title: Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysis.
abstract: BACKGROUND
  Amyotrophic 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  we 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 intersection Dom epistatic model; SNP1 and SNP3 had a p-value of 0.042 under the Dom x Dom multiplicative model.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Mathematical Sciences, Michigan Technological University, Houghton, MI, USA. qsha@mtu.edu
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Sha
authors.forename: Zhaogong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Schymick
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Shuanglin
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016013:Likelihood Functions; D008957:Models, Genetic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide