肌萎缩侧索硬化症与帕金森病的共享遗传学和共病基因。

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

机构信息

Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.

Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.

出版信息

Mov Disord. 2023 Oct;38(10):1813-1821. doi: 10.1002/mds.29572. Epub 2023 Aug 3.

DOI:10.1002/mds.29572

PMID:37534731

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 = 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 ). 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.

摘要

背景

肌萎缩侧索硬化症（ALS）和帕金森病（PD）之间存在共病，但遗传因素的作用尚不清楚。

目的

我们旨在研究 ALS 和 PD 之间的遗传相关性、因果关系和共病基因。

方法

利用最大的全基因组关联研究数据（ALS：27205 例，110881 例对照；PDG：33674 例，449056 例对照），我们使用连锁不平衡评分回归和孟德尔随机化分析进行遗传相关性和因果推断。我们通过多性状全基因组关联研究的全基因组交叉性状分析和跨表型关联来识别特定的单核苷酸多态性，然后进行功能映射和注释。整合来自 13 个大脑区域的表达数量性状基因座数据，我们通过基于功能汇总的内插和联合组织内插进行全转录组关联研究，以探索共病基因，然后进行途径富集分析。

结果

我们发现 PD 与 ALS 呈正相关（r=0.144，P=0.026），并具有因果效应（比值比=1.09，95%置信区间：1.03-1.15，P=3.00×10-3）。我们鉴定了九个单核苷酸多态性（八个新的），与三个风险位点（染色体 4、10 和 17）和七个基因（TMEM175、MAPT、NSF、LRRC37A2、ARHGAP27、GAK 和 FGFRL1）相关。在全转录组关联研究分析中，我们显示了六个以前未报道的多效性基因（KANSL1、ARL17B、EFNA1、WNT3、ERCC8 和 ADAM15），并且我们发现这些候选基因主要富集在神经元投射发育的负调控（GO：0010977）。