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 (GWA) meta-analysis based in 135,458 cases and 344,901 control, We 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 relations 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 and define the basis of major depression and imply a continuous measure of risk underlies the clinical phenotype.
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Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)
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Despite strong evidence supporting the heritability of Major Depressive Disorder, previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-reported data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 reporting no history of depression through 23andMe, and meta-analyzed these results with published MDD GWAS results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with pval<1.0×10−5 in the meta-analysis were further analyzed in a replication dataset (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint-analysis over all three datasets. Some of these loci were also implicated in GWAS of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to traditional means of ascertainment for neuropsychiatric disease genomics.
Highlights d Three groups of highly genetically-related disorders among 8 psychiatric disorders d Identified 109 pleiotropic loci affecting more than one disorder d Pleiotropic genes show heightened expression beginning in 2 nd prenatal trimester d Pleiotropic genes play prominent roles in neurodevelopmental processes Authors Cross-Disorder Group of the Psychiatric Genomics Consortium
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