Paternally inherited cis-regulatory structural variants are associated with autism.
Por:
Brandler WM, Antaki D, Gujral M, Kleiber ML, Whitney J, Maile MS, Hong O, Chapman TR, Tan S, Tandon P, Pang T, Tang SC, Vaux KK, Yang Y, Harrington E, Juul S, Turner DJ, Thiruvahindrapuram B, Kaur G, Wang Z, Kingsmore SF, Gleeson JG, Bisson D, Kakaradov B, Telenti A, Venter JC, Corominas R, Toma C, Cormand B, Rueda I, Guijarro S, Messer KS, Nievergelt CM, Arranz MJ, Courchesne E, Pierce K, Muotri AR, Iakoucheva LM, Hervás A, Scherer SW, Corsello C and Sebat J
Publicada:
20 abr 2018
Resumen:
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.
Filiaciones:
Brandler WM:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Human Longevity, Inc., San Diego, CA 92121, USA
Antaki D:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA
Gujral M:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Kleiber ML:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Whitney J:
The Centre for Applied Genomics, Genetics, and Genome Biology, The Hospital for Sick Children, Toronto, Canada
Maile MS:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Hong O:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Chapman TR:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Tan S:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Tandon P:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Pang T:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Rady Children's Hospital, San Diego, CA 92123, USA
Tang SC:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA
Rady Children's Hospital, San Diego, CA 92123, USA
Vaux KK:
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
Yang Y:
Oxford Nanopore Technologies, Inc., NY 10013, USA
Harrington E:
Oxford Nanopore Technologies, Inc., NY 10013, USA
Juul S:
Oxford Nanopore Technologies, Inc., NY 10013, USA
Turner DJ:
Oxford Nanopore Technologies Ltd., Oxford, UK
Thiruvahindrapuram B:
The Centre for Applied Genomics, Genetics, and Genome Biology, The Hospital for Sick Children, Toronto, Canada
Kaur G:
The Centre for Applied Genomics, Genetics, and Genome Biology, The Hospital for Sick Children, Toronto, Canada
Wang Z:
The Centre for Applied Genomics, Genetics, and Genome Biology, The Hospital for Sick Children, Toronto, Canada
Kingsmore SF:
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA
Gleeson JG:
Howard Hughes Medical Institute, Rady Children's Institute of Genomic Medicine, Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA
Bisson D:
Human Longevity, Inc., San Diego, CA 92121, USA
Kakaradov B:
Human Longevity, Inc., San Diego, CA 92121, USA
Telenti A:
Human Longevity, Inc., San Diego, CA 92121, USA
Venter JC:
Human Longevity, Inc., San Diego, CA 92121, USA
J. Craig Venter Institute, La Jolla, CA 92037, USA
Corominas R:
Genetics Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
Toma C:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Catalonia, Spain
Neuroscience Research Australia, Sydney, Australia
School of Medical Sciences, University of New South Wales, Sydney, Australia
Cormand B:
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Catalonia, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Catalonia, Spain
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues, Catalonia, Spain
Rueda I:
Department of Psychiatry, Hospital Sant Joan de Déu, Barcelona, Spain
Guijarro S:
Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
Messer KS:
Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA 92093, USA
Nievergelt CM:
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Arranz MJ:
Research Laboratory Unit, Fundacio Docencia I Recerca Mutua Terrassa, Barcelona, Spain
Courchesne E:
Autism Center of Excellence, Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA
Pierce K:
Autism Center of Excellence, Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA
Muotri AR:
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Iakoucheva LM:
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Hervás A:
Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
Scherer SW:
The Centre for Applied Genomics, Genetics, and Genome Biology, The Hospital for Sick Children, Toronto, Canada
Department of Molecular Genetics, University of Toronto, Toronto, Canada
McLaughlin Centre, University of Toronto, Toronto, Canada
Corsello C:
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Rady Children's Hospital, San Diego, CA 92123, USA
Sebat J:
Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA 92093, USA.
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
Open Access
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