Regional collapsing of rare variation implicates specific genic regions in ALS

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 coll...

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Published inbioRxiv
Main Authors Gelfman, Sahar, Dugger, Sarah A, Cristiane Araujo Martins Moreno, 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, Slave, Allen, Andrew, Harms, Matthew B, Goldstein, David B
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 24.07.2018
Subjects
Amyotrophic lateral sclerosis
Genes
Homology
Nek1 protein
Superoxide dismutase
Variation
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Summary: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.
DOI:10.1101/375774