Sequential Use of Transcriptional Profiling, Expression Quantitative Trait Mapping and Gene Association Implicates MMP20 in Human Kidney Aging
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Figure 1. Total expression analysis. Genotypic associations with total expression level. (A) Boxplot of RPS26 expression according to genotype at the promoter SNP rs705704 (p = 1.2 x 10-20). The boxes define the interquartile range and the thick line is the median. Open dots are possible outliers. (B) Haploview linkage disequilibrium plot of RPS26 region. The SNP rs705704 is 274 bp upstream of the RPS26 transcription start site. Values in boxes correspond to the pairwise r2 LD values (darker boxes correspond to higher r2 values) for the HapMap CEU population. rs705704 (red) is partially linked to three SNPs (black) previously shown to associate with RPS26 expression levels.
|Figure 2. Distribution of allele-specific expression. The white bars show the distribution of the allelic expression ratio for all heterozygotes that express the transcript of the 309 SNPs tested. The red bars show the distribution of the allelic expression ratio for heterozygotes that show allele-specific expression.|
|Figure 3. Allele-specific expression analysis. The red lines indicate the 95% confidence interval surrounding the normalized genomic DNA allelic ratio. Each bar represents one heterozygous individual at the particular SNP listed. Individuals above the upper bound or below the lower bound display allele-specific expression. (A) Allele-specific expression was observed at SNP locus rs2245803 in the gene MMP20 in 11 of 12 heterozygotes tested. The A allele was expressed higher than the C allele in all the individuals displaying allele-specific expression. (B) Allele-specific expression was observed at SNP locus rs8643 in the gene TXNDC5 in 14 of 15 heterozygotes tested. The G allele was expressed higher than the A allele in all the individuals displaying allele-specific expression. (C) Boxplot of TXNDC5 total expression according to genotype at the 3’ UTR SNP rs8643 (p = 1.2 x 10-4). The boxes define the interquartile range and the thick line is the median. Open dots are possible outliers.|
|Figure 4. A SNP in MMP20 associates with a kidney aging phenotype. Loess smoothing lines through a scatter plot of creatinine clearance versus age stratified by genotype at rs1711437 in the BLSA (A) and InCHIANTI (B) populations. (corrected p=0.01).|
|Figure 5. Linkage disequilibrium pattern of MMP20. The two SNPs (green) for which we found significant associations with kidney aging are located in introns of MMP20. They are linked to each other and to two nonsynonymous SNPs (black) located in exon 6 of MMP20. Pairwise r2 LD values (darker boxes correspond to higher r2 values) from the HapMap CEU population are displayed. These four SNPs are not linked to the SNP (red) in exon 1 that associated with expression level of the gene.|