The role of circadian rhythm-related genes in type 2 diabetes from a multi-omics perspective.

Background: Recent studies have established a connection between circadian rhythm disruption and the development of type 2 diabetes mellitus (T2DM), yet the underlying genetic mechanisms remain inadequately understood. This research aims to elucidate the causal relationships between circadian rhythm-related genes and T2DM by utilising a multi-omics approach.

Methods: The study employed the GeneCards database to identify genes associated with circadian rhythms. Integration of quantitative trait loci (QTL) data for gene expression (eQTLs), DNA methylation (mQTLs), and protein expression (pQTLs) was conducted alongside genome-wide association study summary data for T2DM sourced from the Integrative Epidemiology Unit (IEU) and FinnGen databases.

Results: The summary-databased Mendelian randomization (SMR) methodology was utilised to analyse potential causal relationships, supported by colocalisation analyses to confirm the origin of genetic signals. The analysis yielded 47 mQTLs, five eQTLs, and three pQTLs significantly correlated with T2DM outcomes, maintaining a significance threshold of P_SMR_multi <0.05, P_SMR<0.05, and P-HEIDI>0.01.

Conclusions: The integration of mQTL and eQTL data identified 20 critical methylation sites and 13 associated genes relevant to T2DM, with Heat Shock Factor 1(HSF1) emerging as a pivotal gene. Notably, high methylation at the site cg18814314 was inversely correlated with T2DM risk, while increased expression of HSF1 showed a positive correlation. These findings suggest that HSF1 plays a vital role in the pathogenesis of T2DM through circadian rhythm regulation, highlighting its potential as a target for early intervention strategies. Further research is warranted to investigate the timing of circadian gene expression and methylation in T2DM development.