A genome-wide association study identifies that SAMD5 interacts with regular Sun exposure to influence nasolabial...

Skin ageing is influenced by genetics, chronological age, and Sun exposure. Nasolabial folds are wrinkles prevalent among young ethnic Chinese participants in the Singapore/Malaysia Cross-sectional Genetics Epidemiology Study (SMCGES).

We analysed data from 4421 SMCGES ethnic Chinese young adults. Collected data included demographics, Sun exposure, Fitzpatrick Skin Type, and nasolabial fold presence, assessed using validated questionnaires and photo-numeric scales. Genetic data were obtained through SNP genotyping, imputation, and whole transcriptome sequencing. Buccal cell samples from 2776 participants across three sites (National University of Singapore [NUS], University of Tunku Abdul Rahman [UTAR], and Sunway University [SU]) were used for SNP genotyping, and peripheral blood mononuclear cell samples from 658 participants at NUS and UTAR for sequencing. Analyses were performed using HaploView, RStudio, and PLINK, integrating data from the Genotype-Tissue Expression (GTEx) portal, eQTLGen consortium, and NCBI Gene Expression Omnibus.

Our GWAS identified SAMD5 as associated with nasolabial folds among individuals with regular Sun exposure. SAMD5 SNPs might modulate binding of microRNAs hsa-miR-216a and hsa-miR-485-5p, suppressing SAMD5 expression and promoting nasolabial folds. rs844607 increased odds of nasolabial folds (AOR = 2.67 [1.89-3.77], p = 2.27 × 10^-8) and forms a risk haplotype with 3'-end SNPs predicted as miRNA binding sites. The likely causal SNP, rs702344, strengthens miRNA binding (hsa-miR-216a: score 151, ΔG = - 19.64 kcal/mol; hsa-miR-485-5p: score 157, ΔG = - 22.36 kcal/mol), suppressing SAMD5 expression. eQTL data from GTEx (NES = - 0.72, p = 2.79 × 10^-52) and eQTLGen (Z = 6.16, p = 6.59 × 10^-6) supported this model. Lower SAMD5 expression was observed among chronologically aged individuals (GEO GSE200002, logFC = - 0.639, adj. p = 7.57 × 10^-3) and in untreated photo-aged dermal fibroblasts relative to retinoid-treated ones (GEO GSE294121, adj. p = 3.00 × 10^-2). SAMD5 promotes melanogenesis and UV protection; t-allele carriers showed 1.6-fold higher odds of melanin-poor burning skin types (95% CI 1.11-2.28; p = 0.012). Regular Sun exposure increased odds of nasolabial folds 1.26-fold (95% CI 1.08-1.46; p = 0.0028), whereas melanin-rich tanning skin types reduced the odds (AOR = 0.68; 95% CI 0.47-0.98; p = 0.048).

These findings support a model where rs702344 enhances miRNA binding, downregulates SAMD5, reduces melanogenesis, and promotes nasolabial folds in Sun-exposed young adults.