Li Chun Yu, Yang Tian Mi, Ou Ru Wei, Wei Qian Qian, Shang Hui Fang
Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, China.
BMC Med. 2021 Feb 5;19(1):27. doi: 10.1186/s12916-021-01903-y.
Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders. However, little is known about their shared genetic architecture.
To examine the relation between ALS and 10 autoimmune diseases, including asthma, celiac disease (CeD), Crohn's disease (CD), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and ulcerative colitis (UC), and identify shared risk loci, we first estimated the genetic correlation using summary statistics from genome-wide association studies, and then analyzed the genetic enrichment leveraging the conditional false discovery rate statistical method.
We identified a significant positive genetic correlation between ALS and CeD, MS, RA, and SLE, as well as a significant negative genetic correlation between ALS and IBD, UC, and CD. Robust genetic enrichment was observed between ALS and CeD and MS, and moderate enrichment was found between ALS and UC and T1D. Thirteen shared genetic loci were identified, among which five were suggestively significant in another ALS GWAS, namely rs3828599 (GPX3), rs3849943 (C9orf72), rs7154847 (G2E3), rs6571361 (SCFD1), and rs9903355 (GGNBP2). By integrating cis-expression quantitative trait loci analyses in Braineac and GTEx, we further identified GGNBP2, ATXN3, and SLC9A8 as novel ALS risk genes. Functional enrichment analysis indicated that the shared risk genes were involved in four pathways including membrane trafficking, vesicle-mediated transport, ER to Golgi anterograde transport, and transport to the Golgi and subsequent modification.
Our findings demonstrate a specific genetic correlation between ALS and autoimmune diseases and identify shared risk loci, including three novel ALS risk genes. 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）与自身免疫性疾病之间存在共病现象。然而，对于它们共同的遗传结构知之甚少。
为了研究ALS与10种自身免疫性疾病之间的关系，包括哮喘、乳糜泻（CeD）、克罗恩病（CD）、炎症性肠病（IBD）、多发性硬化症（MS）、银屑病、类风湿性关节炎（RA）、系统性红斑狼疮（SLE）、1型糖尿病（T1D）和溃疡性结肠炎（UC），并确定共同的风险基因座，我们首先使用全基因组关联研究的汇总统计数据估计遗传相关性，然后利用条件错误发现率统计方法分析遗传富集情况。
我们发现ALS与CeD、MS、RA和SLE之间存在显著的正遗传相关性，而ALS与IBD、UC和CD之间存在显著的负遗传相关性。在ALS与CeD和MS之间观察到强大的遗传富集，在ALS与UC和T1D之间发现中等程度的富集。确定了13个共同的遗传基因座，其中5个在另一项ALS全基因组关联研究中具有提示性意义，即rs3828599（GPX3）、rs3849943（C9orf72）、rs7154847（G2E3）、rs6571361（SCFD1）和rs9903355（GGNBP2）。通过整合Braineac和GTEx中的顺式表达定量性状基因座分析，我们进一步确定GGNBP2、ATXN3和SLC9A8为新的ALS风险基因。功能富集分析表明，共同的风险基因涉及四个途径，包括膜运输、囊泡介导的运输、内质网到高尔基体的顺向运输以及向高尔基体的运输和随后的修饰。
我们的研究结果证明了ALS与自身免疫性疾病之间存在特定的遗传相关性，并确定了共同的风险基因座，包括三个新的ALS风险基因。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。
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