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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Gelfman, S; Dugger, S; de Araujo Martins Moreno, C; Ren, Z; Wolock, CJ; Shneider, NA; Phatnani, H; Cirulli, ET; Lasseigne, BN; Harris, T; Maniatis, T; Rouleau, GA; Brown, RH; Gitler, AD; Myers, RM; Petrovski, S; Allen, A; Goldstein, DB; Harms, MB

Published Date

  • May 2019

Published In

Volume / Issue

  • 29 / 5

Start / End Page

  • 809 - 818

PubMed ID

  • 30940688

Pubmed Central ID

  • PMC6499321

Electronic International Standard Serial Number (EISSN)

  • 1549-5469

Digital Object Identifier (DOI)

  • 10.1101/gr.243592.118


  • eng

Conference Location

  • United States