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Title: A new approach for rare variation collapsing on functional protein domains implicates specific genic regions in ALS.
Austin Authors: Gelfman, Sahar;Dugger, Sarah;de Araujo Martins Moreno, Cristiane;Ren, Zhong;Wolock, Charles J;Shneider, Neil A;Phatnani, Hemali;Cirulli, Elizabeth T;Lasseigne, Brittany N;Harris, Tim;Maniatis, Tom;Rouleau, Guy A;Brown, Robert H;Gitler, Aaron D;Myers, Richard M;Petrovski, Slavé;Allen, Andrew;Goldstein, David B;Harms, Matthew B
Affiliation: Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, 10032, USA
Department of Neurology, Columbia University Irving Medical Center, New York, New York 10032, USA
Motor Neuron Center, Columbia University Irving Medical Center, New York, New York 10032, USA
New York Genome Center, New York, New York 10013, USA
Human Longevity, Incorporated, San Diego, California 92121, USA
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA
SV Health Investors, Boston, Massachusetts 02108, USA
Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, New York 10032, USA
Department of Neurology and Neurosurgery, McGill University, Montreal, H3A 2B4 Canada
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne VIC 3050, Australia
Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina 27708, USA
Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York 10032, USA
Issue Date: May-2019 2019-04-02
Publication information: Genome research 2019; 29(5): 809-818
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 the other is a 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 3093 ALS cases and 8186 controls of European ancestry, and also 3239 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.
DOI: 10.1101/gr.243592.118
ORCID: 0000-0002-4727-7862
Journal: Genome research
PubMed URL: 30940688
Type: Journal Article
Appears in Collections:Journal articles

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