Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, 610041 China.
Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, 610041 China.
Neurobiol Aging. 2021 Jun;102:211.e1-211.e9. doi: 10.1016/j.neurobiolaging.2021.01.023. Epub 2021 Feb 3.
Epidemiological and clinical studies have suggested comorbidities between amyotrophic lateral sclerosis (ALS) and obesity-related traits. However, little is known about their shared genetic architecture. To examine whether genetic enrichment exists between ALS and obesity-related traits and to identify shared risk loci, we analyzed summary statistics from genome-wide association studies using the conditional false discovery rate statistical framework, and further conducted functional enrichment analysis. Robust genetic enrichment was observed for ALS conditional on body mass index, body fat percentage, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and type 2 diabetes. Nine shared genetic loci were identified, among which 6 were replicated in a second ALS cohort, including C9orf72, G2E3, SCFD1, ATXN3, CLCN3 and GGNBP2. We further identified GGNBP2 as a novel ALS risk gene, by integrating summary data-based Mendelian randomization analysis. Functional enrichment analysis indicated that the shared risk genes were involved in 2 pathways, namely membrane trafficking and vesicle-mediated transport. These results provide a better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.
流行病学和临床研究表明，肌萎缩侧索硬化症（ALS）和肥胖相关特征之间存在共病。然而，它们共同的遗传结构仍知之甚少。为了研究 ALS 和肥胖相关特征之间是否存在遗传富集，并确定共同的风险位点，我们使用条件错误发现率统计框架分析了全基因组关联研究的汇总统计数据，并进一步进行了功能富集分析。在 BMI、体脂肪百分比、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇和 2 型糖尿病条件下，观察到 ALS 存在稳健的遗传富集。确定了 9 个共同的遗传位点，其中 6 个在第二个 ALS 队列中得到了复制，包括 C9orf72、G2E3、SCFD1、ATXN3、CLCN3 和 GGNBP2。我们通过整合基于汇总数据的孟德尔随机化分析，进一步确定了 GGNBP2 是一个新的 ALS 风险基因。功能富集分析表明，共同的风险基因参与了 2 个途径，即膜转运和囊泡介导的运输。这些结果为 ALS 的多效性提供了更好的理解，并对未来的治疗试验具有启示意义。
