MC_PC_17228 United Kingdom MRC_ Medical Research Council; S10 OD018164 United States OD NIH HHS; R01 MH059588 United States MH NIMH NIH HHS; U01 MH046318 United States MH NIMH NIH HHS; MR/L023784/2 United Kingdom MRC_ Medical Research Council; MR/L010305/1 United Kingdom MRC_ Medical Research Council Date of Electronic Publication: 2018 Apr 26. ; Original Imprints: Publication: New York, NY : Nature Pub. 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