For many years, the depressed phenotype has been refractory to genetic inquiry due to issues regarding statistical power. Recently, studies have successfully identified loci associated with depression by either substantially increasing the sample size7,8 or by refining the phenotype by illness course9, recurrence and sex6. In this study we used techniques designed to interrogate complex traits to ascertain whether maximizing the sample size (nmax = 43,062) or phenotypic stratification by recurrence or sex was more advantageous for investigating the genetic architecture of MDD, using data from two large UK cohorts. Each MDD definition was evaluated using several metrics: the successful identification of variants reaching genome-wide significance in GWAS meta-analysis, an increased SNP-based heritability estimate, identification of significant genetic correlations with other traits using LD score regression, and increased variance explained by polygenic profile scores for MDD derived from three independent cohorts.
