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Nat Genet. 2014 Jul;46(7):742-7. doi: 10.1038/ng.2980. Epub 2014 May 25.

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

Author information

1
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
2
1] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Center of Neurodevelopmental Disorders (KIND), Neuropsychiatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
3
Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada.
4
1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5
1] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
6
1] Donnelly Centre, University of Toronto, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
7
1] Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada. [2] Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
8
1] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada. [3] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

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.

PMID:
24859339
DOI:
10.1038/ng.2980
[Indexed for MEDLINE]
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