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

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

Siting Li  1 , Jiang Gui  1 , Michael N Passarelli  1 , Angeline S Andrew  1 , Kathleen M Sullivan  1 , Kevin A Cornell  1 , Bryan J Traynor  1 , Ali Stark  1 , Ruth Chia  1 , Rebecca M Kuenzler  1 , Erik P Pioro  1 , Walter G Bradley  1 , Elijah W Stommel  1
Affiliations

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

Siting Li et al. Neurol Genet. .

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.

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Conflict of interest statement

B. J. Traynor holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Go to Neurology.org/NG for full disclosures.

Figures

Figure 1
Figure 1. Manhattan Plot for SNPs in Northern New England and Ohio ALS Cohort
The dashed line in blue indicates the significance threshold of 5E-8, and the line in red indicates the threshold of 1E-5. Twelve loci passed the suggestive significance threshold of 1E-5.
Figure 2
Figure 2. Manhattan Plot for SNP-Smoking Interactions in Northern New England and Ohio ALS Cohort
The dashed line in blue indicates the significance threshold of 5E-8, and the line in red indicates the threshold of 1E-5. Seven loci passed the suggestive significance threshold of 1E-5.
See this image and copyright information in PMC

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