Paternally inherited cis-regulatory structural variants are associated with autism

William M Brandler; Danny Antaki; Madhusudan Gujral; Morgan L Kleiber; Joe Whitney; Michelle S Maile; Oanh Hong; Timothy R Chapman; Shirley Tan; Prateek Tandon; Timothy Pang; Shih C Tang; Keith K Vaux; Yan Yang; Eoghan Harrington; Sissel Juul; Daniel J Turner; Bhooma Thiruvahindrapuram; Gaganjot Kaur; Zhuozhi Wang; Stephen F Kingsmore; Joseph G Gleeson; Denis Bisson; Boyko Kakaradov; Amalio Telenti; J Craig Venter; Roser Corominas; Claudio Toma; Bru Cormand; Isabel Rueda; Silvina Guijarro; Karen S Messer; Caroline M Nievergelt; Maria J Arranz; Eric Courchesne; Karen Pierce; Alysson R Muotri; Lilia M Iakoucheva; Amaia Hervas; Stephen W Scherer; Christina Corsello; Jonathan Sebat

doi:10.1126/science.aan2261

Paternally inherited cis-regulatory structural variants are associated with autism

Science. 2018 Apr 20;360(6386):327-331. doi: 10.1126/science.aan2261.

Authors

William M Brandler^{1

2

3

4}, Danny Antaki^{1

2

3

5}, Madhusudan Gujral^{1

2

3}, Morgan L Kleiber^{1

2

3}, Joe Whitney⁶, Michelle S Maile^{1

2

3}, Oanh Hong^{1

2

3}, Timothy R Chapman^{1

2

3}, Shirley Tan^{1

2

3}, Prateek Tandon^{1

2

3}, Timothy Pang^{1

7}, Shih C Tang^{1

7}, Keith K Vaux⁸, Yan Yang⁹, Eoghan Harrington⁹, Sissel Juul⁹, Daniel J Turner¹⁰, Bhooma Thiruvahindrapuram⁶, Gaganjot Kaur⁶, Zhuozhi Wang⁶, Stephen F Kingsmore¹¹, Joseph G Gleeson¹², Denis Bisson⁴, Boyko Kakaradov⁴, Amalio Telenti⁴, J Craig Venter^{4

13}, Roser Corominas^{14

15}, Claudio Toma^{16

17

18}, Bru Cormand^{15

16

19

20}, Isabel Rueda²¹, Silvina Guijarro²², Karen S Messer²³, Caroline M Nievergelt², Maria J Arranz²⁴, Eric Courchesne²⁵, Karen Pierce²⁵, Alysson R Muotri³, Lilia M Iakoucheva², Amaia Hervas²², Stephen W Scherer^{6

26

27}, Christina Corsello^{2

7}, Jonathan Sebat^{28

2

3}

Affiliations

¹ Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA.
² Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
³ Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
⁴ Human Longevity, Inc., San Diego, CA 92121, USA.
⁵ Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA.
⁶ The Centre for Applied Genomics, Genetics, and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
⁷ Rady Children's Hospital, San Diego, CA 92123, USA.
⁸ Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁹ Oxford Nanopore Technologies, Inc., NY 10013, USA.
¹⁰ Oxford Nanopore Technologies Ltd., Oxford, UK.
¹¹ Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
¹² Howard Hughes Medical Institute, Rady Children's Institute of Genomic Medicine, Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA.
¹³ J. Craig Venter Institute, La Jolla, CA 92037, USA.
¹⁴ Genetics Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
¹⁵ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
¹⁶ Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Catalonia, Spain.
¹⁷ Neuroscience Research Australia, Sydney, Australia.
¹⁸ School of Medical Sciences, University of New South Wales, Sydney, Australia.
¹⁹ Institut de Biomedicina de la Universitat de Barcelona (IBUB), Catalonia, Spain.
²⁰ Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues, Catalonia, Spain.
²¹ Department of Psychiatry, Hospital Sant Joan de Déu, Barcelona, Spain.
²² Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain.
²³ Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA 92093, USA.
²⁴ Research Laboratory Unit, Fundacio Docencia I Recerca Mutua Terrassa, Barcelona, Spain.
²⁵ Autism Center of Excellence, Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA.
²⁶ Department of Molecular Genetics, University of Toronto, Toronto, Canada.
²⁷ McLaughlin Centre, University of Toronto, Toronto, Canada.
²⁸ Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA. jsebat@ucsd.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Autism Spectrum Disorder / genetics*
Exons
Gene Expression Regulation
Genetic Predisposition to Disease*
Genetic Variation*
Genome, Human
Humans
Mutation
Paternal Inheritance*
Pedigree
Promoter Regions, Genetic / genetics*
RNA, Untranslated / genetics
Selection, Genetic
Sequence Deletion
Transcription Factors / genetics

Substances

LEO1 protein, human
RNA, Untranslated
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding