DNA methylation-predicted protein differences between Yakutian and Central Russian populations.

Background: Populations in subarctic regions, like Yakutia in the Russian Sakha Republic, have adapted to extreme environmental conditions, including intense cold, pronounced shifts in daylight, and variable food availability. However, the biological mechanisms underlying these adaptations remain poorly understood despite insights from genome-wide (GWAS) and epigenome-wide association studies (EWAS).

Methods: Since protein profiles may more directly reflect functional physiology, we analyzed DNA methylation data from 245 healthy Russian participants using methylation-based estimators of circulating protein levels to investigate estimated proteomic differences between residents of Yakutia and Central Russia.

Results: We identified regional variation in 25 protein surrogates enriched in pathways, including MET receptor activation and PI3K-Akt signaling. Some proteins mapped to previously identified GWAS genes. To our knowledge, none mapped to previously identified, differentially methylated in EWAS genes, suggesting that methylation-based protein estimation may capture distinct, complementary aspects of physiological regulation.

Conclusion: These findings align with prior -omics research by highlighting regional molecular differences possibly associated with cold adaptation. They also underscore the potential of methylation-derived proteomic proxies as a useful, indirect approach for studying proteomic variation when direct protein measurements are unavailable. While promising, this method warrants further validation, particularly with respect to potential genetic confounding.