Allele-specific expression in the brain links genetic risk and cortical thinning in psychiatric disorders

Allele-specific expression (ASE), where genetic variants exert dynamic control over gene expression, is not well studied in major psychiatric disorders. Here, we used transcriptome analysis in postmortem brain to identify genes with ASE, quantify differences in ASE in Schizophrenia (SCZ), Bipolar Disorder (BD), and Major Depressive Disorder (MDD), and explore regional relationships between differential ASE (dASE) and cortical thickness. Genome-wide analysis of ASE was performed by comparing RNA-sequencing read ratios of parental alleles in subgenual anterior cingulate cortex (sgACC) from 185 individuals with SCZ, BD, MDD, or no psychiatric disorder. ASE was detected by read-back phasing using phASER. dASE between cases and controls was performed using ASEP, a mixed model that accounts for sample information and correlation among SNPs. Heritability enrichment was calculated using linkage disequilibrium score regression. The Allen human brain atlas was used to map regional expression of dASE genes, which were compared with regional neuroanatomical changes reported in psychiatric patients. Of all 11,234 genes considered, 27% showed ASE at FDR < 0.05. Partitioned heritability analysis showed that ASE SNPs accounted for 13-16% of the heritability of MDD, BD and SCZ (enrichment p < 0.001). ASE SNPs significantly (p < 0.001) overlapped with GWAS variants in SCZ (odds ratio (OR) = 3.15), BD (OR = 2) and MDD (OR = 1.52). At FDR < 0.05, 1871 genes showed dASE in one or more diagnostic groups. These genes were enriched for regions with neuropsychiatric copy number variants (CNVs) and for several brain-relevant functional categories, especially those related to synapses. Expression of genes with dASE was increased in brain regions previously reported to show cortical thinning in patients with psychiatric disorders. This is the first study to explore the role of ASE in 3 major adult psychiatric disorders. We show that ASE is widespread in sgACC, that ASE SNPs contribute disproportionately to psychiatric disease heritability, dASE genes cluster in genomic regions with known neuropsychiatric CNVs and are most highly expressed in brain regions reported to show cortical thinning in psychiatric patients. Taken together, these findings highlight the importance of ASE in psychiatric disease risk and suggest that dysregulation of gene expression contributes to thinning of the cerebral cortex associated with psychiatric disorders.