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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 B. 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
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA
3Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
4Program in Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA 02138, USA
5Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02446, 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
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, 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
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, 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 15213, 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
13Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
14Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
15Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
16Department of Genetics and Genomic Sciences, 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
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, 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
18Departments of Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry (by courtesy), Stanford University, CA, 94305, USA
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Elise B. Robinson
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
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
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA
3Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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Abstract

Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9246 families with autism spectrum disorder, intellectual disability, or developmental delay, we show ~1/3 of de novo variants are independently observed as standing variation in the Exome Aggregation Consortium’s cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further use a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes that contain the observed signal of associated de novo protein truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs; though the strongest de novo impacted genes contribute little to this, suggesting the excess of inherited risk resides lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.

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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 February 08, 2017.
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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 B. 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 B. Robinson, Mark J. Daly
bioRxiv 052886; doi: https://doi.org/10.1101/052886

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