Roughly 60-70% of familial and 10% of sporadic amyotrophic lateral sclerosis (ALS) cases have an identifiable disease-causing mutation, the majority of which involve C9ORF72 or SOD11. Recent efforts in gene discovery, largely driven by advances in sequencing and identification of rare variants, have implicated several new genes in ALS pathogenesis including TBK1, NEK1, ANXA11 and CCNF 2-10. Despite this progress, the majority of sporadic cases still do not have identifiable disease-causing mutations.
To address this gap, researchers developed two novel gene-collapsing strategies, one focuses on collapsing rare variation using homology-based protein domains and the other strategy incorporates signatures of purifying selection into a gene-level approach. The application of these two collapsing methods to sequencing data collected from over 6,000 ALS cases and almost 20,000 controls, pinpoints genetic regions associated with ALS disease risk within several genes, including SOD1, NEK1, TARDBP and FUS. These new approaches highlight the importance of a regional view in the study of ALS genetics
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bioRxiv preprint first posted online Jul. 24, 2018; doi: http://dx.doi.org/10.1101/375774.
