TY - JOUR T1 - Regional Collapsing of Rare Variation Implicates Specific Genic Regions in ALS JF - bioRxiv DO - 10.1101/375774 SP - 375774 AU - Sahar Gelfman AU - Sarah Dugger AU - Cristiane de Araujo Martins Moreno AU - Zhong Ren AU - Charles J. Wolock AU - Neil A. Shneider AU - Hemali Phatnani AU - Elizabeth T. Cirulli AU - Brittany N. Lasseigne AU - Tim Harris AU - Tom Maniatis AU - Guy A. Rouleau AU - Robert H. Brown, Jr. AU - Aaron D. Gitler AU - Richard M. Myers AU - Slavé Petrovski AU - Andrew Allen AU - Matthew B. Harms AU - David B. Goldstein Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/07/24/375774.abstract N2 - 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. ER -