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
- Cunyou Zhao
2025-11-04
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.