Convergent human genetic evidence implicates serine biosynthesis in diabetic peripheral neuropathy

Abstract

BackgroundDiabetic 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. MethodsWe 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. FindingsAmong individuals with type 2 diabetes, we identified seven genome-wide significant loci (p<5x10{square} {square}) 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{middle dot}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{middle dot}9, 20{middle dot}4]), PSPH (OR 8{middle dot}5 [7{middle dot}2, 10{middle dot}2]), PHKG1 (OR 4{middle dot}8 [3{middle dot}7, 6{middle dot}3], and LARGE1 (OR 0{middle dot}007 [0{middle dot}0004, 0{middle dot}1]). InterpretationConvergent 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. FundingThis research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by MVP000 and by awards MVP009/MVP037 I01-BX005831 and MVP051. S.R. is supported by VA award I01-BX006417. V.F. is supported by NIH award 1K23DK118202-01A1. S.Z. is supported by the CMT Association, CMT Research Foundation, All of US Research Program (3OT2OD037907), and NIH (1R21HG013397, 5R01NS072248). J.R. is supported by VA awards BX002046 and CX001532, NIH awards DK124344, HL165433, AG087809, P30DK116073, UM1 TR004399, and the Ludeman Center. L.S.P. is supported in part by VA awards CSP #2008, I01 CX001899, I01 CX001737, and I01 BX005831, NIH awards R01 DK127083, R03 AI133172, R21 AI156161, U01 DK098246, UL1 TR002378, and a Cystic Fibrosis Foundation award PHILLI12A0. L.VdV. was supported by the Peripheral Nerve Society Laura Feltri Basic Research Fellowship.