A new approach for rare variation collapsing on functional protein domains implicates specific genic regions in ALS

  1. Matthew B. Harms1,2,3,15
  1. 1Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, 10032, USA;
  2. 2Department of Neurology, Columbia University Irving Medical Center, New York, New York 10032, USA;
  3. 3Motor Neuron Center, Columbia University Irving Medical Center, New York, New York 10032, USA;
  4. 4New York Genome Center, New York, New York 10013, USA;
  5. 5Human Longevity, Incorporated, San Diego, California 92121, USA;
  6. 6HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA;
  7. 7SV Health Investors, Boston, Massachusetts 02108, USA;
  8. 8Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, New York 10032, USA;
  9. 9Department of Neurology and Neurosurgery, McGill University, Montreal, H3A 2B4 Canada;
  10. 10Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA;
  11. 11Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
  12. 12Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne VIC 3050, Australia;
  13. 13Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina 27708, USA;
  14. 14Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York 10032, USA

  1. ↵15 These authors contributed equally to this work.

  • Corresponding author: matthew.harms{at}columbia.edu

    • 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.

    Footnotes

    • Received September 11, 2018.
    • Accepted March 21, 2019.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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    This Article

    1. Published in Advance April 2, 2019, doi: 10.1101/gr.243592.118 Genome Res. 29: 809-818 © 2019 Gelfman et al.; Published by Cold Spring Harbor Laboratory Press

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    ORCID

    1. Profile for Gelfman, S.http://orcid.org/0000-0002-4727-7862

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