Functional variants at 1p36.23 confer risk of schizophrenia through modulating RERE

Genome-wide association studies have identified 1p36.23 as a schizophrenia risk locus. However, the functional variants and genes driving the association remain unknown. Here, we identified two functional variants (i.e., rs159961 and rs301792) at the 1p36.23 risk locus. Both variants reside introns of RERE and exhibit allele-specific enhancer activity. Risk alleles of rs159961 and rs301792 increase enhancer activity by altering REST and POLR2A binding, leading to RERE upregulation. Consistently, RERE was significantly elevated in brains of schizophrenia cases. Functionally, RERE-overexpression impaired neurogenesis, altered dendritic spine density and dendritic complexity, and altered genes related to dendrite development and glutamatergic synapses. Through interacting with RARB and RXRA at the Grin2a promoter, RERE regulates the well-known schizophrenia risk gene Grin2a (encodes an NMDAR subunit), and RERE-overexpression impairs excitatory synaptic transmission. Our study indicates that functional variants rs159961 and rs301792 confer schizophrenia risk by upregulating RERE, which affects neuronal development and synaptic function.