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 PHGDH and PSPH, key enzymes in serine biosynthesis, TEAD1, CYP4F11, LARGE1, FTO, and COBLL1. No significant loci were identified in individuals without diabetes or with type 1 diabetes. Four loci (PHGDH, TEAD1, FTO and CYP4F11) replicated in AoU (p <0·05). Mendelian randomization showed that higher genetically predicted serine levels were associated with lower DPN risk, consistent with a causal role of serine metabolism in disease pathogenesis. Rare-variant burden analyses demonstrated association of predicted deleterious variants with inherited neuropathy cases for PHGDH (odds ratio [OR] 12.7 [95% CI 7·9, 20·4]), PSPH (OR 8·5 [7·2, 10·2]), PHKG1 (OR 4·8 [3·7, 6·3], and LARGE1 (OR 0·007 [0·0004, 0·1]).

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.