Paternally inherited cis-regulatory structural variants are associated with autism

被引：136

作者：

Brandler, William M. ^{[1
,2
,3
,4
]}

Antaki, Danny ^{[1
,2
,3
,5
]}

Gujral, Madhusudan ^{[1
,2
,3
]}

Kleiber, Morgan L. ^{[1
,2
,3
]}

Whitney, Joe ^{[6
]}

Maile, Michelle S. ^{[1
,2
,3
]}

Hong, Oanh ^{[1
,2
,3
]}

Chapman, Timothy R. ^{[1
,2
,3
]}

Tan, Shirley ^{[1
,2
,3
]}

Tandon, Prateek ^{[1
,2
,3
]}

Pang, Timothy ^{[1
,7
]}

Tang, Shih C. ^{[1
,7
]}

Vaux, Keith K. ^{[8
]}

Yang, Yan ^{[9
]}

Harrington, Eoghan ^{[9
]}

Juul, Sissel ^{[9
]}

Turner, Daniel J. ^{[10
]}

Thiruvahindrapuram, Bhooma ^{[6
]}

Kaur, Gaganjot ^{[6
]}

Wang, Zhuozhi ^{[6
]}

Kingsmore, Stephen F. ^{[11
]}

Gleeson, Joseph G. ^{[12
]}

Bisson, Denis ^{[4
]}

Kakaradov, Boyko ^{[4
]}

Telenti, Amalio ^{[4
]}

Venter, J. Craig ^{[4
,13
]}

Corominas, Roser ^{[14
,15
]}

Toma, Claudio ^{[16
,17
,18
]}

Cormand, Bru ^{[15
,16
,19
,20
]}

Rueda, Isabel ^{[21
]}

Guijarro, Silvina ^{[22
]}

Messer, Karen S. ^{[23
]}

Nievergelt, Caroline M. ^{[2
]}

Arranz, Maria J. ^{[24
]}

Courchesne, Eric ^{[25
]}

Pierce, Karen ^{[25
]}

Muotri, Alysson R. ^{[3
]}

Iakoucheva, Lilia M. ^{[2
]}

Hervas, Amaia ^{[22
]}

Scherer, Stephen W. ^{[6
,26
,27
]}

Corsello, Christina ^{[2
,7
]}

Sebat, Jonathan ^{[1
,2
,3
]}

机构：

[1] Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Cellular & Mol Med & Pediat, La Jolla, CA 92093 USA

[4] Human Longev Inc, San Diego, CA 92121 USA

[5] Univ Calif San Diego, Biomed Sci Grad Program, La Jolla, CA 92093 USA

[6] Hosp Sick Children, Ctr Appl Genom Genet & Genome Biol, Toronto, ON, Canada

[7] Rady Childrens Hosp, San Diego, CA 92123 USA

[8] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[9] Oxford Nanopore Technol Inc, New York, NY 10013 USA

[10] Oxford Nanopore Technol Ltd, Oxford, England

[11] Rady Childrens Hosp, Rady Childrens Inst Genom Med, San Diego, CA 92123 USA

[12] Univ Calif San Diego, Howard Hughes Med Inst, Rady Childrens Inst Genom Med, Dept Neurosci, La Jolla, CA 92093 USA

[13] J Craig Venter Inst, La Jolla, CA 92037 USA

[14] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Genet Unit, Barcelona, Spain

[15] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain

[16] Univ Barcelona, Fac Biol, Dept Genet Microbiol & Estat, Catalonia, Spain

[17] Neurosci Res Australia, Sydney, NSW, Australia

[18] Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia

[19] IBUB, Catalonia, Spain

[20] IR SJD, Esplugues, Catalonia, Spain

[21] Hosp St Joan Deu, Dept Psychiat, Barcelona, Spain

[22] Hosp Univ Mutua Terrassa, Child & Adolescent Mental Hlth Unit, Barcelona, Spain

[23] Univ Calif San Diego, Dept Family Med & Publ Hlth, Div Biostat & Bioinformat, La Jolla, CA 92093 USA

[24] Fdn Docencia Recerca Mutua Terrassa, Res Lab Unit, Barcelona, Spain

[25] Univ Calif San Diego, Dept Neurosci, Autism Ctr Excellence, La Jolla, CA 92093 USA

[26] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[27] Univ Toronto, McLaughlin Ctr, Toronto, ON, Canada

来源：

SCIENCE | 2018年 / 360卷 / 6386期

基金：

加拿大健康研究院; 欧盟地平线“2020”;

关键词：

DE-NOVO; SPECTRUM DISORDER; MUTATIONS; GENOME; ARCHITECTURE; GENES; TRANSCRIPTION; PATTERNS; RISK; RARE;

D O I：

10.1126/science.aan2261

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.

引用

页码：327 / 330

页数：4

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