Abstract
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.
Highlights
Autism spectrum disorder (ASD [multiple neurodegenerative diseases including Alzheimer’s disease (MIM): 209850]) is a highly heritable neurodevelopmental disorder affecting 1.5% of the world population [1]
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
Summary
Autism spectrum disorder (ASD [MIM: 209850]) is a highly heritable neurodevelopmental disorder affecting 1.5% of the world population [1]. Whole-exome sequencing (WES) studies for ASD have identified numerous ultra-rare or de novo single-nucleotide variants, small insertions and deletions (indels), and copy number variants (CNVs) [3,4,5,6,7] These protein-disrupting genetic variations have large effects on the disease risk, they are only found in a moderate proportion of ASD probands. A recent GWAS meta-analysis of 18,381 ASD cases and 27,969 controls identified multiple genome-wide significant loci, but did not implicate apparent associations at ASD risk genes identified in WES studies [10] These results suggested that distinct mechanistic pathways may underlie the ASD risk attributed to rare and common genetic variants, but our understanding of their interplay remains incomplete
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