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.
Funder
Clinical and Translational Science Awards TL1 Training Award
R.D. Wright Career Development Fellowship
National Health and Medical Research Council
Eleanor and Lou Gehrig ALS Center at Columbia University research fund
ALS Association, Greater New York Chapter of the ALS Association, and Biogen Idec
The ALS Association
The Tow Foundation
Publisher
Cold Spring Harbor Laboratory
Subject
Genetics (clinical),Genetics
Cited by
20 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献