Linkage analysis of complex diseases using microsatellites and single-nucleotide polymorphisms: application to alcoholism.
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.
Nsengimana
Jérémie
J
Genetic Epidemiology Group, International Agency for Research on Cancer, World Health Organization, 150 Cours Albert Thomas, 69008 Lyon, France. jeremie.nsengimana@cancer.org.uk
Renard
Hélène
H
Goldgar
David
D
D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics*; D003198:Computer Simulation; D008040:Genetic Linkage; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D018709:Statistics, Nonparametric