Identification of 15 genetic loci associated with risk of major depression in individuals of European descent

Abstract

Despite strong evidence supporting the heritability of major depressive disorder (MDD), previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-report data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 individuals reporting no history of depression through 23andMe and carried out meta-analysis of these results with published MDD genome-wide association study results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with a P value <1.0 × 10(-5) in the meta-analysis were further analyzed in a replication data set (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 data sets. Some of these loci were also implicated in genome-wide association studies of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to data collected from traditional means of ascertainment for neuropsychiatric disease genomics.

Figure 1

Discovery phase meta-analysis of 23andMe self-report ascertainment of major depression (75,607 cases and 231,747 controls) and PGC MDD (9,240 cases and 9,519 controls). a) Manhattan plot of Discovery phase 23andMe GWAS. LD score regression calculated intercept was used for inflation correction. The threshold for genome-wide significance (p < 5×10⁻⁸) is indicated by the purple line. Red dots represent SNPs with p-values smaller than the genome-wide significant threshold. Regions labeled in black denote loci that reached genome-wide significance in the join-analysis. b) Q-Q plot for the 23andMe MDD GWAS.

Figure 2

Regional association plots for genome-wide significant regions and secondary independent signals identified in each region. a) OLFM4 locus (rs12552), b) TMEM161B-MEF2C (rs10514299), c) MEIS2-TMCO5A locus (rs8025231), and d) NEGR1 locus (rs11209948). Secondary signals in TMEM161B-MEF2C and NEGR1 (rs454214, rs2422321 respectively) are shown. Purple diamonds represent smallest p-value for each locus.