Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

A meta-genome-wide association study across eight psychiatric disorders has highlighted the genetic architecture of pleiotropy in major psychiatric disorders. However, mechanisms underlying pleiotropic effects of the associated variants remain to be explored. We conducted a massively parallel reporter assay to decode the regulatory logic of variants with pleiotropic and disorder-specific effects. Pleiotropic variants differ from disorder-specific variants by exhibiting chromatin accessibility that extends across diverse cell types in the neuronal lineage and by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. We mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches. In vitro CRISPR perturbation of selected variants confirmed the variant-gene relationships, and in vivo CRISPR perturbation of a pleiotropic and a disorder-specific gene suggests that pleiotropy may involve regulation of genes expressed broadly across neuronal cell types and with higher network connectivity.