Allele‐Specific Regulation of PAXIP1‐AS1 by SMC3/CEBPB at rs112651172 in Psychiatric Disorders Drives Synaptic and Behavioral Dysfunctions in Mice

This study identifies a functional noncoding variant, rs112651172 (C/G), that drives allele‐specific expression of PAXIP1‐AS1 in monozygotic twin pairs discordant for schizophrenia and bipolar disorder. The risk G allele enhances CEBPB binding, leading to lncRNA upregulation, CNTNAP3 derepression, and synaptic and behavioral deficits in mice. These findings highlight ASE‐mediated lncRNA dysregulation as a novel mechanism and therapeutic targets in psychiatric pathogenesis. Abstract 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, whole‐genome and transcriptome analyses of monozygotic twin pairs discordant for BPD or SCZ are performed, identifying that noncoding genetic variants drive differential ASE patterns of long noncoding RNAs (lncRNAs) in affected individuals compared to their unaffected co‐twins. The rs112651172 (C/G) is identified 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. Eevated PAXIP1‐AS1 expression is consistently observed in SCZ and BPD postmortem brain tissues from PsychENCODE or LIBD datasets. In mice, G allele overexpression in the prefrontal cortex induces anxiety‐ and depression‐like behaviors, social deficits, memory impairments, sensorimotor gating abnormalities, and reduced neuronal excitability. Mechanistically, PAXIP1‐AS1 upregualtes CNTNAP3 by sequestering the transcriptional repressor ZGPAT. Knockdown of CNTNAP3 reversed the observed phenotypes. These findings establish rs112651172 as a regulatory variant linking noncoding genetic risk to psychiatric phenotypeshrough ASE‐driven lncRNA dysregulation, suggesting new therapeutic targets in SCZ and BPD. This study identifies a functional noncoding variant, rs112651172 (C/G), that drives allele-specific expression of PAXIP1-AS1 in monozygotic twin pairs discordant for schizophrenia and bipolar disorder. The risk G allele enhances CEBPB binding, leading to lncRNA upregulation, CNTNAP3 derepression, and synaptic and behavioral deficits in mice. These findings highlight ASE-mediated lncRNA dysregulation as a novel mechanism and therapeutic targets in psychiatric pathogenesis. Abstract 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, whole-genome and transcriptome analyses of monozygotic twin pairs discordant for BPD or SCZ are performed, identifying that noncoding genetic variants drive differential ASE patterns of long noncoding RNAs (lncRNAs) in affected individuals compared to their unaffected co-twins. The rs112651172 (C/G) is identified 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. Eevated PAXIP1-AS1 expression is consistently observed in SCZ and BPD postmortem brain tissues from PsychENCODE or LIBD datasets. In mice, G allele overexpression in the prefrontal cortex induces anxiety- and depression-like behaviors, social deficits, memory impairments, sensorimotor gating abnormalities, and reduced neuronal excitability. Mechanistically, PAXIP1-AS1 upregualtes CNTNAP3 by sequestering the transcriptional repressor ZGPAT. Knockdown of CNTNAP3 reversed the observed phenotypes. These findings establish rs112651172 as a regulatory variant linking noncoding genetic risk to psychiatric phenotypeshrough ASE-driven lncRNA dysregulation, suggesting new therapeutic targets in SCZ and BPD. Advanced Science, Volume 12, Issue 44, November 27, 2025.