Publication: Deecke et al., Variants in the TERT gene increase the occurrence of solar lentigines by modifying telomerase expression exclusively in the skin, manuscript under revision Brief summary: Solar lentigines (SL) are a characteristic of the aging skin. Their occurrence is likely determined by a combination of genetic variants and environmental factors such as chronic sun exposure. However, the genetic factors underlying SL formation remain largely unknown. A recently performed genome-wide association study (GWAS) of SL in two Chinese cohorts reported TERT and OCA2 as novel genome-wide significant genetic loci for SL, while only the TERT locus could be validated in a cohort of European descent (Peng et al, 2023). The telomerase reverse transcriptase TERT is known to be involved in the process of maintenance of telomere lengths, but interestingly no causal relationship between telomere length and the SL GWAS results was observed by the investigators. In this study, we quantified the heritability of SL located on the back of the hands and performed a de novo GWAS in 1,137 elderly participants (aged 60 and more) of European descent from the Berlin Aging Study II. We confirmed TERT as the only genome-wide significant locus for SL (top SNP: rs2735940, p= 1.35E-16). In line with the previous Mendelian Randomization (MR) results by Peng et al., our updated MR using substantially larger datasets did not show a causal relationship between the occurrence of SL and telomere lengths measured in blood leukocytes. Importantly, rs2735940 modifies TERT expression in skin tissue (based on GTEx data), but not in any of the other GTEx tissues including blood. Furthermore, colocalization analyses suggested a shared causal effect of rs2735940 on SL occurrence and on TERT expression in skin but not in blood. Thus, we could show that variants in the TERT gene increase the occurrence of SL by modifying TERT expression exclusively in the skin, based on currently available GTEx data. This skin-specific effect was not reported previously and may provide the hitherto missing functional link for the occurrence of SLs via TERT expression and telomere length alterations.