Genetic Basis of Psychiatric Disorders

Genome-wide association studies (GWAS) of psychiatric disorders have shed light on the genetic architecture of psychiatric disorders. One of the key characteristics of the genetic architecture of psychiatric disorders is pleiotropy, which is thought to account for phenotypic comorbidity observed across different psychiatric disorders. To investigate the pleiotropic effects of genetic variants on psychiatric disorders, the Cross-Disorder Group of the Psychiatric Genomics Consortium (PGC) conducted a GWAS combining eight psychiatric disorders. Among 136 GWAS loci the study identified, 109 loci were associated with more than one disorder, underscoring widespread pleiotropy in psychiatric genetics. Functional characterization of these loci suggested neurodevelopmental origin of pleiotropy, but mechanisms by which a subset of variants have a broader influence on psychiatric conditions that cross diagnostic boundaries remain an open question. We conducted a massively parallel reporter assay (MPRA) to decipher the regulatory logic of variants with disorder-specific and pleiotropic effects.