Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.
| العنوان: | Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS. |
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| المؤلفون: | 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. |
| مؤلفون مشاركون: | New York Genome Center ALS Sequencing Consortium, Scottish Genomes Partnership, ALS COSMOS Study Group, PLS COSMOS Study Group, GTAC Investigators |
| المصدر: | Research square [Res Sq] 2023 Dec 21. Date of Electronic Publication: 2023 Dec 21. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101768035 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: Res Sq Subsets: PubMed not MEDLINE |
| مستخلص: | 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. |
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| معلومات مُعتمدة: | K01 MH098126 United States MH NIMH NIH HHS; RC2 MH089915 United States MH NIMH NIH HHS; P01 HD080642 United States HD NICHD NIH HHS; R01 MH097971 United States MH NIMH NIH HHS; RC2 NS070344 United States NS NINDS NIH HHS; UL1 TR000040 United States TR NCATS NIH HHS; UL1 TR001873 United States TR NCATS NIH HHS; UM1 AI100645 United States AI NIAID NIH HHS; P30 AG028377 United States AG NIA NIH HHS; U54 NS078059 United States NS NINDS NIH HHS; P01 AG007232 United States AG NIA NIH HHS; MC_PC_15080 United Kingdom MRC_ Medical Research Council; RF1 AG054023 United States AG NIA NIH HHS; R01 HD048805 United States HD NICHD NIH HHS; U01 HG007672 United States HG NHGRI NIH HHS; U01 NS053998 United States NS NINDS NIH HHS; U01 NS077303 United States NS NINDS NIH HHS; U19 AI067854 United States AI NIAID NIH HHS; R01 AG037212 United States AG NIA NIH HHS; R01 ES016348 United States ES NIEHS NIH HHS |
| فهرسة مساهمة: | Keywords: ALS; Amyotrophic lateral sclerosis; Burden testing; PLS; Rare-variant analyses; peripheral lateral sclerosis |
| تواريخ الأحداث: | Date Created: 20240110 Latest Revision: 20240306 |
| رمز التحديث: | 20240306 |
| مُعرف محوري في PubMed: | PMC10775375 |
| DOI: | 10.21203/rs.3.rs-3721598/v1 |
| PMID: | 38196621 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.21203/rs.3.rs-3721598/v1 |
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