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Study 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 phs000101.v1.p1 and was associated with the following publication: Schymick JC et al. (2007) Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data. 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, phs000101.v1.p1. 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 (phs000101.v2.p1) 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 two-stage genome wide association study of sporadic amyotrophic lateral sclerosis. 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 (phs000101.v3.p1). This data release was associated with the following publication: Traynor BJ et al. (2010) Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients. 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 NINDS Repository Motor Neuron Disease/ALS Study, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection.

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

Inclusion/exclusion criteria for cases

All DNA samples were obtained from patients who:

  1. had been diagnosed with probable, probable-laboratory supported or definite ALS according to the El Escorial diagnostic criteria published by the World Federation of Neurology;
  2. were White and non-Hispanics (by self-report);
  3. had signed informed consent.

Inclusion/exclusion criteria for controls

All DNA samples were obtained from patients who:

  1. were neurologically normal;
  2. were White and non-Hispanics (by self-report);
  3. had signed informed consent.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Genotyping Illumina HumanHap300v1.1 317503 33879
Whole Genome Genotyping Illumina HumanHap250Sv1.0 241847 38544 Also referenced as HumanHap240Sv1.0
Whole Genome Genotyping Illumina HumanHap550v3.0 561466 51468
Whole Genome Genotyping Illumina HumanHap550v1.1 555352 38431
Whole Genome Genotyping Illumina Human610_Quadv1_B 601273 1048904
Targeted Region Genotyping Illumina iSelect Custom Panel 7100 N/A
Study History

This study is divided into three stages. The first stage was entitled "Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data", and was published in Lancet Neurology in 2007 (Schymick et al., 6(4):322-8). The data from the first stage analysis was made available on the dbGAP website (study accession: phs000101.v1.p1), and was used in the second stage (see below).

The second stage was entitled "A two-stage genome wide association study of sporadic amyotrophic lateral sclerosis" and was published in Human Molecular Genetics in 2009 (Chiò et al, 18(8):1524-32). The data from the second stage analysis was made available on the dbGAP website (study accession: phs000101.v2.p1). This paper utilized data from 2,713 case samples and 5,346 control samples. This release of data includes 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.

The third stage was entitled "Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients" and was published in Proceedings of the National Academy of Sciences in 2010 (Traynor et al, 107(27):12335-8). The data from the third stage analysis was made available on the dbGAP website (study accession: phs000101.v3.p1). This paper utilized data from 504 case samples. This release of data includes 500 case samples for which participants provided consent to make their data publicly available. Of note, 264 of these samples were previously released as part of the Chiò et al paper (see above), and 236 samples have not been previously released. The 264 previously released samples were genotyped on Illumina HumanHap550v1.1 SNP chips, whereas the 236 newly released samples were genotyped on Illumina Human610Quadv1 SNP chips. Please note that 95 of the 236 samples for which whole genome data is being released in the third stage 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).

Selected publications
Diseases/Traits Related to Study (MESH terms)
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Study Attribution