新英格兰北部和俄亥俄肌萎缩侧索硬化症队列的全基因组和转录组关联研究。
Genome-Wide and Transcriptome-Wide Association Studies on Northern New England and Ohio Amyotrophic Lateral Sclerosis Cohorts.
作者信息
Li Siting, Gui Jiang, Passarelli Michael N, Andrew Angeline S, Sullivan Kathleen M, Cornell Kevin A, Traynor Bryan J, Stark Ali, Chia Ruth, Kuenzler Rebecca M, Pioro Erik P, Bradley Walter G, Stommel Elijah W
机构信息
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.
出版信息
Neurol Genet. 2024 Sep 6;10(5):e200188. doi: 10.1212/NXG.0000000000200188. eCollection 2024 Oct.
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, = 3.95E-6) in the 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 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.
背景与目的
肌萎缩侧索硬化症（ALS）是一种与年龄相关的致命性神经退行性疾病，可导致进行性瘫痪和呼吸衰竭。ALS的遗传结构仍 largely未知。
方法
我们进行了一项全基因组关联研究（GWAS）和转录组全关联研究（TWAS），以了解ALS的遗传风险因素，该研究采用基于人群的病例对照研究，纳入了来自新英格兰北部和俄亥俄州的435例ALS病例和279例对照。使用Illumina NeuroChip阵列进行单核苷酸多态性（SNP）基因分型。使用协变量调整的逻辑回归估计优势比。我们还进行了全基因组SNP-吸烟相互作用筛查。TWAS分析使用PrediXcan来估计15种组织（13种脑组织、骨骼肌和全血）中预测基因表达水平与ALS风险之间的关联。
结果
GWAS分析在 基因中鉴定出p.A382T错义变体（rs367543041， = 3.95E-6），该变体先前已被报道与ALS风险增加相关，并发现与撒丁岛单倍型具有密切亲和力。GWAS和TWAS分析均表明 与ALS风险降低相关。
讨论
我们的结果支持未来进行评估的必要性，以阐明这些潜在的ALS遗传风险因素的作用，并了解对环境风险因素的遗传易感性。
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