An early criticism of GWAS meta-analysis was that combining samples from multiple sites to increase sample size would introduce crippling heterogeneity. This concern was not borne out by experience. Indeed, the number of significant associations has increased as more individual studies have been combined using meta-analysis for other heterogeneous diseases such as Type 2 diabetes mellitus,32 inflammatory bowel disease78 and multiple cancers79,80 along with anthropometric traits like height29 and body mass.30 It is possible that MDD might be exceptional, and have greater clinical and etiological heterogeneity, as well as non-genetic phenocopies. The different endorsement rates of the MDD criteria between cohorts may support this conjecture (Supplementary Table S12). Higher heterogeneity implies reduced statistical power as the genetic effect size distribution will be diluted. Higher heterogeneity— that is, many different ‘types’ of MDD—would suggest that identifying more optimal MDD-related phenotypes may be a practical step forward if adequate sample sizes could be achieved.
