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Regional Collapsing of Rare Variation Implicates Specific Genic Regions in ALS

View ORCID ProfileSahar Gelfman, Sarah Dugger, Cristiane de Araujo Martins Moreno, Zhong Ren, Charles J. Wolock, Neil A. Shneider, Hemali Phatnani, Elizabeth T. Cirulli, Brittany N. Lasseigne, Tim Harris, Tom Maniatis, Guy A. Rouleau, Robert H. Brown Jr., Aaron D. Gitler, Richard M. Myers, Slavé Petrovski, Andrew Allen, Matthew B. Harms, David B. Goldstein
doi: https://doi.org/10.1101/375774
Sahar Gelfman
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA
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  • ORCID record for Sahar Gelfman
Sarah Dugger
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA
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Cristiane de Araujo Martins Moreno
Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032 USA
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Zhong Ren
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA
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Charles J. Wolock
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA
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Neil A. Shneider
Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032 USAMotor Neuron Center, Columbia University Irving Medical Center, New York, NY 10032 USA
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Hemali Phatnani
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USADepartment of Neurology, Columbia University Irving Medical Center, New York, NY 10032 USANew York Genome Center, New York, NY 10013 USA
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Elizabeth T. Cirulli
Human Longevity INC, San Diego, CA 92121 USA
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Brittany N. Lasseigne
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806 USA
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Tim Harris
SV Health Investors, Boston, MA 02108 USA
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Tom Maniatis
Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY 10032 USA
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Guy A. Rouleau
Department of Neurology and Neurosurgery, McGill University, Montreal, H3A 2B4 Canada
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Robert H. Brown
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655 USA
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Aaron D. Gitler
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA
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Richard M. Myers
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806 USA
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Slavé Petrovski
Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
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Andrew Allen
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27708, USA
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Matthew B. Harms
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USADepartment of Neurology, Columbia University Irving Medical Center, New York, NY 10032 USAMotor Neuron Center, Columbia University Irving Medical Center, New York, NY 10032 USA
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David B. Goldstein
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
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Abstract

Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies, one focuses rare variation collapsing on homology-based protein domains as the unit for collapsing and another gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3,093 ALS cases and 8,186 controls of European ancestry, and also 3,239 cases and 11,808 controls of diversified populations, pinpoints risk regions of ALS genes including SOD1, NEK1, TARDBP and FUS. While not clearly implicating novel ALS genes, the new analyses not only pinpoint risk regions in known genes but also highlight candidate genes as well.

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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 4.0 International license.
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Posted July 24, 2018.
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Regional Collapsing of Rare Variation Implicates Specific Genic Regions in ALS
Sahar Gelfman, Sarah Dugger, Cristiane de Araujo Martins Moreno, Zhong Ren, Charles J. Wolock, Neil A. Shneider, Hemali Phatnani, Elizabeth T. Cirulli, Brittany N. Lasseigne, Tim Harris, Tom Maniatis, Guy A. Rouleau, Robert H. Brown Jr., Aaron D. Gitler, Richard M. Myers, Slavé Petrovski, Andrew Allen, Matthew B. Harms, David B. Goldstein
bioRxiv 375774; doi: https://doi.org/10.1101/375774
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Regional Collapsing of Rare Variation Implicates Specific Genic Regions in ALS
Sahar Gelfman, Sarah Dugger, Cristiane de Araujo Martins Moreno, Zhong Ren, Charles J. Wolock, Neil A. Shneider, Hemali Phatnani, Elizabeth T. Cirulli, Brittany N. Lasseigne, Tim Harris, Tom Maniatis, Guy A. Rouleau, Robert H. Brown Jr., Aaron D. Gitler, Richard M. Myers, Slavé Petrovski, Andrew Allen, Matthew B. Harms, David B. Goldstein
bioRxiv 375774; doi: https://doi.org/10.1101/375774

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