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. 2010 Apr 8;6(4):e1000899.
doi: 10.1371/journal.pgen.1000899.

Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression

Michael S Cunnington  1 , Mauro Santibanez Koref, Bongani M Mayosi, John Burn, Bernard Keavney
Affiliations

Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression (VSports)

Michael S Cunnington et al. PLoS Genet. .

Abstract

Single nucleotide polymorphisms (SNPs) on chromosome 9p21 are associated with coronary artery disease, diabetes, and multiple cancers. Risk SNPs are mainly non-coding, suggesting that they influence expression and may act in cis. We examined the association between 56 SNPs in this region and peripheral blood expression of the three nearest genes CDKN2A, CDKN2B, and ANRIL using total and allelic expression in two populations of healthy volunteers: 177 British Caucasians and 310 mixed-ancestry South Africans. Total expression of the three genes was correlated (P<0. 05), suggesting that they are co-regulated. SNP associations mapped by allelic and total expression were similar (r = 0. 97, P = 4. 8x10(-99)), but the power to detect effects was greater for allelic expression. The proportion of expression variance attributable to cis-acting effects was 8% for CDKN2A, 5% for CDKN2B, and 20% for ANRIL. SNP associations were similar in the two populations (r = 0. 94, P = 10(-72)). Multiple SNPs were independently associated with expression of each gene (P<0 VSports手机版. 05 after correction for multiple testing), suggesting that several sites may modulate disease susceptibility. Individual SNPs correlated with changes in expression up to 1. 4-fold for CDKN2A, 1. 3-fold for CDKN2B, and 2-fold for ANRIL. Risk SNPs for coronary disease, stroke, diabetes, melanoma, and glioma were all associated with allelic expression of ANRIL (all P<0. 05 after correction for multiple testing), while association with the other two genes was only detectable for some risk SNPs. SNPs had an inverse effect on ANRIL and CDKN2B expression, supporting a role of antisense transcription in CDKN2B regulation. Our study suggests that modulation of ANRIL expression mediates susceptibility to several important human diseases. .

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V体育安卓版 - Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. SNPs associated with disease in the chromosome 9p21.3 region.
Genes are illustrated in blue at the top, with arrows representing the direction of transcription. SNPs typed in our study and SNPs associated with various diseases are represented by black bars. Diseases in bold are those with association data from genomewide association studies. The hatched box represents the core risk haplotype for CAD defined by Broadbent et al . Promoter regions for each gene are shown as pale blue boxes. DM = diabetes mellitus type II; BCC = basal cell carcinoma.
Figure 2
Figure 2. Significance of associations and effect size estimates using total and allelic expression.
Scatter plots depict the P-values (A) and estimates of effect size (B) obtained for each SNP for all three genes by eQTL (X-axis) and aeQTL (Y-axis) mapping. Bar charts show the comparison of the significance of association for CDKN2A (C), CDKN2B (D), and ANRIL (E); and the effect size estimates for CDKN2A (F), CDKN2B (G), and ANRIL (H). The Y-axes on the bar charts show the 56 SNPs ordered by chromosome location (most telomeric at the top). Grey bars to the left represent total expression and black bars to the right represent allelic expression.
Figure 3
Figure 3. SNP effects in the SA and Caucasian cohorts.
Scatter plots show the correlation between aeQTL results obtained in the SA (Y-axis) and Caucasian cohorts (X-axis) for: (A) significance of association with expression (−log P value) for all three genes; (B) effect size at each SNP for all three genes; (C) effect size at each SNP for CDKN2A only; (D) effect size at each SNP for CDKN2B only; (E) effect size at each SNP for ANRIL only. Linear regression line for the association is shown as a solid line with the 95% confidence intervals shown as dotted lines.
Figure 4
Figure 4. Significance of association with expression for SNPs in the combined population.
The Y-axis represents the −log P value for individual SNPs (shown in chromosomal order along the X-axis) for: CDKN2A (A); CDKN2B (B); ANRIL (C). The horizontal black line on each graph represents the significance threshold after adjustment for multiple testing (family wise error rate of 0.05 corresponding to −log10P = 3.05). The relative location of genes and promoter elements is represented at the top (CDKN2A and CDKN2A/ARF promoters yellow; ANRIL promoter blue; CDKN2B promoter orange; CDKN2A/ARF regulatory domain red). Letters along the bottom represent associations from GWA studies (C = CAD, D = diabetes, M = melanoma, G = glioma) and the black bar at the bottom represents the core risk haplotype for CAD defined by Broadbent et al .
Figure 5
Figure 5. Effect of sequential adjustment for most highly associated SNPs.
Bars represent the significance of association (−log10P) for each SNP. (A) Unadjusted. (B) Adjusted for the most highly associated SNP for each gene (CDKN2A rs7036656, CDKN2B rs3218018, ANRIL rs564398). (C) Adjusted for the two most highly associated SNPs for each gene (CDKN2A rs7036656 and rs36228834, CDKN2B rs3218018 and rs3814960, ANRIL rs564398 and rs10965215). Values in the top right corner are the number of significantly associated SNPs after each round of adjustment, following correction for multiple testing. The horizontal black line on each graph represents the significance threshold after adjustment for multiple testing (family wise error rate of 0.05 corresponding to −log10P = 3.05).
Figure 6
Figure 6. Effect of genotype at rs10965215 on allelic expression ratio of transcribed ANRIL SNP rs564398.
Diamonds represent the allelic expression ratio for each individual, all of whom are heterozygous for the transcribed SNP rs564398. The first column shows individuals who are homozygous for rs10965215 (mean ratio 1.57), and the second column shows individuals who are heterozygous for rs10965215 (mean ratio 2.00). The third column shows the expression ratio obtained from genomic DNA in individuals who are heterozygous for the transcribed SNP rs564398, where the two alleles are present in a 1∶1 ratio (mean ratio 1.00).
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