scholarly journals C9orf72andUNC13Aare shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: A genome-wide meta-analysis

2014 ◽  
Vol 76 (1) ◽  
pp. 120-133 ◽  
Author(s):  
Frank P. Diekstra ◽  
Vivianna M. Van Deerlin ◽  
John C. van Swieten ◽  
Ammar Al-Chalabi ◽  
Albert C. Ludolph ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Meta Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Shared Risk ◽  
Lateral Sclerosis

scholarly journals A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ryoichi Nakamura ◽  
Kazuharu Misawa ◽  
Genki Tohnai ◽  
Masahiro Nakatochi ◽  
Sho Furuhashi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
European Ancestry ◽  
Japanese Cohort ◽  
Genome Wide ◽  
Sporadic Als ◽  
A Genome ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

scholarly journals Genome-wide genetic links between amyotrophic lateral sclerosis and autoimmune diseases

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chun Yu Li ◽  
Tian Mi Yang ◽  
Ru Wei Ou ◽  
Qian Qian Wei ◽  
Hui Fang Shang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Autoimmune Diseases ◽  
Genetic Correlation ◽  
Functional Enrichment ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
Genome Wide ◽  
Shared Risk ◽  
Lateral Sclerosis ◽  
Shared Genetic

Abstract Background Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders. However, little is known about their shared genetic architecture. Methods 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. Results 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. Conclusions 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.

Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen

2008 ◽  
Vol 7 (4) ◽  
pp. 319-326 ◽  
Author(s):  
Hylke M Blauw ◽  
Jan H Veldink ◽  
Michael A van Es ◽  
Paul W van Vught ◽  
Christiaan GJ Saris ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Copy Number Variation ◽  
Copy Number ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Genome Wide ◽  
A Genome ◽  
Number Variation ◽  
Lateral Sclerosis

scholarly journals Shared Genetic Links Between Amyotrophic Lateral Sclerosis and Obesity-Related Traits: A Genome-Wide Association Study

2020 ◽  
Author(s):  
Chunyu Li ◽  
Ruwei Ou ◽  
Xiaojing Gu ◽  
Qianqian Wei ◽  
HuiFang Shang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Density Lipoprotein ◽  
Functional Enrichment ◽  
Genome Wide Association ◽  
Lipoprotein Cholesterol ◽  
Risk Gene ◽  
Genome Wide ◽  
Shared Risk ◽  
Lateral Sclerosis ◽  
Shared Genetic

Abstract Background: Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and obesity-related traits. However, little is known about their shared genetic architecture.Objective: To examine whether there exist genetic enrichment between ALS and eleven obesity-related traits, including body mass index (BMI), waist hip ratio, body fat percentage (BFP), birth weight, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), type 2 diabetes (T2D), fasting glucose, fasting insulin, and identify shared loci among them.Methods: Using the conditional false discovery rate (FDR) statistical framework, we analyzed genome wide association summary statistics for ALS (n=80610) and obesity-related traits, and further conducted functional enrichment analysis.Results: Robust genetic enrichment was observed for ALS conditional on BMI, BFP, HDL-C, LDL-C and T2D, but minimal enrichment on the other traits. 9 shared genetic loci with conjunctional FDR < 0.05 was identified, among which 6 were replicated in a second ALS cohort, including rs3849942 (C9orf72), rs170663 (G2E3), rs8018993 (SCFD1), rs978220 (ATXN3), rs62333164 (CLCN3) and rs12603276 (GGNBP2). We further identified GGNBP2 as a novel potential ALS risk gene, by integrating cis-expression quantitative trait loci analysis in human brain tissue and summary-data-based Mendelian randomization analysis. Functional analysis indicated the shared risk genes were involved in pathways membrane trafficking and vesicle-mediated transport.Conclusions: Our findings demonstrate selective genetic overlap between ALS and obesity-related traits, and identified new shared risk loci, including novel potential ALS risk gene GGNBP2. These results provide better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.

scholarly journals Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study

2010 ◽  
Vol 9 (10) ◽  
pp. 978-985 ◽  
Author(s):  
Hannu Laaksovirta ◽  
Terhi Peuralinna ◽  
Jennifer C Schymick ◽  
Sonja W Scholz ◽  
Shaoi-Lin Lai ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Chromosome 9P21 ◽  
Genome Wide ◽  
A Genome ◽  
Lateral Sclerosis

scholarly journals The Association betweenC9orf72Repeats and Risk of Alzheimer’s Disease and Amyotrophic Lateral Sclerosis: A Meta-Analysis

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Li Shu ◽  
Qiying Sun ◽  
Yuan Zhang ◽  
Qian Xu ◽  
Jifeng Guo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Meta Analysis ◽  
Sporadic Als ◽  
Repeat Expansions ◽  
Positive Correlations ◽  
The Relationship ◽  
Lateral Sclerosis

C9orf72is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasian populations. However, the relationship betweenC9orf72repeats and Alzheimer’s disease (AD) was not clear. Additionally, there were few articles assessingC9orf72in other ethnicities with ALS. In this meta-analysis, we aimed to investigate the relationship betweenC9orf72repeat expansions (≥30 repeats) and intermediate repeat copies (20–29 repeats) and AD or ALS. The results suggested positive correlations betweenC9orf72repeat expansions and the risk of Alzheimer’s disease (OR = 6.36, 95% CI = 3.13–12.92, andp<0.00001), while intermediate repeat copies ofC9orf72gene were not associated with the risk of the disease.C9orf72repeat expansions were positively correlated with the risk of familial and sporadic ALS (OR = 293.25, 95% CI = 148.17–580.38, andp<0.00001; OR = 35.57, 95% CI = 19.61–64.51, andp<0.00001). There was a positive correlation between the gene variations and ALS risk among Caucasians and Asians (OR = 57.56, 95% CI = 36.73–90.22, andp<0.00001; OR = 6.35, 95% CI = 1.39–29.02, andp=0.02).

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