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

IF 3 3区医学 Q2 CLINICAL NEUROLOGY

Neurology-Genetics Pub Date : 2024-09-06 eCollection Date: 2024-10-01 DOI:10.1212/NXG.0000000000200188

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

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引用次数: 0

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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新英格兰北部和俄亥俄州肌萎缩侧索硬化症队列的全基因组和全转录组关联研究。

背景和目的：肌萎缩性脊髓侧索硬化症（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 的遗传结构在很大程度上仍然未知：方法：我们进行了一项全基因组关联研究（GWAS）和全转录组关联研究（TWAS），通过对来自新英格兰北部和俄亥俄州的 435 例 ALS 病例和 279 例对照进行基于人群的病例对照研究，了解 ALS 的遗传风险因素。使用 Illumina NeuroChip 阵列进行了单核苷酸多态性 (SNP) 基因分型。使用协变量调整的逻辑回归估算了比值比。我们还进行了全基因组 SNP 与吸烟相互作用筛选。TWAS分析使用PrediXcan估计了15种组织（13种脑组织、骨骼肌和全血）的预测基因表达水平与ALS风险之间的关联：GWAS分析发现了TARDBP基因中的p.A382T错义变异（rs367543041，p = 3.95E-6），该变异之前已被报道与ALS风险增加有关，并被发现与撒丁岛单倍型有密切的亲缘关系。GWAS 和 TWAS 分析表明，ZNF235 与 ALS 风险降低有关：我们的研究结果表明，今后有必要进行评估，以明确这些潜在的 ALS 遗传风险因素的作用，并了解环境风险因素的遗传易感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurology-Genetics Medicine-Neurology (clinical)

CiteScore

6.30

自引率

3.20%

发文量

107

审稿时长

15 weeks

期刊介绍： Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.