Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.

Autor:	Pottinger TD; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Internal Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Motelow JE; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, United States of America., Povysil G; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Moreno CAM; Department of Neurology, School of Medicine, Universidade de São Paulo, São Paul, Brazil., Ren Z; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Phatnani H; Department of Neurology, Columbia University Irving Medical Center, New York, New York, United States of America.; Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, New York, United States of America.; New York Genome Center, New York, New York, United States of America., Aitman TJ; Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, Scotland., Santoyo-Lopez J; Edinburgh Genomics, University of Edinburgh, Edinburgh, Scotland., Mitsumoto H; Department of Neurology, Columbia University Irving Medical Center, New York, New York, United States of America., Goldstein DB; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Harms MB; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Neurology, Columbia University Irving Medical Center, New York, New York, United States of America.; Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, New York, United States of America.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Dec 21. Date of Electronic Publication: 2023 Dec 21.
DOI:	10.21203/rs.3.rs-3721598/v1
Abstrakt:	Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation. Methods: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS. Results: A gene based collapsing model showed significant associations with SOD1 , TARDBP , and TBK1 (OR=19.18, p = 3.67 × 10 -39 ; OR=4.73, p = 2 × 10 -10 ; OR=2.3, p = 7.49 × 10 -9 , respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10 -7 ), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 × 10 -16 ). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 × 10 -6 ). Conclusions: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3 . A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2 . Competing Interests: COMPETING INTERESTS The authors declare that they have no competing interests Additional Declarations: No competing interests reported.
Databáze:	MEDLINE
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