PT  - JOURNAL ARTICLE
AU  - Huang, Kunling
AU  - Wu, Yuchang
AU  - Shin, Junha
AU  - Zheng, Ye
AU  - Siahpirani, Alireza Fotuhi
AU  - Lin, Yupei
AU  - Ni, Zheng
AU  - Chen, Jiawen
AU  - You, Jing
AU  - Keles, Sunduz
AU  - Wang, Daifeng
AU  - Roy, Sushmita
AU  - Lu, Qiongshi
TI  - Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
AID  - 10.1101/835678
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 835678
4099  - http://biorxiv.org/content/early/2019/11/15/835678.short
4100  - http://biorxiv.org/content/early/2019/11/15/835678.full
AB  - 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 (TF) mainly expressed in developmental brain. TF targets regulated by POU3F2 showed a 2.1-fold enrichment for known ASD genes (p=4.6e-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 clear example of the connection between ASD genes affected by very rare mutations and an unlinked key regulator affected by common genetic variations.