There are many reasons why identifying causal loci for MDD has proven difficult12. MDD is probably influenced by many genetic loci each with small effects17, as are most common diseases18 including psychiatric disorders19,20. Estimates of the proportion of variance attributable to genome-wide SNPs (SNP heritability, hSNP2) indicate that around a quarter of the h2 for MDD is due to common genetic variants21,22, and demonstrate that a genetic signal is detectable in GWA data, implying that larger sample sizes are needed to detect specific loci given their effect sizes. Such a strategy has been proven in schizophrenia studies, the flagship adult psychiatric disorder in genomics research. We thus accumulated clinical, population, and volunteer cohorts23. This pragmatic approach takes the view that sample size can overcome heterogeneity to identify risk alleles that are robustly associated with major depression. Potential concerns about combining carefully curated research cohorts with volunteer cohorts were ameliorated via multiple lines of evidence that suggest the results are likely to be applicable to clinical MDD. As discussed more fully below, our analyses have neurobiological, clinical, and therapeutic relevance for major depression.
