Genome-Wide and Transcriptome-Wide Association Studies on Northern New England and Ohio Amyotrophic Lateral Sclerosis Cohorts

Siting Li; Jiang Gui; Michael N Passarelli; Angeline S Andrew; Kathleen M Sullivan; Kevin A Cornell; Bryan J Traynor; Ali Stark; Ruth Chia; Rebecca M Kuenzler; Erik P Pioro; Walter G Bradley; Elijah W Stommel

doi:10.1212/NXG.0000000000200188

Genome-Wide and Transcriptome-Wide Association Studies on Northern New England and Ohio Amyotrophic Lateral Sclerosis Cohorts

Neurol Genet. 2024 Sep 6;10(5):e200188. doi: 10.1212/NXG.0000000000200188. eCollection 2024 Oct.

Affiliation

¹ From the Departments of Biomedical Data Science (S.L., J.G.), Epidemiology (S.L., M.N.P.), and Neurology, Geisel School of Medicine at Dartmouth (E.W.S.), Dartmouth College, Hanover; Dartmouth Health (A.S.A., K.M.S., K.A.C., E.W.S.), Lebanon, NH; Neuromuscular Diseases Research Section (B.J.T., A.S., R.C.), National Institute on Aging; National Institute of Neurological Disorders and Stroke (B.J.T.), National Institutes of Health, Bethesda; RNA Therapeutics Laboratory (B.J.T.), National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD; Cleveland Clinic (R.M.K.), OH; Department of Medicine (E.P.P.), University of British Columbia, Vancouver, BC, Canada; and University of Miami Miller School of Medicine (W.G.B.), FL.

Abstract

Background and objectives: Amyotrophic lateral sclerosis (ALS) is an age-associated, fatal neurodegenerative disorder causing progressive paralysis and respiratory failure. The genetic architecture of ALS is still largely unknown.

Methods: We performed a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) to understand genetic risk factors for ALS using a population-based case-control study of 435 ALS cases and 279 controls from Northern New England and Ohio. Single nucleotide polymorphism (SNP) genotyping was conducted using the Illumina NeuroChip array. Odds ratios were estimated using covariate-adjusted logistic regression. We also performed a genome-wide SNP-smoking interaction screening. TWAS analyses used PrediXcan to estimate associations between predicted gene expression levels across 15 tissues (13 brain tissues, skeletal muscle, and whole blood) and ALS risk.

Results: GWAS analyses identified the p.A382T missense variant (rs367543041, p = 3.95E-6) in the TARDBP gene, which has previously been reported in association with increased ALS risk and was found to share a close affinity with the Sardinian haplotype. Both GWAS and TWAS analyses suggested that ZNF235 is associated with decreased ALS risk.

Discussion: Our results support the need for future evaluation to clarify the role of these potential genetic risk factors for ALS and to understand genetic susceptibility to environmental risk factors.