Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder

Recent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we introduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied this framework to conduct a transcriptome-wide association study (TWAS) on 7,805 ASD proband-parent trios, and replicated our findings using 35,740 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identified POU3F2 (p = 2.1E-7), a transcription factor mainly expressed in developmental brain. Gene targets regulated by POU3F2 showed a 2.7-fold enrichment for known ASD genes (p = 2.0E-5) and a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands (p = 7.1E-5). These results provide a novel connection between rare and common variants, whereby ASD genes affected by very rare mutations are regulated by an unlinked transcription factor affected by common genetic variations.Author summary: Autism spectrum disorder is a neurodevelopmental disorder with complex genetic etiology. Mutational variant studies link damaging and typically rare variants in protein-coding genes with disease outcomes, while genome-wide association studies identify genetic variations that are common in the human population associated with autism risk. Interestingly, studies targeting common and rare variants have implicated distinct risk pathways for autism. Here, we introduce a novel statistical framework for risk gene mapping, i.e., TITANS, to better analyze common genetic variants from parent-proband trios. TITANS integrates transmission disequilibrium information with tissue-specific regulatory annotations of multiple linked variants to infer risk genes. We pinpoint a novel autism gene POU3F2, which encodes a key transcription factor regulating multiple autism risk genes implicated in exome sequencing studies. Our findings provide a novel connection between rare and common variants, whereby autism genes affected by rare mutations are regulated by an unlinked transcription factor affected by common genetic variations.