Massively parallel reporter assays investigate shared genetic variants of eight psychiatric disorders
A meta-genome-wide association study encompassing eight psychiatric disorders has shed light on the genetic architecture of pleiotropy. However, mechanisms underlying pleiotropic effects of these variants remain to be investigated. We conducted a massively parallel reporter assay to decipher the regulatory logic of variants with disease-specific and pleiotropic effects. Pleiotropic variants differ from disease-specific variants by manifesting chromatin accessibility that extends across diverse cell types in the neuronal lineage, and altering motifs for transcription factors with higher connectivity in protein-protein interaction (PPI) networks. Next, we mapped pleiotropic and disease-specific variants to putative target genes, which may offer insights into potential mechanisms of pleiotropy. Compared with disease-specific genes, pleiotropic genes demonstrate associations with generic biological pathways, widespread temporal dynamics during neuronal lineage, and higher connectivity in PPI networks. Collectively, variants exert pleiotropic effects by regulating genes involved in global biological functions. Overall design: Massively parallel reporter assay (MPRA) on risk variants of eight psychiatric disorders in human neural progenitors (HNP)