Dataset Information

No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis.

ABSTRACT: Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.

SUBMITTER: Goris A

PROVIDER: S-EPMC3943520 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis.

Goris An A van Setten Jessica J Diekstra Frank F Ripke Stephan S Patsopoulos Nikolaos A NA Sawcer Stephen J SJ van Es Michael M Andersen Peter M PM Melki Judith J Meininger Vincent V Hardiman Orla O Landers John E JE Brown Robert H RH Shatunov Aleksey A Leigh Nigel N Al-Chalabi Ammar A Shaw Christopher E CE Traynor Bryan J BJ Chiò Adriano A Restagno Gabriella G Mora Gabriele G Ophoff Roel A RA Oksenberg Jorge R JR Van Damme Philip P Compston Alastair A Robberecht Wim W Dubois Bénédicte B van den Berg Leonard H LH De Jager Philip L PL Veldink Jan H JH de Bakker Paul I W PI

Human molecular genetics 20131113 7

Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological stud ...[more]

PMID: 24234648

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Project description:Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02-2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12-0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.

Dataset Information

No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis.

Publications

No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis.

Similar Datasets

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