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A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.

ABSTRACT: The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.

SUBMITTER: Chio A

PROVIDER: S-EPMC2664150 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.

Chiò Adriano A Schymick Jennifer C JC Restagno Gabriella G Scholz Sonja W SW Lombardo Federica F Lai Shiao-Lin SL Mora Gabriele G Fung Hon-Chung HC Britton Angela A Arepalli Sampath S Gibbs J Raphael JR Nalls Michael M Berger Stephen S Kwee Lydia Coulter LC Oddone Eugene Z EZ Ding Jinhui J Crews Cynthia C Rafferty Ian I Washecka Nicole N Hernandez Dena D Ferrucci Luigi L Bandinelli Stefania S Guralnik Jack J Macciardi Fabio F Torri Federica F Lupoli Sara S Chanock Stephen J SJ Thomas Gilles G Hunter David J DJ Gieger Christian C Wichmann H Erich HE Calvo Andrea A Mutani Roberto R Battistini Stefania S Giannini Fabio F Caponnetto Claudia C Mancardi Giovanni Luigi GL La Bella Vincenzo V Valentino Francesca F Monsurrò Maria Rosaria MR Tedeschi Gioacchino G Marinou Kalliopi K Sabatelli Mario M Conte Amelia A Mandrioli Jessica J Sola Patrizia P Salvi Fabrizio F Bartolomei Ilaria I Siciliano Gabriele G Carlesi Cecilia C Orrell Richard W RW Talbot Kevin K Simmons Zachary Z Connor James J Pioro Erik P EP Dunkley Travis T Stephan Dietrich A DA Kasperaviciute Dalia D Fisher Elizabeth M EM Jabonka Sibylle S Sendtner Michael M Beck Marcus M Bruijn Lucie L Rothstein Jeffrey J Schmidt Silke S Singleton Andrew A Hardy John J Traynor Bryan J BJ

Human molecular genetics 20090204 8

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consist ...[more]

PMID: 19193627

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Project description:BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS-frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries.MethodsWe collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10(-7)FindingsAfter quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10(-6); odds ratio [OR] 1·39, 95% CI 1·21-1·59) and rs2814707 (p=3·32×10(-6); 1·38, 1·20-1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10(-10); OR 1·22, 95% CI 1·15-1·30) and rs2814707 (p=4·72×10(-10); 1·22, 1·15-1·30) were associated with ALS.InterpretationWe have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene.

Project description:BackgroundThe genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population.MethodsWe did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus.FindingsWe obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318 167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7-48·1) and that for D90A homozygosity was 25·5% (16·9-34·1).InterpretationThe chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.FundingNational Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.

Dataset Information

A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.

Publications

A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.

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