Convergent human genetic evidence implicates serine biosynthesis in diabetic peripheral neuropathy.

Background: Diabetic peripheral neuropathy (DPN) is a common and disabling complication of diabetes for which no disease-modifying therapies are currently available. Glycemic and metabolic drivers do not fully explain why only a subset of individuals with diabetes develop DPN, and underling genetic contributors remain poorly defined. Methods: We performed a multi-population GWAS of neuropathy in individuals with and without diabetes using the VA Million Veteran Program and UK Biobank, with replication in the All of Us Research Program (AoU). Gene-based and gene-set analyses were used to identify enriched biological pathways. The relationship between circulating serine levels and DPN was further investigated, using two-sample Mendelian randomization. To extend the findings beyond common variation and DPN, we assessed the burden of rare, predicted high-impact variants in GWAS-prioritized genes in individuals with unsolved inherited neuropathies using the GENESIS platform. Findings: Among individuals with type 2 diabetes, we identified seven genome-wide significant loci (p<5×10) including variants in Interpretation: Convergent genetic evidence across common and rare variation implicates the serine synthesis pathway in DPN susceptibility. These findings link diabetic and inherited neuropathies through a shared metabolic mechanism and provide a genetically supported rationale for investigating serine-directed therapeutic strategies.