Abstract

Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people world‑ wide. 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 continue to develop, such as antisense oligonucleotides, 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 multi‑ethnic cohort of 6,970 ALS patients, 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 associ‑ ated 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, collapsing analyses 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.

Document Type

Article

Publication Date

2024

Notes/Citation Information

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom‑ mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Digital Object Identifier (DOI)

https://doi.org/10.1186/s12864-024-10538-1

Funding Information

he collection of ALS and PLS samples and data was funded in part by: The Scottish Genomes Partnership (Chief Scientist Office of the Scottish Govern‑ ment Health Directorates (SGP/1) and The Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080); The New York Genome Center ALS Consortium (ALS Association 15‑LGCA‑234, 19‑SI‑ 459, and the Tow Foundation; The GTAC study (ALS Association 16‑LGCA‑310 and Biogen Idec); ALS Exome Sequencing Consortium (Biogen Idec). Funding for the ALS 561 COSMOS and PLS COSMOS studies was provided by NIEHS R01ES016348, the Muscular 562 Dystrophy Association, MDA Wings Over Wall Street, Spastic Paraplegia Foundation (SPF), private 563 donations from Mr. and Mrs. Marren, the Adams Foundation, and Ride for Life. The collection of control samples and data was funded in part by: Bryan ADRC NIA P30 AG028377; NIH RO1 HD048805; Gilead Sciences, Inc.; D. Murdock; National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vac‑ cine Immunology (CHAVI) (U19‑AI067854); National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (UM1‑AI100645); Bill and Melinda Gates Foundation; NINDS Award# RC2NS070344; New York‑Presbyterian Hospital; The Columbia University College of Physicians and Surgeons; The Columbia University Medical Center; NIH U54 NS078059; NIH P01 HD080642; The J. Willard and Alice S. Marriott Foundation; The Muscular Dystrophy Association; The Nicholas Nunno Foundation; The JDM Fund for Mitochondrial Research; The Arturo Estopinan TK2 Research Fund; UCB; Epilepsy Genetics Initiative, A Signature Program of CURE; Epi4K Gene Discovery in Epilepsy study (NINDS U01‑NS077303) and The Epilepsy Genome/Phenome Project (EPGP ‑ NINDS U01‑NS053998); The Ellison Medical Foundation New Scholar award AG‑NS‑0441‑08; National Institute Of Mental Health of the National Institutes of Health under Award Number K01MH098126; B57 SAIC‑Fredrick Inc. M11‑074; OCD Rare 1R01MH097971‑ 01A1. This research was supported in part by funding from Funding from the Duke Chancellor’s Discovery Program Research Fund 2014; an American Academy of Child and Adolescent Psychiatry (AACAP) Pilot Research Award; NIMH Grant RC2MH089915; Endocrine Fellows Foundation Grant; The NIH Clinical and Translational Science Award Program (UL1TR000040); NIH U01HG007672; The Washington Heights Inwood Columbia Aging Project; The Stanley Institute for Cognitive Genomics at Cold Spring Harbor Laboratory and the Utah Foundation for Biomedical Research. Data collection and sharing for the WHICAP project (used as controls in this analysis) was supported by The Washington Heights–Inwood Columbia Aging Project (WHICAP, PO1AG07232, R01AG037212, RF1AG054023) funded by the National Institute on Aging (NIA) and by The National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873. This manuscript has been reviewed by WHICAP investigators for scientific content and consistency of data interpretation with previous WHICAP Study publications. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Download

Share

COinS