TY - JOUR
T1 - Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder
AU - Uddin, Mohammed
AU - Tammimies, Kristiina
AU - Pellecchia, Giovanna
AU - Alipanahi, Babak
AU - Hu, Pingzhao
AU - Wang, Zhuozhi
AU - Pinto, Dalila
AU - Lau, Lynette
AU - Nalpathamkalam, Thomas
AU - Marshall, Christian R.
AU - Blencowe, Benjamin J.
AU - Frey, Brendan J.
AU - Merico, Daniele
AU - Yuen, Ryan K.C.
AU - Scherer, Stephen W.
N1 - Funding Information:
and the Autism Genome Project for sharing data. We thank J. Buchanan for critical review and editing of the manuscript. This work was supported by grants from the University of Toronto McLaughlin Centre, NeuroDevNet, Genome Canada and the Ontario Genomics Institute (project 4445), the Canadian Institutes for Health Research (CIHR) (FRN 74527 and FRNXGG818), the Canadian Institute for Advanced Research, the Canada Foundation for Innovation, the government of Ontario (GL2-01-013), the Ontario Brain Institute and Autism Speaks. R.K.C.Y. holds an Autism Speaks Meixner Fellowship in Translational Research. K.T. holds a fellowship from the Swedish Research Council. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and the Hospital for Sick Children.
PY - 2014/7
Y1 - 2014/7
N2 - A universal challenge in genetic studies of autism spectrum disorders (ASDs) is determining whether a given DNA sequence alteration will manifest as disease. Among different population controls, we observed, for specific exons, an inverse correlation between exon expression level in brain and burden of rare missense mutations. For genes that harbor de novo mutations predicted to be deleterious, we found that specific critical exons were significantly enriched in individuals with ASD relative to their siblings without ASD (P < 1.13 × 10-38; odds ratio (OR) = 2.40). Furthermore, our analysis of genes with high exonic expression in brain and low burden of rare mutations demonstrated enrichment for known ASD-associated genes (P < 3.40 × 10-11; OR = 6.08) and ASD-relevant fragile-X protein targets (P < 2.91 × 10-157; OR = 9.52). Our results suggest that brain-expressed exons under purifying selection should be prioritized in genotype-phenotype studies for ASD and related neurodevelopmental conditions.
AB - A universal challenge in genetic studies of autism spectrum disorders (ASDs) is determining whether a given DNA sequence alteration will manifest as disease. Among different population controls, we observed, for specific exons, an inverse correlation between exon expression level in brain and burden of rare missense mutations. For genes that harbor de novo mutations predicted to be deleterious, we found that specific critical exons were significantly enriched in individuals with ASD relative to their siblings without ASD (P < 1.13 × 10-38; odds ratio (OR) = 2.40). Furthermore, our analysis of genes with high exonic expression in brain and low burden of rare mutations demonstrated enrichment for known ASD-associated genes (P < 3.40 × 10-11; OR = 6.08) and ASD-relevant fragile-X protein targets (P < 2.91 × 10-157; OR = 9.52). Our results suggest that brain-expressed exons under purifying selection should be prioritized in genotype-phenotype studies for ASD and related neurodevelopmental conditions.
UR - http://www.scopus.com/inward/record.url?scp=84903590570&partnerID=8YFLogxK
U2 - 10.1038/ng.2980
DO - 10.1038/ng.2980
M3 - Article
C2 - 24859339
AN - SCOPUS:84903590570
SN - 1061-4036
VL - 46
SP - 742
EP - 747
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -