Gain of Alternative Allele Expression of LINC02449 at rs149707223 in Schizophrenia and Bipolar Disorder: Inducing Synaptic Transmission and Behavioral Deficits in Mice

Tengfei Yang, Jin-Ming Liu, Qiaqi Chen, Zhiying Deng, Chaoying Ni, Yunqian Wang, Yuting Lan, Tingyun Jiang, Shufen Li, Meijun Jiang, Hong Xue, Xiong Cao (), Zhongju Wang () and Cunyou Zhao ()
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Tengfei Yang: Southern Medical University
Jin-Ming Liu: Southern Medical University
Qiaqi Chen: Southern Medical University
Zhiying Deng: Southern Medical University
Chaoying Ni: Southern Medical University
Yunqian Wang: Southern Medical University
Yuting Lan: Southern Medical University
Tingyun Jiang: Zhongshan
Shufen Li: Southern Medical University
Meijun Jiang: Southern Medical University
Hong Xue: Clear Water Bay
Xiong Cao: Southern Medical University
Zhongju Wang: Southern Medical University
Cunyou Zhao: Southern Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Bipolar disorder (BD) and schizophrenia (SZ) are complex psychiatric disorders with overlapping features. Their heterogeneity may arise from interactions between genetic variants and environmental or epigenetic modifiers. Allele-specific expression (ASE), an imbalance in expression between gene alleles, provides a key mechanism linking these interactions to disease. We conducted transcriptomic and genomic analyses in phenotype-discordant monozygotic twins to investigate ASE in psychiatric risk. Nine ASE-affected long non-coding RNAs were identified, including LINC02449, which showed a consistent allele-specific shift in BD/SZ patients favoring the alternative G allele at rs149707223. Functional analyses revealed that overexpression of the LINC02449 G allele in mice induced social deficits and repetitive behaviors. These phenotypes were associated with enhanced excitatory transmission within the mPFC-NAc circuit, mediated by the synaptic regulator CPLX1. Our findings demonstrate that ASE-driven dysregulation of LINC02449 contributes to synaptic and behavioral abnormalities, underscoring ASE as a potentially important regulatory mechanism in BD and SZ pathogenesis.

Date: 2025
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DOI: 10.1038/s41467-025-64717-z

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