Allele-Specific Expression of PAXIP1-AS1 at rs112651172 in Schizophrenia and Bipolar Disorder Contributes to Synaptic Dysfunction and Behavioral Abnormalities in Mice

Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable psychiatric disorders with complex genetic and environmental underpinnings. Allele-specific expression (ASE) has emerged as a critical mechanism linking noncoding genetic variants to disease risk through epigenetic and environmental modulation. Here, we performed whole-genome and transcriptome analyses of monozygotic twin pairs discordant for BPD or SCZ and identified that noncoding genetic variants drive differential ASE patterns of long noncoding RNA (lncRNAs) in affected individuals compared to their unaffected co-twins. We identified rs112651172 (C/G) as a functional ASE variant regulating PAXIP1-AS1 expression via allele-specific transcription factor binding: SMC3 binds the C allele, while CEBPB binds the G allele, resulting in G allele-specific upregulation in patients. In mice, G allele overexpression in the prefrontal cortex induced anxiety- and depression-like behaviors, social deficits, memory impairments, sensorimotor gating abnormalities, and synaptic dysfunction characterized by reduced neuronal excitability. Mechanistically, PAXIP1-AS1 promotes CNTNAP3 expression by sequestering the transcriptional repressor ZGPAT. Knockdown of CNTNAP3 in PAXIP1-AS1-overexpressing mice rescued synaptic and behavioral phenotypes. These findings establish rs112651172 as a functional noncoding variant that contributes to psychiatric phenotypes through ASE-driven, lncRNA-mediated regulation, highlighting the relevance of lncRNAs and ASE as potential molecular mechanisms and therapeutic targets in SCZ and BPD.