Exploring the genetic overlap between twelve psychiatric disorders

The widespread comorbidity among psychiatric disorders demonstrated in epidemiological studies1–5 is mirrored by non-zero, positive genetic correlations from large-scale genetic studies6–10. To identify shared biological processes underpinning this observed phenotypic and genetic covariance and enhance molecular characterization of general psychiatric disorder liability11–13, we used several strategies aimed at uncovering pleiotropic, that is, cross-trait-associated, single-nucleotide polymorphisms (SNPs), genes and biological pathways. We conducted cross-trait meta-analysis on 12 psychiatric disorders to identify pleiotropic SNPs. The meta-analytic signal was driven by schizophrenia, hampering interpretation and joint biological characterization of the cross-trait meta-analytic signal. Subsequent pairwise comparisons of psychiatric disorders identified substantial pleiotropic overlap, but mainly among pairs of psychiatric disorders, and mainly at less stringent P-value thresholds. Only annotations related to evolutionarily conserved genomic regions were significant for multiple (9 out of 12) psychiatric disorders. Overall, identification of shared biological mechanisms remains challenging due to variation in power and genetic architecture between psychiatric disorders. Cross-trait meta-analysis on 12 psychiatric disorders identifies the genetic overlap between pairs of disorders and highlights the challenges of cross-trait genetic research.