Evaluation of linkage disequilibrium and its effect on non-parametric multipoint linkage analysis using two high density single-nucleotide polymorphism mapping panels

Abstract

Genotype data from the Illumina Linkage III SNP panel (n = 4,720 SNPs) and the Affymetrix 10 k mapping array (n = 11,120 SNPs) were used to test the effects of linkage disequilibrium (LD) between SNPs in a linkage analysis in the Collaborative Study on the Genetics of Alcoholism pedigree collection (143 pedigrees; 1,614 individuals). The average r2 between adjacent markers across the genetic map was 0.099 +/- 0.003 in the Illumina III panel and 0.17 +/- 0.003 in the Affymetrix 10 k array. In order to determine the effect of LD between marker loci in a nonparametric multipoint linkage analysis, markers in strong LD with another marker (r2 > 0.40) were removed (n = 471 loci in the Illumina panel; n = 1,804 loci in the Affymetrix panel) and the linkage analysis results were compared to the results using the entire marker sets. In all analyses using the ALDX1 phenotype, 8 linkage regions on 5 chromosomes (2, 7, 10, 11, X) were detected (peak markers p < 0.01), and the Illumina panel detected an additional region on chromosome 6. Analysis of the same pedigree set and ALDX1 phenotype using short tandem repeat markers (STRs) resulted in 3 linkage regions on 3 chromosomes (peak markers p < 0.01). These results suggest that in this pedigree set, LD between loci with spacing similar to the SNP panels tested may not significantly affect the overall detection of linkage regions in a genome scan. Moreover, since the data quality and information content are greatly improved in the SNP panels over STR genotyping methods, new linkage regions may be identified due to higher information content and data quality in a dense SNP linkage panel.

Figure 1

LD strength in the Illumina Linkage III SNP panel (ILMN) and the Affymetrix 10 k mapping array (AFFY). a) Distribution of marker pairs by LD strength (r²); b) Proportion of marker pairs r² > 0.4 by chromosome (chromosome 23 = X chromosome).

Figure 2

Multipoint NPL analysis of ALDX1 phenotype using the Illumina III SNP linkage panel. Multipoint NPL scores across the entire chromosome for all SNPs (blue line) and a subset of SNPs with weak or no LD (orange line) are shown for the six chromosomes that have regions with corresponding p-values < 0.01. In addition, the information content (IC) curves are also shown for all loci (green line) and the subset of SNPs with weak or no LD (pink line).

Figure 3

Multipoint NPL analysis of ALDX1 phenotype using the Affymetrix 10 k Mapping Array. Multipoint NPL scores across the entire chromosome for all SNPs (blue line) and a subset of SNPs with weak or no LD (orange line) are shown for six chromosomes. Chromosomes 2, 7, 10, 11, and X have regions with corresponding p-values < 0.01; chromosome 6 is shown for comparison with the Illumina SNP mapping panel results. In addition, the information content (IC) curves are also shown for all loci (green line) and the subset of SNPs with weak or no LD (pink line).