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Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples

Jack A. Kosmicki, Kaitlin E. Samocha, Daniel P. Howrigan, Stephan J. Sanders, Kamil Slowikowski, Monkol Lek, Konrad J. Karczewski, David J. Cutler, Bernie Devlin, Kathryn Roeder, Joseph D. Buxbaum, Benjamin M. Neale, Daniel G. MacArthur, Dennis P. Wall, Elise Robinson, Mark J. Daly
doi: https://doi.org/10.1101/052886
Jack A. Kosmicki
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
4Program in Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA 02138, USA
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Kaitlin E. Samocha
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
3Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
5Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02446, USA
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Daniel P. Howrigan
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
3Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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Stephan J. Sanders
6Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA
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Kamil Slowikowski
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA
4Program in Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA 02138, USA
7Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02446, USA
8Partners Center for Personalized Genetic Medicine, Boston, MA 02446, USA
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Monkol Lek
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA
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Konrad J. Karczewski
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA
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David J. Cutler
9Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
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Bernie Devlin
10Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 1513, USA
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Kathryn Roeder
11Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Joseph D. Buxbaum
12Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
17Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Benjamin M. Neale
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
3Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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Daniel G. MacArthur
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA
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Dennis P. Wall
18Department of Pediatrics and Psychiatry (by courtesy), Division of Systems Medicine, Stanford University, CA, 94305, USA
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Elise Robinson
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
3Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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Mark J. Daly
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
3Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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Abstract

Recent research has established the significant role of newly arising (de novo) variation in neurodevelopmental disorders. Using aggregated data from 5603 families affected by ASD, intellectual disability (ID), or developmental delay (DD), we show that overall ~1/3 of de novo variants are independently observed as standing variation in the Exome Aggregation Consortium’s (ExAC) cohort of 60,706 adults without severe neurodevelopmental disease, and that these de novo variants do not contribute substantively to neurodevelopmental risk. We further use a loss-of-function intolerance metric derived from ExAC to identify a small subset of genes that contain the entire signal of associated de novo protein truncating variants (PTVs) in neurodevelopmental disorders (ASD: rate ratio (RR) = 3.24, P < 10−16; ID/DD: RR = 6.70, P < 10−38). These same genes carry a moderate excess of PTVs inherited by individuals with ASD from their unaffected parents (RR = 1.16, P = 0.00985), and a larger excess in 404 ASD cases and 3654 controls (OR = 2.66; P = 6.34 × 10−19), with again no association seen outside these genes. These findings illustrate the importance of population-based cohorts as reference samples for the interpretation of candidate pathogenic variants, even for the analysis of de novo variation.

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Posted May 12, 2016.
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Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples
Jack A. Kosmicki, Kaitlin E. Samocha, Daniel P. Howrigan, Stephan J. Sanders, Kamil Slowikowski, Monkol Lek, Konrad J. Karczewski, David J. Cutler, Bernie Devlin, Kathryn Roeder, Joseph D. Buxbaum, Benjamin M. Neale, Daniel G. MacArthur, Dennis P. Wall, Elise Robinson, Mark J. Daly
bioRxiv 052886; doi: https://doi.org/10.1101/052886
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Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples
Jack A. Kosmicki, Kaitlin E. Samocha, Daniel P. Howrigan, Stephan J. Sanders, Kamil Slowikowski, Monkol Lek, Konrad J. Karczewski, David J. Cutler, Bernie Devlin, Kathryn Roeder, Joseph D. Buxbaum, Benjamin M. Neale, Daniel G. MacArthur, Dennis P. Wall, Elise Robinson, Mark J. Daly
bioRxiv 052886; doi: https://doi.org/10.1101/052886

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