Ethnic-difference markers for use in mapping by admixture linkage disequilibrium

Abstract

Mapping by admixture linkage disequilibrium (MALD) is a potentially powerful technique for the mapping of complex genetic diseases. The practical requirements of this method include (a) a set of markers spanning the genome that have large allele-frequency differences between the parental ethnicities contributing to the admixed population and (b) an understanding of the extent of admixture in the study population. To this end, a DNA-pooling technique was used to screen microsatellite and diallelic insertion/deletion markers for allele-frequency differences between putative representatives of the parental populations of the admixed Mexican American (MA) and African American (AA) populations. Markers with promising pooled differences were then confirmed by individual genotyping in both the parental and admixed populations. For the MA population, screening of >600 markers identified 151 ethnic-difference markers (EDMs) with delta>0.30 (where delta is the absolute value of each allele-frequency difference between two populations, summed over all marker alleles and divided by two) that are likely to be useful for MALD analysis. For the AA population, analysis of >400 markers identified 97 EDMs. In addition, individual genotyping of these markers in Pima Amerindians, Yavapai Amerindians, European American (EA) individuals, Africans from Zimbabwe, MA individuals, and AA individuals, as well as comparison to the CEPH genotyping set, suggests that the differences between subpopulations of an ethnicity are small for many markers with large interethnic differences. Estimates of admixture that are based on individual genotyping of these markers are consistent with a 60% EA:40% Amerindian contribution to MA populations and with a 20% EA:80% African contribution to AA populations. Taken together, these data suggest that EDMs with large interpopulation and small intrapopulation differences can be readily identified for MALD studies in both AA and MA populations.

Figure 1

Percent difference between predicted and actual admixed population allele frequencies, on the basis of microsatellite and insertion/deletion data from putative parental and admixed populations. Microsatellite data are plotted as both the total percent difference (raw data) and the percent difference after conversion of the microsatellite to a diallelic marker by grouping of alleles (see text). Asterisks (*) indicate that, for these percent contributions, the predicted admixed-population allele frequencies are not significantly different from the actual admixed-population allele frequencies, by least-squares analysis. A, Difference between predicted and actual AA allele frequencies, plotted at varying admixture ratios. Predicted frequencies are based on mixing of EA and AF allele frequencies in the indicated percentages. An average of 90 EA, 90 AF, and 270 AA individuals were typed for each marker. B, Difference between predicted and actual MA allele frequencies, plotted at varying admixture ratios. Predicted frequencies are based on mixing of EA and AI allele frequencies in the indicated percentages. An average of 90 EA, 80 AI, and 300 MA individuals were typed for each marker.