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.