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Paternally inherited noncoding structural variants contribute to autism

William M. Brandler, Danny Antaki, Madhusudan Gujral, Morgan L. Kleiber, 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, Stephen F. Kingsmore, Joseph G. Gleeson, Boyko Kakaradov, Amalio Telenti, J Craig Venter, Roser Corominas, Bru Cormand, Isabel Rueda, Karen S. Messer, Caroline M. Nievergelt, Maria J. Arranz, Eric Courchesne, Karen Pierce, Alysson R. Muotri, Lilia M. Iakoucheva, Amaia Hervas, Christina Corsello, Jonathan Sebat
doi: https://doi.org/10.1101/102327
William M. Brandler
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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Danny Antaki
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
4Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, 92093 USA.
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Madhusudan Gujral
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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Morgan L. Kleiber
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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Michelle S. Maile
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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Oanh Hong
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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Timothy R. Chapman
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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Shirley Tan
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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Prateek Tandon
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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Timothy Pang
5Rady Children’s Hospital, La Jolla, CA, 92123 USA.
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Shih C. Tang
5Rady Children’s Hospital, La Jolla, CA, 92123 USA.
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Keith K. Vaux
6Department of Medicine, University of California San Diego, La Jolla, CA, 92093 USA.
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Yan Yang
7Oxford Nanopore Technologies Inc., New York, NY, 10013 USA.
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Eoghan Harrington
7Oxford Nanopore Technologies Inc., New York, NY, 10013 USA.
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Sissel Juul
7Oxford Nanopore Technologies Inc., New York, NY, 10013 USA.
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Daniel J. Turner
8Oxford Nanopore Technologies Inc., Oxford, UK.
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Stephen F. Kingsmore
9Rady Children Institute for Genomic Medicine, Rady Children Hospital, San Diego, CA, 92123 USA.
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Joseph G. Gleeson
10Howard Hughes Medical Institute, Rady Children Institute of Genomic Medicine, Department of Neurosciences, University of California San Diego, San Diego, CA, 92093 USA.
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Boyko Kakaradov
9Rady Children Institute for Genomic Medicine, Rady Children Hospital, San Diego, CA, 92123 USA.
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Amalio Telenti
11Human Longevity Inc., San Diego, CA, 92121 USA.
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J Craig Venter
11Human Longevity Inc., San Diego, CA, 92121 USA.
12J. Craig Venter Institute, La Jolla, CA, 92037 USA.
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Roser Corominas
13Genetics Research Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
14Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
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Bru Cormand
14Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
15Institut de Biomedicina de la Universitat de Barcelona (IBUB), Catalonia, Spain.
16Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Catalonia, Spain.
17Institut de Recerca Sant Joan de Dèu (IR-SJD), Espluges, Catalonia, Spain.
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Isabel Rueda
18Department of Psychiatry, Hospital Sant Joan de Deu, Barcelona, Spain.
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Karen S. Messer
19Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA, 92093 USA.
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Caroline M. Nievergelt
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
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Maria J. Arranz
20Research Laboratory Unit, Fundacio Docencia I Recerca Mútua Terrassa, Barcelona, Spain.
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Eric Courchesne
21Department of Neuroscience, University of California San Diego, La Jolla, CA, 92093 USA.
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Karen Pierce
21Department of Neuroscience, University of California San Diego, La Jolla, CA, 92093 USA.
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Alysson R. Muotri
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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Lilia M. Iakoucheva
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
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Amaia Hervas
22Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain.
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Christina Corsello
5Rady Children’s Hospital, La Jolla, CA, 92123 USA.
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Jonathan Sebat
1Beyster Center for Genomics of Psychiatric Diseases, University of California San Diego, La Jolla, CA, 92093 USA.
2Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093 USA.
3Department of Cellular and Molecular Medicine and Pediatrics, University of California San Diego, La Jolla, CA, 92093 USA.
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  • For correspondence: jsebat@ucsd.edu
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Abstract

The genetic architecture of autism spectrum disorder (ASD) is known to consist of contributions from gene-disrupting de novo mutations and common variants of modest effect. We hypothesize that the unexplained heritability of ASD also includes rare inherited variants with intermediate effects. We investigated the genome-wide distribution and functional impact of structural variants (SVs) through whole genome analysis (≥30X coverage) of 3,169 subjects from 829 families affected by ASD. Genes that are intolerant to inactivating variants in the exome aggregation consortium (ExAC) were depleted for SVs in parents, specifically within fetal-brain promoters, UTRs and exons. Rare paternally-inherited SVs that disrupt promoters or UTRs were over-transmitted to probands (P = 0.0013) and not to their typically-developing siblings. Recurrent functional noncoding deletions implicate the gene LEO1 in ASD. Protein-coding SVs were also associated with ASD (P = 0.0025). Our results establish that rare inherited SVs predispose children to ASD, with differing contributions from each parent.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 27, 2017.
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Paternally inherited noncoding structural variants contribute to autism
William M. Brandler, Danny Antaki, Madhusudan Gujral, Morgan L. Kleiber, 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, Stephen F. Kingsmore, Joseph G. Gleeson, Boyko Kakaradov, Amalio Telenti, J Craig Venter, Roser Corominas, Bru Cormand, Isabel Rueda, Karen S. Messer, Caroline M. Nievergelt, Maria J. Arranz, Eric Courchesne, Karen Pierce, Alysson R. Muotri, Lilia M. Iakoucheva, Amaia Hervas, Christina Corsello, Jonathan Sebat
bioRxiv 102327; doi: https://doi.org/10.1101/102327
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Paternally inherited noncoding structural variants contribute to autism
William M. Brandler, Danny Antaki, Madhusudan Gujral, Morgan L. Kleiber, 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, Stephen F. Kingsmore, Joseph G. Gleeson, Boyko Kakaradov, Amalio Telenti, J Craig Venter, Roser Corominas, Bru Cormand, Isabel Rueda, Karen S. Messer, Caroline M. Nievergelt, Maria J. Arranz, Eric Courchesne, Karen Pierce, Alysson R. Muotri, Lilia M. Iakoucheva, Amaia Hervas, Christina Corsello, Jonathan Sebat
bioRxiv 102327; doi: https://doi.org/10.1101/102327

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