Susceptibility genes for age-related maculopathy on chromosome 10q26

Abstract

On the basis of genomewide linkage studies of families affected with age-related maculopathy (ARM), we previously identified a significant linkage peak on 10q26, which has been independently replicated by several groups. We performed a focused SNP genotyping study of our families and an additional control cohort. We identified a strong association signal overlying three genes, PLEKHA1, LOC387715, and PRSS11. All nonsynonymous SNPs in this critical region were genotyped, yielding a highly significant association (P < .00001) between PLEKHA1/LOC387715 and ARM. Although it is difficult to determine statistically which of these two genes is most important, SNPs in PLEKHA1 are more likely to account for the linkage signal in this region than are SNPs in LOC387715; thus, this gene and its alleles are implicated as an important risk factor for ARM. We also found weaker evidence supporting the possible involvement of the GRK5/RGS10 locus in ARM. These associations appear to be independent of the association of ARM with the Y402H allele of complement factor H, which has previously been reported as a major susceptibility factor for ARM. The combination of our analyses strongly implicates PLEKHA1/LOC387715 as primarily responsible for the evidence of linkage of ARM to the 10q26 locus and as a major contributor to ARM susceptibility. The association of either a single or a double copy of the high-risk allele within the PLEKHA1/LOC387715 locus accounts for an odds ratio of 5.0 (95% confidence interval 3.2-7.9) for ARM and a population attributable risk as high as 57%.

Figure 1

Location of CIDR SNPs and locally genotyped SNPs with respect to candidate genes. Positions, distances, and nucleotide positions along chromosome 10 are derived from NCBI Entrez Gene and dSNP databases.

Figure 2

A, LD patterns in GRK5 (Block 1), RGS10 (SNP 6), PLEKHA1 (Block 2), LOC387715 (Block 3), and PRSS11 (Block 4). B, LD patterns in CFH (Block 1). Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D^′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D^′=1 without statistical significance. Significant SNPs from the CCREL allele test are highlighted in green (see table 6). Three SNPs (rs6428352, rs12258692, and rs11538141) were not included, because of very low heterozygosity, and one SNP (rs2736911) was not included, because it was uninformative. Note that the blocks were drawn to show clearly the position of the genes and do not represent haplotype blocks.

Figure 3

Two-point (2pt) and multipoint (mpt) linkage results on chromosome 10. The panel on the left summarizes the results when all SNPs were used for analysis. The panel on the right summarizes the results when only htSNPs were used. The peaks marked “F” represent likely false peaks due to high SNP-SNP LD, whereas the peaks marked “G” and “P” correspond to the loci containing GRK5 and PLEKHA1, respectively. The horizontal lines indicate the 1-unit support interval of multipoint S_all (i.e., maximum S_all-1).

Figure 4

LD patterns on chromosome 10 based on analysis of 196 CIDR SNPs and 179 unrelated controls. A, The false peak at 135 cM (see fig. 3); the SNP with the largest S_all in the peak is highlighted in green. B, The false peak at 142 cM (see fig. 3); the SNP with the largest S_all in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie the five genes (GRK5, RGS10, PLEKHA1, LOC387715, and PRSS11) are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D^′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D^′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.

Figure 4

LD patterns on chromosome 10 based on analysis of 196 CIDR SNPs and 179 unrelated controls. A, The false peak at 135 cM (see fig. 3); the SNP with the largest S_all in the peak is highlighted in green. B, The false peak at 142 cM (see fig. 3); the SNP with the largest S_all in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie the five genes (GRK5, RGS10, PLEKHA1, LOC387715, and PRSS11) are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D^′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D^′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.

Figure 4

LD patterns on chromosome 10 based on analysis of 196 CIDR SNPs and 179 unrelated controls. A, The false peak at 135 cM (see fig. 3); the SNP with the largest S_all in the peak is highlighted in green. B, The false peak at 142 cM (see fig. 3); the SNP with the largest S_all in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie the five genes (GRK5, RGS10, PLEKHA1, LOC387715, and PRSS11) are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D^′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D^′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.

Figure 5

Multipoint linkage results for chromosome 1. The panel on the left summarizes results when all SNPs were used for analysis, and the panel on the right summarizes results when only htSNPs were used. The peaks marked “F” represent likely false peaks due to high SNP-SNP LD, whereas the peak marked “C” corresponds to the CFH gene. The horizontal lines indicate the 1-unit support interval of multipoint S_all (i.e., maximum S_all over CFH-1).

Figure 6

LD patterns on chromosome 1 based on analysis of 679 CIDR SNPs and 179 unrelated controls. A, The false peak at 188 cM (see fig. 5); the SNP with the largest S_all in the peak is highlighted in green. B, The false peak at 202 cM (see fig. 5); the SNP with the largest S_all in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie CFH are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D^′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D^′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.

Figure 6

LD patterns on chromosome 1 based on analysis of 679 CIDR SNPs and 179 unrelated controls. A, The false peak at 188 cM (see fig. 5); the SNP with the largest S_all in the peak is highlighted in green. B, The false peak at 202 cM (see fig. 5); the SNP with the largest S_all in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie CFH are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D^′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D^′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.

Figure 6

LD patterns on chromosome 1 based on analysis of 679 CIDR SNPs and 179 unrelated controls. A, The false peak at 188 cM (see fig. 5); the SNP with the largest S_all in the peak is highlighted in green. B, The false peak at 202 cM (see fig. 5); the SNP with the largest S_all in the peak is highlighted in green. C, Linkage peak. Significant SNPs, from CCREL (table 5), that overlie CFH are highlighted in green. Squares shaded pink or red indicate significant LD between SNP pairs (bright red indicates pairwise D^′=1), white squares indicate no evidence of significant LD, and blue squares indicate pairwise D^′=1 without statistical significance. LD is measured using D′, and the values within the squares give pairwise LD in D′/100.