We confirmed that MDD disease liability reflects the combined small effects of a large number of genetic variants across the genome(5;6). MDD case/control status was significantly predicted by GPRS-MDD based on the largest dataset to date(4), especially by scores including SNPs associated with MDD at liberal significance thresholds. This pattern indicates that the explanatory power of the scores is increased by the addition of many variants of small effect scattered across the genome. The score including all independent SNPs explained 0.6% of the variance in MDD liability. Consistently with previous cross-disorders analyses by PGC(28;29), we also confirmed that MDD shares genetic risk with major psychiatric disorders such as bipolar disorder and schizophrenia. Among the GPRS for psychiatric disorders, schizophrenia scores explained the highest proportions of variance in MDD liability (1.6%). This higher explanatory power is attributable to the larger training dataset (43), leading to smaller sampling variance on the individual SNP effects. For GPRS based on the latest schizophrenia PGC-GWAS(34) the discovery sample size was ~150K samples, whereas this was ~16K for GPRS based on MDD(4) and bipolar disorder(44). In
