Exploring the genetic overlap between 12 psychiatric disorders

The widespread comorbidity among psychiatric disorders (PDs) demonstrated in epidemiological studies1-5 is mirrored by non-zero, positive genetic correlations from large scale genetic studies6-10. We employed several strategies to uncover pleiotropic SNPs, genes and biological pathways7,8 underlying this genetic covariance. First, we conducted cross-trait meta-analysis on 12 PDs to identify pleiotropic SNPs. However, the majority of meta-analytic signal was driven by only one or a few PDs, hampering interpretation and joint biological characterization of the meta-analytic signal. Next, we performed pairwise comparisons of PDs on the SNP, gene, genomic region, gene-set, tissue-type, and cell-type level. Substantial overlap was observed, but mainly among pairs of PDs, and mainly at less stringent p-value thresholds. Only heritability enrichment for "conserved genomic regions" and "nucleotide diversity" was significant for multiple (9 out of 12) PDs. Overall, identification of shared biological mechanisms remains challenging due to variation in power and genetic architecture between PDs.