Comparative Study

.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

Mohammed Uddin¹, Kristiina Tammimies², Giovanna Pellecchia¹, Babak Alipanahi³, Pingzhao Hu¹, Zhuozhi Wang¹, Dalila Pinto⁴, Lynette Lau¹, Thomas Nalpathamkalam¹, Christian R Marshall⁵, Benjamin J Blencowe⁶, Brendan J Frey⁷, Daniele Merico¹, Ryan K C Yuen¹, Stephen W Scherer⁸

Affiliations

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.

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.

.2014 Jul;46(7):742-7.

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

Authors

Affiliations

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.

PMID:24859339
DOI: 10.1038/ng.2980

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.

PubMed Disclaimer

Cited by

Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.
Lal D, Ruppert AK, Trucks H, Schulz H, de Kovel CG, Kasteleijn-Nolst Trenité D, Sonsma AC, Koeleman BP, Lindhout D, Weber YG, Lerche H, Kapser C, Schankin CJ, Kunz WS, Surges R, Elger CE, Gaus V, Schmitz B, Helbig I, Muhle H, Stephani U, Klein KM, Rosenow F, Neubauer BA, Reinthaler EM, Zimprich F, Feucht M, Møller RS, Hjalgrim H, De Jonghe P, Suls A, Lieb W, Franke A, Strauch K, Gieger C, Schurmann C, Schminke U, Nürnberg P; EPICURE Consortium; Sander T.Lal D, et al.PLoS Genet. 2015 May 7;11(5):e1005226. doi: 10.1371/journal.pgen.1005226. eCollection 2015 May.PLoS Genet. 2015.PMID:25950944Free PMC article.
Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder.
Krishnan A, Zhang R, Yao V, Theesfeld CL, Wong AK, Tadych A, Volfovsky N, Packer A, Lash A, Troyanskaya OG.Krishnan A, et al.Nat Neurosci. 2016 Nov;19(11):1454-1462. doi: 10.1038/nn.4353. Epub 2016 Aug 1.Nat Neurosci. 2016.PMID:27479844Free PMC article.
Fmrp targets or not: long, highly brain-expressed genes tend to be implicated in autism and brain disorders.
Ouwenga RL, Dougherty J.Ouwenga RL, et al.Mol Autism. 2015 Mar 11;6:16. doi: 10.1186/s13229-015-0008-1. eCollection 2015.Mol Autism. 2015.PMID:25789151Free PMC article.
TBR1 regulates autism risk genes in the developing neocortex.
Notwell JH, Heavner WE, Darbandi SF, Katzman S, McKenna WL, Ortiz-Londono CF, Tastad D, Eckler MJ, Rubenstein JL, McConnell SK, Chen B, Bejerano G.Notwell JH, et al.Genome Res. 2016 Aug;26(8):1013-22. doi: 10.1101/gr.203612.115. Epub 2016 Jun 20.Genome Res. 2016.PMID:27325115Free PMC article.
Copy Number Variation Analysis of Euploid Pregnancy Loss.
Gu C, Gao H, Li K, Dai X, Yang Z, Li R, Wen C, He Y.Gu C, et al.Front Genet. 2022 Mar 23;13:766492. doi: 10.3389/fgene.2022.766492. eCollection 2022.Front Genet. 2022.PMID:35401693Free PMC article.

See all "Cited by" articles

References

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

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Associated data

dbGaP/PHS000267.V4.P2

Related information

Grants and funding

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations

Movatterモバイル変換

Account

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Full text links

Actions

Share

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

Affiliations

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

Authors

Affiliations

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Associated data

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources