A new approach for rare variation collapsing on functional protein domains implicates specific genic regions in ALS
- Sahar Gelfman1,11,
- Sarah A Dugger1,
- Cristiane Araujo Martins Moreno1,
- Zhong Ren1,
- Charles J Wolock1,
- Neil Shneider1,
- Hemali Phatnani2,
- Elizabeth T Cirulli3,
- Brittany N Lasseigne4,
- Timothy Harris5,
- Tom Maniatis1,
- Guy Rouleau6,
- Robert H Brown7,
- Aaron D Gitler8,
- Richard M Myers4,
- Slave Petrovski9,
- Andrew Allen10,
- David B Goldstein1 and
- Matthew B Harms1
- 1 Columbia University Medical Center;
- 2 New York Genome Center;
- 3 Human Longevity INC;
- 4 HudsonAlpha Institute for Biotechnology;
- 5 SV Health Investors;
- 6 McGill University;
- 7 University of Massachusetts Medical School;
- 8 Stanford University School of Medicine;
- 9 University of Melbourne;
- 10 Duke University
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.
- Received September 11, 2018.
- Accepted March 21, 2019.
- Published by Cold Spring Harbor Laboratory Press
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