Mapping Genes Underlying Ethnic Differences in Disease Risk by Linkage
Disequilibrium in Recently Admixed Populations
P.M. McKeigue
American Journal of Human Genetics ,
60(1), 188-96 (Jan 1997)
Abstract
Where recent admixture has occurred between two populations that
have different disease rates for genetic reasons, family-based association
studies can be used to map the genes underlying these differences, if the
ancestry of the alleles at each locus examined can be assigned to one of the two
founding populations. This article explores the statistical power and design
requirements of this approach. Markers suitable for assigning the ancestry of
genomic regions could be defined by grouping alleles at closely spaced
microsatellite loci into haplotypes, or generated by representational difference
analysis. For a given relative risk between populations, the sample size required
to detect a disease locus that accounts for this relative risk by
linkage-disequilibrium mapping in an admixed population is not critically
dependent on assumptions about genotype penetrances or allele frequencies.
Using the transmission-disequilibrium test to search the genome for a locus
that accounts for a relative risk of between 2 and 3 in a high-risk population,
compared with a low-risk population, generally requires between 150 and 800
case-parent pairs of mixed descent. The optimal strategy is to conduct an
initial study using markers spaced at < or = 10 cM with cases from the second
and third generations of mixed descent, and then to map the disease loci more
accurately in a subsequent study of a population with a longer history of
admixture. This approach has greater statistical power than allele-sharing
designs and has obvious applications to the genetics of hypertension,
non-insulin-dependent diabetes, and obesity.
Association Studies