Human genetic evidence links serine biosynthesis to diabetic peripheral neuropathy
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Background
Diabetic peripheral neuropathy (DPN) is a common and disabling condition for which no disease-modifying therapies are available. Glycemic and metabolic drivers do not fully explain why only a subset of individuals with diabetes develop DPN, and genetic contributors remain poorly defined. We aimed to perform a multi-population genome-wide association study (GWAS) of DPN to highlight potential new etiological pathways and therapeutic targets.
Methods
We performed a multi-population GWAS of neuropathy in people with and without diabetes using the VA Million Veteran Program and UK Biobank, followed by replication in the All of Us Research Program (AoU), and gene-based and gene-set analyses to identify implicated pathways. Causal relationships between circulating serine levels and DPN were further tested using two-sample Mendelian randomization. To further evaluate pathogenic potential, we analyzed rare, high-impact variants in GWAS-implicated genes among individuals with unresolved inherited neuropathies using the GENESIS platform.
Findings
Among individuals with type 2 diabetes, we identified seven genome-wide significant loci (p<5×10 −8 ): PHGDH and PSPH (key serine-synthesis genes), TEAD1, CYP4F11, LARGE1, FTO , and COBLL1 . No loci were significant in individuals without diabetes or with type 1 diabetes. Four loci ( PHGDH, TEAD1, FTO and CYP4F11) replicated in AoU ( p <0.05). Mendelian randomization demonstrated 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 revealed associations of predicted deleterious variants with inherited neuropathy case status in 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 serine synthesis as a key pathway in DPN. These findings link diabetic and inherited neuropathies through a shared metabolic mechanism, identifying serine metabolism as a potential therapeutic target.
Funding
This 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.E.B.R. is supported by VA awards BX002046, CX001532, the CU Diabetes Research Center award DK11607, 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.
