Linkage analysis of complex diseases using microsatellites and single-nucleotide polymorphisms: application to alcoholism

BMC Genet. 2005 Dec 30;6 Suppl 1(Suppl 1):S10. doi: 10.1186/1471-2156-6-S1-S10.

Abstract

The efficacy of linkage studies using microsatellites and single-nucleotide polymorphisms (SNPs) was evaluated. Analyzed data were supplied by the Collaborative Study on the Genetics of Alcoholism (COGA). Alcoholism was analyzed together with a simulated trait caused by a gene of known position, through a nonparametric linkage test (NPL). For the alcoholism trait, four densities of SNPs (1 SNP per 0.2 cM, 0.5 cM, 1 cM and 2 cM) showed higher peaks of NPL z scores and smaller significant p-values than the usual 10-cM density of microsatellites. However, the two highest densities of SNPs had unstable z score signals, and therefore were difficult to interpret. Analyzing a simulated trait with the same markers in the same pedigrees, we confirmed the higher power of all four densities of SNPs compared to the 10-cM microsatellites panel, although the existence of other confounding peaks was confirmed for maps that are denser than 1 SNP/cM. We further showed that estimating the gene position using SNPs is far less biased than using the usual panel of microsatellites (biases of 0-2 cM for SNPs vs. 8.9 cM for microsatellites). We conclude that using dense maps of SNPs in linkage analysis is more powerful and less biased than using the 10-cM maps of microsatellites. However, linkage signals can be unstable and difficult to interpret when several SNPs are genotyped per centimorgan. The power and accuracy of 1 SNP/cM or 1 SNP/2 cM may be sufficient in a genome-wide linkage scan while denser maps may be most useful in fine-gene mapping studies exploiting linkage disequilibrium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcoholism / epidemiology
  • Alcoholism / genetics*
  • Computer Simulation
  • Genetic Linkage*
  • Haplotypes / genetics
  • Humans
  • Microsatellite Repeats / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Quantitative Trait, Heritable
  • Statistics, Nonparametric