Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder - PubMed (original) (raw)

Comparative Study

doi: 10.1038/ng.2980. Epub 2014 May 25.

Kristiina Tammimies 2, Giovanna Pellecchia 1, Babak Alipanahi 3, Pingzhao Hu 1, Zhuozhi Wang 1, Dalila Pinto 4, Lynette Lau 1, Thomas Nalpathamkalam 1, Christian R Marshall 5, Benjamin J Blencowe 6, Brendan J Frey 7, Daniele Merico 1, Ryan K C Yuen 1, Stephen W Scherer 8

Affiliations

• PMID: 24859339
• DOI: 10.1038/ng.2980

Comparative Study

Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder

Mohammed Uddin et al. Nat Genet. 2014 Jul.

Abstract

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.

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References

1. 1. Nature. 2012 Apr 04;485(7397):242-5 - PubMed
2. 1. Cell. 2013 Nov 21;155(5):1008-21 - PubMed
3. 1. PLoS Genet. 2013;9(8):e1003709 - PubMed
4. 1. Hum Mol Genet. 2012 Nov 1;21(21):4781-92 - PubMed
5. 1. Nat Methods. 2010 Dec;7(12):1009-15 - PubMed

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