A genomewide single-nucleotide-polymorphism panel for Mexican American admixture mapping

Abstract

For admixture mapping studies in Mexican Americans (MAM), we define a genomewide single-nucleotide-polymorphism (SNP) panel that can distinguish between chromosomal segments of Amerindian (AMI) or European (EUR) ancestry. These studies used genotypes for >400,000 SNPs, defined in EUR and both Pima and Mayan AMI, to define a set of ancestry-informative markers (AIMs). The use of two AMI populations was necessary to remove a subset of SNPs that distinguished genotypes of only one AMI subgroup from EUR genotypes. The AIMs set contained 8,144 SNPs separated by a minimum of 50 kb with only three intermarker intervals >1 Mb and had EUR/AMI FST values >0.30 (mean FST = 0.48) and Mayan/Pima FST values <0.05 (mean FST < 0.01). Analysis of a subset of these SNP AIMs suggested that this panel may also distinguish ancestry between EUR and other disparate AMI groups, including Quechuan from South America. We show, using realistic simulation parameters that are based on our analyses of MAM genotyping results, that this panel of SNP AIMs provides good power for detecting disease-associated chromosomal segments for genes with modest ethnicity risk ratios. A reduced set of 5,287 SNP AIMs captured almost the same admixture mapping information, but smaller SNP sets showed substantial drop-off in admixture mapping information and power. The results will enable studies of type 2 diabetes, rheumatoid arthritis, and other diseases among which epidemiological studies suggest differences in the distribution of ancestry-associated susceptibility.

Figure 1.

Admixture mapping distribution for each chromosome. The admixture mapping information (ordinate) is shown for each position on the deCODE sex-average map. The information was determined using the ADMIXMAP analysis of genotyping results with use of 8,144 SNP AIMs.

Figure 2.

Power for admixture mapping as a function of admixture mapping information. The power was determined from simulations with 800 cases and 800 controls and SNP sets with admixture information corresponding to the legend for the SNP set used (see the “Methods” section). The power curves were determined using the ADMIXMAP program and deCODE genetics map for either case only (CO) or case control (CC). The appropriate α level for these analyses was a normalized score of 4.0, based on extensive simulations. The result for each measurement point is based on a minimum of 50 separate simulations for each of three different genomic positions and analyses. The simulations were performed with the assumption of 15 generations, a continuous-gene-flow model, and 50:50 EUR:AMI admixture. The power simulations were performed under an additive model. Previous studies have shown similar power for additive, multiplicative, and even recessive models when the theoretic limits (ancestry for each segment known) are examined.

Figure 3.

Clustering of SNPs showing large F_ST between Pima and Mayan AMIs on chromosome 6. The ordinate shows the number of markers with Pima/EUR F_ST>0.35 in each 2 cM (above abscissa) and the frequency of all SNPs (below abscissa). The abscissa shows the chromosome position in cM. The results are from analysis of genotypes with use of the 317K Illumina array. The same peak is also observed in the 100K gene-enriched array after removal of all SNPs overlapping with the 317K Illumina array. The peak could not be explained by the density of SNPs on the genetic map, which averaged 122 SNPs/cM on chromosome 6 and was 196 SNPs/cM in the HLA region.