Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease

遗传学 生物 退行性疾病 帕金森病 肌萎缩侧索硬化 物理医学与康复 神经科学 疾病 医学 病理
作者
Ye Tian,Guochen Ma,Haoqi Li,Yaxian Zeng,Siquan Zhou,Xiaoyu Wang,Shufang Shan,Yujie Xu,Jingyuan Xiong,Guo Cheng
出处
期刊:Movement Disorders [Wiley]
卷期号:38 (10): 1813-1821 被引量:14
标识
DOI:10.1002/mds.29572
摘要

Abstract Background Comorbidity exists between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), but the role of genetic factors is unclear. Objective We aim to investigate genetic correlation, causal relationship, and comorbid genes between ALS and PD. Methods Leveraging the largest genome‐wide association study data (ALS: 27,205 cases, 110,881 controls; PDG: 33,674 cases, 449,056 controls), we used linkage disequilibrium score regression and Mendelian randomization analysis for genetic correlation and causal inference. We performed genome‐wide cross‐trait analysis via Multi‐Trait Analysis of Genome‐Wide Association Studies and Cross‐Phenotype Association to identify specific single‐nucleotide polymorphisms, followed by functional mapping and annotation. Integrating expression quantitative trait loci data from 13 brain regions, we conducted a transcriptome‐wide association study via functional summary‐based imputation and joint‐tissue imputation to explore comorbid genes, followed by pathway enrichment analysis. Results We found that PD positively correlates with ALS ( r g = 0.144, P = 0.026) and confers a causal effect (odds ratio = 1.09, 95% confidence interval: 1.03–1.15, P = 3.00 × 10 −3 ). We identified nine single‐nucleotide polymorphisms (eight new), associating with three risk loci (chromosomes 4, 10, and 17) and seven genes ( TMEM175 , MAPT , NSF , LRRC37A2 , ARHGAP27 , GAK , and FGFRL1 ). In transcriptome‐wide association study analysis, we showed six previously unreported pleiotropic genes ( KANSL1 , ARL17B , EFNA1 , WNT3 , ERCC8 , and ADAM15 ), and we found these candidate genes are mainly enriched in negative regulation of neuron projection development (GO:0010977). Conclusions Our work demonstrates shared genetic architecture between ALS and PD, reports new pleiotropic genes, and sheds light on the comorbid mechanism. © 2023 International Parkinson and Movement Disorder Society.
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