Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
Autoři:
Kunling Huang aff001; Yuchang Wu aff002; Junha Shin aff002; Ye Zheng aff003; Alireza Fotuhi Siahpirani aff004; Yupei Lin aff005; Zheng Ni aff005; Jiawen Chen aff005; Jing You aff005; Sunduz Keles aff001; Daifeng Wang aff002; Sushmita Roy aff002; Qiongshi Lu aff001
Působiště autorů:
Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
aff001; Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
aff002; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
aff003; Department of Computer Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
aff004; University of Wisconsin-Madison, Madison, Wisconsin, United States of America
aff005; Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
aff006; Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
aff007
Vyšlo v časopise:
Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder. PLoS Genet 17(2): e1009309. doi:10.1371/journal.pgen.1009309
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009309
Souhrn
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.
Klíčová slova:
Autism spectrum disorder – Gene expression – Genetic loci – Genome-wide association studies – Hippocampus – Medical risk factors – Metaanalysis – Transcriptome analysis
Zdroje
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