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

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). 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. 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. 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. People living in subarctic regions such as Yakutia in the Russian Far East have adapted to some of the harshest environments in the world. These include extreme cold, long winter nights, and limited access to food. Scientists believe these adaptations are reflected in the body’s biology, but studies examining genes and other molecular traits have not fully explained how these changes occur. In this study, we used a new method that estimates protein levels in the body based on patterns of DNA methylation. DNA methylation is a type of chemical change on DNA that can show how the environment influences the body. We applied this method to blood samples from 245 healthy adults living in two regions of Russia, Yakutia and Central Russia. We found differences in 25 estimated protein levels between the two groups. These proteins are involved in important processes like managing energy use. To our knowledge, these proteins were not linked to genes found in previous epigenetic studies. This suggests the method may provide new insights. Our findings show that estimating protein levels from DNA can help uncover unique biological features in populations adapted to extreme environments. This approach could help guide future research on human adaptation and health.