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

by Kunling Huang, Yuchang Wu, Junha Shin, Ye Zheng, Alireza Fotuhi Siahpirani, Yupei Lin, Zheng Ni, Jiawen Chen, Jing You, Sunduz Keles, Daifeng Wang, Sushmita Roy, Qiongshi Lu

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 int roduce 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 35,74 0 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identifiedPOU3F2 (p = 2.1E-7), a transcription factor mainly expressed in developmental brain. Gene targets regulated byPOU3F2 showed a 2.7-fold enrichment for known ASD genes (p = 2.0E-5) and a 2.7-fold enrichment for loss-of-functionde 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.

Source: PLoS Genetics - February 4, 2021 Category: Genetics & Stem Cells Authors: Kunling Huang Source Type: research