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Science. 2018 Dec 14;362(6420). pii: eaat6576. doi: 10.1126/science.aat6576.

Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder.

Author information

1
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
2
Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
3
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
4
Department of Neurology, Harvard Medical School, Boston, MA, USA.
5
Program in Medical and Population Genetics and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
6
Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
7
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
8
Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
9
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
10
Institute for Human Genetics, University of California, San Francisco, CA, USA.
11
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
12
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
13
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
14
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15
Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA.
16
Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA.
17
Analytical and Translational Genetics Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
18
Department of Medicine, Harvard Medical School, Boston, MA, USA.
19
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA.
20
USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT, USA.
21
Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
22
Quantitative Biosciences Institute, University of California, San Francisco, CA, USA.
23
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. talkowski@chgr.mgh.harvard.edu devlinbj@upmc.edu roeder@andrew.cmu.edu stephan.sanders@ucsf.edu.
24
Departments of Pathology and Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
25
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. talkowski@chgr.mgh.harvard.edu devlinbj@upmc.edu roeder@andrew.cmu.edu stephan.sanders@ucsf.edu.
26
Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA. talkowski@chgr.mgh.harvard.edu devlinbj@upmc.edu roeder@andrew.cmu.edu stephan.sanders@ucsf.edu.
27
Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
28
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA. talkowski@chgr.mgh.harvard.edu devlinbj@upmc.edu roeder@andrew.cmu.edu stephan.sanders@ucsf.edu.

Abstract

Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.

PMID:
30545852
PMCID:
PMC6432922
DOI:
10.1126/science.aat6576
[Indexed for MEDLINE]
Free PMC Article

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