To evaluate the impact of combining major depression cohorts that used different ascertainment methods, we undertook a series of genetic risk score (GRS) prediction analyses to demonstrate the validity of our GWA results for clinical MDD (Fig. 2). Importantly, the variance explained in out-of-sample prediction increased with the size of the GWA discovery cohort (Fig. 2a), with the GRS from the full discovery sample meta-analysis explaining 1.9% of variance in liability (Fig. 2a, Supplementary Fig. 2, and Supplementary Table 4). For any randomly selected case and control, GRS ranked cases higher than controls with probability 0.57 (i.e., AUC=0.57), and the odds ratio of MDD for those in the 10th versus 1st GRS decile (OR10) was 2.4 (Fig. 2b, Supplementary Table 4). GRS analyses in other disorders (e.g., schizophrenia25) have shown that mean GRS increases with clinical severity in cases. We found significantly higher major depression GRS in those with more severe MDD, as measured in different ways (Fig. 2c). Last, because around half of the major depression cases were identified by self-report (i.e., diagnosis or treatment for clinical depression by
