Analysis of genetic variation in Ashkenazi Jews by high density SNP genotyping

Abstract

Background: Genetic isolates such as the Ashkenazi Jews (AJ) potentially offer advantages in mapping novel loci in whole genome disease association studies. To analyze patterns of genetic variation in AJ, genotypes of 101 healthy individuals were determined using the Affymetrix EAv3 500 K SNP array and compared to 60 CEPH-derived HapMap (CEU) individuals. 435,632 SNPs overlapped and met annotation criteria in the two groups.

Results: A small but significant global difference in allele frequencies between AJ and CEU was demonstrated by a mean FST of 0.009 (P < 0.001); large regions that differed were found on chromosomes 2 and 6. Haplotype blocks inferred from pairwise linkage disequilibrium (LD) statistics (Haploview) as well as by expectation-maximization haplotype phase inference (HAP) showed a greater number of haplotype blocks in AJ compared to CEU by Haploview (50,397 vs. 44,169) or by HAP (59,269 vs. 54,457). Average haplotype blocks were smaller in AJ compared to CEU (e.g., 36.8 kb vs. 40.5 kb HAP). Analysis of global patterns of local LD decay for closely-spaced SNPs in CEU demonstrated more LD, while for SNPs further apart, LD was slightly greater in the AJ. A likelihood ratio approach showed that runs of homozygous SNPs were approximately 20% longer in AJ. A principal components analysis was sufficient to completely resolve the CEU from the AJ.

Conclusion: LD in the AJ versus was lower than expected by some measures and higher by others. Any putative advantage in whole genome association mapping using the AJ population will be highly dependent on regional LD structure.

Figure 1

Comparison of minor allele frequencies between AJ and CEU. a, Allele frequencies were computed for AJ first, and major and minor allele were assigned on the basis of which allele predominated. Therefore, no minor allele in AJ had a frequency greater than 0.50. Minor allele frequencies were plotted using the RcolorBrewer portion of the geneplotter library of Bioconductor in R. Default values were used for the smoothing. All 435,632 SNPs common to AJ and CEU were plotted. b, Karyogram highlighting markers with significantly different allele frequencies between AJ and CEU. Positions of significance are identified with black lines and centromeres are identified by gray. Lines drawn from the top indicate a higher minor allele frequency in AJ lines drawn from the bottom indicate a higher minor allele frequency in CEU. Counts on the right are the number of significant markers on the chromosome for AJ and CEU. The cutoff for significance is a Bonferroni-adjusted P-value of less than 0.05. Dense lines on chromosomes 2 and 6 are evidence for regions of gross allele frequency differences.

Figure 2

Histogram of F_ST versus SNP number. Calculation of F_ST for AJ and CEU was performed as described in the Materials and Methods section [20]. Outlier values with F_ST > 0.2 were excluded from the histogram for purposes of clarity of visualization.

Figure 3

Horizontal back-to-back histograms displaying the direction of Hardy-Weinberg departures across a range of bins of Fisher's Exact test P-values. The number of SNPs with a positive D_A value (excess homozygotes) is graphed above the zero line in each graph. The number of SNPs with a negative D_A value is graphed below the zero line in each graph. a, Data from AJ SNPs. b, Data from CEU SNPs.

Figure 4

Karyogram of clusters of markers out of HWE. The lines from the top of each chromosome are from AJ and the lines from the bottom are from CEU. The closer a line is to the mid-point, the higher the proportion of markers in a cluster out of HWE at α = 0.05. Lines are drawn at the mid-point of the genomic positions of the clusters. Different colors correspond to different numbers of markers in a cluster. Centromeres are left blank. Clusters on the X-chromosome for CEU have been dropped because the CEU population consisted of half males and half females. Clusters were generated using the CBS algorithm [22].

Figure 5

Decay of r² as a function of distance between pairs of SNPs on chromosome 1 for AJ and CEU. Plotted are the average r² values for pairs of SNPs within each bin. The values for AJ and CEU cross at ~200 kb.

Figure 6

P-values from a sign test plotted for each 1 Mb region of chromosome 1. Data were drawn from a random sample replicate of 60 AJ compared to 60 CEU. A positive value indicates greater LD in AJ compared to CEU.

Figure 7

Histograms of autosome block sizes estimated using HAP for AJ and CEU. X chromosome block calculations were excluded from the histogram in order to minimize reliance upon haplotype estimates from the thirty CEU founder males. A small number of outlier blocks greater than 300 kb were also excluded from the figure.

Figure 8

Frequency plot of the percentage of the genome within homozygous tracts. The percentage is shown for each of 101 AJ (a) and 60 CEU (b).

Figure 9

Scatter plot of principal components analysis of 435,632 SNPs. Principal component 1 is plotted on the abscissa, component 2 on the ordinate; CEU are designated as open boxes and AJ as smaller open circles. One AJ can be observed in the CEU cluster. Those case removed from analysis following PCA are denoted by an arrow.