Dataset Information

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

ABSTRACT:

Background

The 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.

Methods

We 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.

Findings

We 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).

Interpretation

The 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.

Funding

National 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.

SUBMITTER: Laaksovirta H

PROVIDER: S-EPMC2965392 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The cause of sporadic amyotrophic lateral sclerosis (ALS) is unknown. To identify the genetic factors underlying this fatal neurodegenerative disease, we performed a series of genome-wide association studies of ALS. These studies are divided into three distinct stages, each associated with a separate data release. A description of each stage is provided below. In the first stage, we genotyped 555,352 SNPs in 276 US cases diagnosed with ALS and 271 US controls. These samples were obtained from the National Institute of Neurological Disorders and Stroke (NINDS) DNA Repository at Coriell. The 276 US cases were genotyped on Illumina HumanHap550v1.1 SNP arrays, whereas the 271 US controls were genotyped on both Illumina HumanHap250Sv1.0 and Illumina HumanHap300v1.1 SNP arrays. The genotype data was released in June 2008 under the accession number <a href="./study.cgi?study_id=phs000101.v1.p1">phs000101.v1.p1</a> and was associated with the following publication: Schymick JC et al. (2007) <a href="http://www.ncbi.nlm.nih.gov/pubmed/17362836" target="_blank">Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data</a>. Lancet Neurology 6:322-8. In the second stage, we extended our genotyping to a larger cohort to identify risk factors with lower effect size. This portion of the project used a two-step approach: in step A, 545,066 SNPs were genotyped in 553 individuals with ALS and 2,338 controls. Of note, this cohort included data from the 276 US cases and 271 US controls that had been previously released in the first stage, <a href="./study.cgi?study_id=phs000101.v1.p1">phs000101.v1.p1</a>. The additional 277 ALS cases that were newly genotyped in this stage were collected in a population-based manner from the North of Italy and were genotyped on Illumina HumanHap550v1.1 SNP arrays. In step B, we brought forward the 7,600 most associated SNPs from step A, and genotyped them in an additional cohort consisting of 2,160 cases and 3,008 controls using an Illumina iSelect custom designed SNP array. The new data generated from this study was released in May 2010 (<a href="./study.cgi?study_id=phs000101.v2.p1">phs000101.v2.p1</a>) and consisted of 1,456 case samples and 773 control samples for which participants provided consent to make their data publicly available. We do not have permission to publicly release the genotype data from the rest of the samples. This data release was associated with the following publication: Chiò A et al. (2009) <a href="http://www.ncbi.nlm.nih.gov/pubmed/19193627" target="_blank">A two-stage genome wide association study of sporadic amyotrophic lateral sclerosis</a>. Human Molecular Genetics 18:1524-32. In the third stage, we genotyped 601,273 SNPs in an additional set of 236 Italian ALS cases. Together with the 264 Italian samples genotyped as part of stage 2, this brought the total number of samples that were whole genome genotyped samples to 504. These additional 236 patients had been collected in a population-based manner from the Piedmonte region in the North of Italy, and were genotyped using Illumina Human610Quad.v1 SNP arrays. The rational for this stage of the study arose from a Proceedings of the National Academy of Sciences (PNAS) publication by Landers et al. 2009, hypothesizing that genetic variation on chromosome 1q24 in the vicinity of the KIFAP3 gene was associated with a significant improvement in survival of ALS patients. Our data failed to replicate this finding suggesting that the original finding may have been a false positive finding. The data generated for the extra 236 Italian ALS cases used in this study was released in April 2011 (<a href="./study.cgi?study_id=phs000101.v3.p1">phs000101.v3.p1</a>). This data release was associated with the following publication: Traynor BJ et al. (2010) <a href="http://www.ncbi.nlm.nih.gov/pubmed/20566859" target="_blank">Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients</a>. PNAS 107:12335-8. Of note, 95 of these 236 samples had also been genotyped on the Illumina iSelect custom designed SNP array used in the second stage of this study (see README.txt file available through dbGaP Authorized Access for list of the 95 samples). This study utilized the <a href="./study.cgi?id=phs000006">NINDS Repository Motor Neuron Disease/ALS Study</a>, and <a href="./study.cgi?id=phs000004">neurologically normal controls</a> from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection.