Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysisReportar como inadecuado




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BMC Medical Genetics

, 10:86

First Online: 09 September 2009Received: 19 September 2008Accepted: 09 September 2009

Abstract

BackgroundAmyotrophic lateral sclerosis ALS is a fatal, degenerative neuromuscular disease characterized by a progressive loss of voluntary motor activity. About 95% of ALS patients are in -sporadic form-meaning their disease is not associated with a family history of the disease. To date, the genetic factors of the sporadic form of ALS are poorly understood.

MethodsWe proposed a two-stage approach based on seventeen biological plausible models to search for two-locus combinations that have significant joint effects to the disease in a genome-wide association study GWAS. We used a two-stage strategy to reduce the computational burden associated with performing an exhaustive two-locus search across the genome. In the first stage, all SNPs were screened using a single-marker test. In the second stage, all pairs made from the 1000 SNPs with the lowest p-values from the first stage were evaluated under each of the 17 two-locus models.

Resultswe performed the two-stage approach on a GWAS data set of sporadic ALS from the SNP Database at the NINDS Human Genetics Resource Center DNA and Cell Line Repository http:-ccr.coriell.org-ninds-. Our two-locus analysis showed that two two-locus combinations-rs4363506 SNP1 and rs3733242 SNP2, and rs4363506 and rs16984239 SNP3 - were significantly associated with sporadic ALS. After adjusting for multiple tests and multiple models, the combination of SNP1 and SNP2 had a p-value of 0.032 under the Dom∩Dom epistatic model; SNP1 and SNP3 had a p-value of 0.042 under the Dom × Dom multiplicative model.

ConclusionThe proposed two-stage analytical method can be used to search for joint effects of genes in GWAS. The two-stage strategy decreased the computational time and the multiple testing burdens associated with GWAS. We have also observed that the loci identified by our two-stage strategy can not be detected by single-locus tests.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2350-10-86 contains supplementary material, which is available to authorized users.

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Autor: Qiuying Sha - Zhaogong Zhang - Jennifer C Schymick - Bryan J Traynor - Shuanglin Zhang

Fuente: https://link.springer.com/



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