Genetic variation in antidiabetic drug targets: associations with Parkinson's disease risk and age at onset
Vincze, Katalin Szwajda, Agnieszka Ploner, Alexander Karlsson, Robert Kang, Xiaoying Tang, Bowen Qin, Chenxi Domenighetti, CloƩ Sugier, Pierre-Emmanuel Ashok Kumar Sreelatha, Ashwin
Vincze, Katalin
Szwajda, Agnieszka
Ploner, Alexander
Karlsson, Robert
Kang, Xiaoying
Tang, Bowen
Qin, Chenxi
Domenighetti, CloƩ
Sugier, Pierre-Emmanuel
Ashok Kumar Sreelatha, Ashwin
Abstract
To investigate whether antidiabetic drugs have a biological basis to be repurposed in PD prevention, we applied a drug target Mendelian randomization framework to assess associations between genetic variation in antidiabetic drug targets and PD risk or age at onset (AAO). Instrumental variables (IVs) were derived from GWAS summary statistics on fasting glucose (FG), glycated hemoglobin (HbA1c), and gene expression data from GTEx. Apart from SGLT2 inhibitors, all other antidiabetic drugs of interest could be instrumented through our methods. Positive and negative control analyses were carried out to validate 20 IVs in the FG arm and 23 IVs in the HbA1c arm. DPP-4 inhibitors failed the positive control. GWAS summary statistics for PD risk and AAO data were sourced from the IPDGC and COURAGE-PD consortia, resulting in 42 083 cases/457 090 controls for risk and 37 103 PD cases for AAO. MR analyses showed no significant associations across consortia or in meta-analysis. These findings do not support a causal role of genetic variation in antidiabetic drug targets in PD risk or AAO.
MIDER Authors
Affiliations
Sandwell and West Birmingham NHS Trust; Karolinska Institutet; Institute of Environmental Medicine; University of Paris-Saclay; et al.
Date
2026-05-28
Type
Article
Subject
Collections
Citation
Vincze K, Szwajda A, Ploner A, Karlsson R, Kang X, Tang B, Qin C, Domenighetti C, Sugier PE, Ashok Kumar Sreelatha A, Schulte C, Portugal B, May P, Bobbili DR, Radivojkov-Blagojevic M, Lichtner P, Singleton AB, Hernandez DG, Edsall C, Mellick GD, Zimprich A, Pirker W, Rogaeva E, Lang AE, Koks S, Taba P, Lesage S, Brice A, Corvol JC, Chartier-Harlin MC, Mutez E, Brockmann K, Deutschlander AB, Burbulla LF, Hadjigeorgiou GM, Dardiotis E, Stefanis L, Simitsi AM, Valente EM, Petrucci S, Straniero L, Zecchinelli A, Pezzoli G, Brighina L, Ferrarese C, Annesi G, Quattrone A, Gagliardi M, Matsuo H, Nakayama A, Hattori N, Nishioka K, Chung SJ, Kim YJ, Kolber P, Van de Warrenburg BP, Bloem BR, Toft M, PihlstrĆøm L, Correia Guedes L, Ferreira JJ, Bardien S, Carr J, Tolosa E, Ezquerra M, Pastor P, Ran C, Belin AC, Puschmann A, Clarke CE, Morrison KE, Tan M, Krainc D, Farrer MJ, Landoulsi Z, Kruger R, Gasser T, Elbaz A, Sharma M, Pedersen NL, Carlsson S, HƤgg S, Wirdefeldt K; Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinsonās Disease (COURAGE-PD) Consortium; Domenighetti C, Sugier PE, Ashok Kumar Sreelatha A, Schulte C, Portugal B, May P, Bobbili DR, Radivojkov-Blagojevic M, Lichtner P, Singleton AB, Hernandez DG, Edsall C, Mellick GD, Zimprich A, Pirker W, Rogaeva E, Lang AE, Koks S, Taba P, Lesage S, Brice A, Corvol JC, Chartier-Harlin MC, Mutez E, Brockmann K, Deutschlander AB, Burbulla LF, Hadjigeorgiou GM, Dardiotis E, Stefanis L, Simitsi AM, Valente EM, Petrucci S, Straniero L, Zecchinelli A, Pezzoli G, Brighina L, Ferrarese C, Annesi G, Quattrone A, Gagliardi M, Matsuo H, Nakayama A, Hattori N, Nishioka K, Chung SJ, Kim YJ, Kolber P, Van de Warrenburg BP, Bloem BR, Toft M, PihlstrĆøm L, Correia Guedes L, Ferreira JJ, Bardien S, Carr J, Tolosa E, Ezquerra M, Pastor P, Ran C, Belin AC, Puschmann A, Clarke CE, Morrison KE, Tan M, Krainc D, Farrer MJ, Landoulsi Z, Kruger R, Gasser T, Elbaz A, Sharma M, Wirdefeldt K. Genetic variation in antidiabetic drug targets: associations with Parkinson's disease risk and age at onset. NPJ Parkinsons Dis. 2026 May 28;12(1):127. doi: 10.1038/s41531-026-01398-5