Genome-wide association study identifies novel loci associated with skin autofluorescence in individuals without diabetes

Abstract

Background: Skin autofluorescence (SAF) is a non-invasive measure reflecting accumulation of advanced glycation endproducts (AGEs) in the skin. Higher SAF levels are associated with an increased risk of developing type 2 diabetes and cardiovascular disease. An earlier genome-wide association study (GWAS) revealed a strong association between NAT2 variants and SAF. The aim of this study was to calculate SAF heritability and to identify additional genetic variants associated with SAF through genome-wide association studies (GWAS).

Results: In 27,534 participants without diabetes the heritability estimate of lnSAF was 33% ± 2.0% (SE) in a model adjusted for covariates. In meta-GWAS for lnSAF five SNPs, on chromosomes 8, 11, 15 and 16 were associated with lnSAF (P < 5 × 10^-8): 1. rs2846707 (Chr11:102,576,358,C > T), which results in a Met30Val missense variant in MMP27 exon 1 (NM_022122.3); 2. rs2470893 (Chr15:75,019,449,C > T), in intergenic region between CYP1A1 and CYP1A2; with attenuation of the SNP-effect when coffee consumption was included as a covariate; 3. rs12931267 (Chr16:89,818,732,C > G) in intron 30 of FANCA and near MC1R; and following conditional analysis 4. rs3764257 (Chr16:89,800,887,C > G) an intronic variant in ZNF276, 17.8 kb upstream from rs12931267; finally, 30 kb downstream from NAT2 5. rs576201050 (Chr8:18,288,053,G > A).

Conclusions: This large meta-GWAS revealed five SNPs at four loci associated with SAF in the non-diabetes population. Further unravelling of the genetic architecture of SAF will help in improving its utility as a tool for screening and early detection of diseases and disease complications.

Keywords: Coffee; Genome-wide association study; Screening; Single nucleotide polymorphism; Skin Autofluorescence; Skin Pigmentation.

Fig. 1

Manhattan plot of genome-wide p- values of association for Skin Autofluoresence in meta-analyses of all models Legends: On the x-axis chromosome numbers, on the y-axis the -log10 P-values. The horizontal red line represents the genome-wide significance threshold at p < 5 × 10 -8, the horizontal blue line represents the p < 1 × 10 -5, for suggestive associations

Fig. 2

QQ-plots for all models in meta-analyses. Legends: On the y-axis the observed log10 P-values with the expected log10 P-values on the x-axis. gc = lambda genomic control

Fig. 3

LocusZoom plots of genome wide significantly associated locus on chromosome 16. Legends: Regional plots of 400 kb surrounding rs12931267 from meta-analysis of models 1–4 (A-D, respectively). On the left y-axis the SNP P values on the x-axis their genomic positions and on the right y-axis the estimated recombination rates

Fig. 4

LocusZoom plots of genome wide significantly associated locus on chromosome 11. Legends: Regional plots of 400 kb surrounding rs2846707 from meta-analysis of models 1–4 (A-D, respectively). On the left y-axis the SNP P values on the x-axis their genomic positions and on the right y-axis the estimated recombination rates

Fig. 5

LocusZoom plots of genome wide significantly associated locus on chromosome 15. Legends: Regional plots of 400 kb surrounding rs2470893 from meta-analysis of models 1–4 (A-D, respectively). On the left y-axis the SNP P values on the x-axis their genomic positions and on the right y-axis the estimated recombination rates

Fig. 6

LocusZoom plots of genome wide significantly associated locus on chromosome 8. Legends: Regional plots of 400 kb surrounding NAT2 from meta-analysis of model 1, A: with r² values for the SNPs surrounding rs76700131 and B: with r² values for the SNPs surrounding rs35583283. On the left y-axis the SNP P values on the x-axis their genomic positions and on the right y-axis the estimated recombination rates. The gray dots indicate that the LD scores cannot be visualized because the SNP was not present in the reference dataset