Artikel
Genome-wide association study identifies TERT as a genetic determinant for skin aging
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Veröffentlicht: | 15. September 2023 |
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Introduction: Age spots or solar lentigines are a predominant characteristic of the aging skin. However, there is substantial interindividual variability in the number of lentigines. Their occurrence is likely determined by a combination of genetic and environmental factors. While chronic sun exposure is the leading contributor to the latter [1], the genetics underlying lentigines formation remains largely unknown. Here, we performed genome-wide screening to quantify the heritability of solar lentigines and to identify specific genetic factors contributing to their generation.
Methods: We performed a genome-wide association study (GWAS) on the presence of solar lentigines in 1137 elderly participants (aged 60 to 85 years, mean age: 68 years) of European descent from the Berlin Aging Study II [2]. Lentigines were quantified using a four-level categorical score based on photographs of the back of each participant’s hands taken in a semi-standardized fashion. Photographs were examined and scored independently by three reviewers. Single nucleotide polymorphism (SNP)-based heritability was estimated using GREML [3]. GWAS analyses were based on linear regression models on 7,171,623 SNPs (following genome-wide SNP imputation) and lentigines score adjusting for sex and the first five principal components. To further characterize the GWAS results we performed colocalization analyses using skin expression eQTL data available in GTEx v.8 (n=517 sun not exposed, n=605 sun exposed).
Results: Our SNP-based heritability estimate for lentigines was 0.66, suggesting that genetics makes a substantial contribution to the development of these age spots. Our GWAS analyses detected genome-wide significant association with SNPs in the TERT gene on chromosome 5p15.33 (top SNP: rs2735940, p= 1.35E-16). The same SNP resulted in a strong alteration of TERT expression in sun exposed skin tissue from GTEx (p=5.5E-6). Subsequent colocalization analyses revealed rs2735940 as a shared causal variant for both the number of lentigines and TERT gene expression in skin (posterior probability: >90%). Furthermore, our top SNP rs2735940 is a major determinant of telomer length (p=4.4E-114 [4]). Finally, as TERT also represents a risk gene for skin cancer, especially melanoma, additional fine-mapping and cross-phenotypes analyses will be presented at the meeting.
Discussion: In the current study, we identified the TERT SNP rs2735940 as a major genetic determinant of the occurrence of solar lentigines on the back of the hands. The same SNP was also associated with both the expression of TERT in the skin and with shorter telomere lengths. Interestingly, solar lentigines can be indicative of an increased risk for sun-exposure associated skin cancer, and genetic variation in TERT has also been implicated in risk of melanoma [5]. However, additional fine-mapping results suggest different molecular mechanisms in the onset of solar lentigines and melanoma.
Conclusion: Our findings provide an important step towards dissecting the biology of skin aging putting the regulation of telomer length at the center of lentigines formation. At the conference, we will provide a detailed presentation of these compelling finding.
The authors declare that they have no competing interests.
The authors declare that a positive ethics committee vote has been obtained.
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