Role of INSR and MTHFR Gene Variants in PCOS: A Multi-Omics Review

Abstract - Polycystic Ovary Syndrome (PCOS) affects 8–13% of reproductive-age women globally, with prevalence reaching 22.5% in urban Indian cohorts. Two of the most consistently implicated genetic variants INSR rs1799817 and MTHFR C677T have almost always been studied in isolation. This review argues that studying them separately is the wrong approach. INSR rs1799817 impairs insulin receptor autophosphorylation, while MTHFR C677T reduces enzymatic activity by 35–70%, depleting S-adenosylmethionine (SAM) and elevating plasma homocysteine. These pathways intersect and amplify each other through what we term the insulin-folate axis. This review synthesises evidence published between 2019 and 2025 across five molecular layers genomics, transcriptomics, epigenomics, metabolomics, and proteomics to construct a unified mechanistic model. We evaluate multi-omics integration frameworks including MOFA+, Similarity Network Fusion, iCluster+, and OmicsAnalyst, identify South Asian populations as critically underrepresented in this research, and propose a cost-effective tiered diagnostic workflow based on Tetra-ARMS PCR genotyping. Key Words: PCOS, INSR rs1799817, MTHFR C677T, insulin-folate axis, multi-omicsintegration, insulin resistance.