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<p>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.</p>

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Genetic variation in antidiabetic drug targets: associations with Parkinson’s disease risk and age at onset

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Katalin Vincze,
  • Agnieszka Szwajda,
  • Alexander Ploner,
  • Robert Karlsson,
  • Xiaoying Kang,
  • Bowen Tang,
  • Chenxi Qin,
  • Cloé Domenighetti,
  • Pierre-Emmanuel Sugier,
  • Ashwin Ashok Kumar Sreelatha,
  • Claudia Schulte,
  • Berta Portugal,
  • Patrick May,
  • Dheeraj Reddy Bobbili,
  • Milena Radivojkov-Blagojevic,
  • Peter Lichtner,
  • Andrew B. Singleton,
  • Dena G. Hernandez,
  • Connor Edsall,
  • George D. Mellick,
  • Alexander Zimprich,
  • Walter Pirker,
  • Ekaterina Rogaeva,
  • Anthony E. Lang,
  • Sulev Koks,
  • Pille Taba,
  • Suzanne Lesage,
  • Alexis Brice,
  • Jean-Christophe Corvol,
  • Marie-Christine Chartier-Harlin,
  • Eugénie Mutez,
  • Kathrin Brockmann,
  • Angela B. Deutschlander,
  • Lena F. Burbulla,
  • Georges M. Hadjigeorgiou,
  • Efthimos Dardiotis,
  • Leonidas Stefanis,
  • Athina Maria Simitsi,
  • Enza Maria Valente,
  • Simona Petrucci,
  • Letizia Straniero,
  • Anna Zecchinelli,
  • Gianni Pezzoli,
  • Laura Brighina,
  • Carlo Ferrarese,
  • Grazia Annesi,
  • Andrea Quattrone,
  • Monica Gagliardi,
  • Hirotaka Matsuo,
  • Akiyoshi Nakayama,
  • Nobutaka Hattori,
  • Kenya Nishioka,
  • Sun Ju Chung,
  • Yun Joong Kim,
  • Pierre Kolber,
  • Bart PC Van de Warrenburg,
  • Bastiaan R. Bloem,
  • Mathias Toft,
  • Lasse Pihlstrøm,
  • Leonor Correia Guedes,
  • Joaquim J. Ferreira,
  • Soraya Bardien,
  • Jonathan Carr,
  • Eduardo Tolosa,
  • Mario Ezquerra,
  • Pau Pastor,
  • Caroline Ran,
  • Andrea C. Belin,
  • Andreas Puschmann,
  • Carl E. Clarke,
  • Karen E. Morrison,
  • Manuela Tan,
  • Dimitri Krainc,
  • Matt J. Farrer,
  • Zied Landoulsi,
  • Rejko Kruger,
  • Thomas Gasser,
  • Alexis Elbaz,
  • Manu Sharma,
  • Nancy L. Pedersen,
  • Sofia Carlsson,
  • Sara Hägg,
  • Karin Wirdefeldt,
  • Cloé Domenighetti,
  • Pierre-Emmanuel Sugier,
  • Ashwin Ashok Kumar Sreelatha,
  • Claudia Schulte,
  • Berta Portugal,
  • Patrick May,
  • Dheeraj Reddy Bobbili,
  • Milena Radivojkov-Blagojevic,
  • Peter Lichtner,
  • Andrew B. Singleton,
  • Dena G. Hernandez,
  • Connor Edsall,
  • George D. Mellick,
  • Alexander Zimprich,
  • Walter Pirker,
  • Ekaterina Rogaeva,
  • Anthony E. Lang,
  • Sulev Koks,
  • Pille Taba,
  • Suzanne Lesage,
  • Alexis Brice,
  • Jean-Christophe Corvol,
  • Marie-Christine Chartier-Harlin,
  • Eugénie Mutez,
  • Kathrin Brockmann,
  • Angela B. Deutschlander,
  • Lena F. Burbulla,
  • Georges M. Hadjigeorgiou,
  • Efthimos Dardiotis,
  • Leonidas Stefanis,
  • Athina Maria Simitsi,
  • Enza Maria Valente,
  • Simona Petrucci,
  • Letizia Straniero,
  • Anna Zecchinelli,
  • Gianni Pezzoli,
  • Laura Brighina,
  • Carlo Ferrarese,
  • Grazia Annesi,
  • Andrea Quattrone,
  • Monica Gagliardi,
  • Hirotaka Matsuo,
  • Akiyoshi Nakayama,
  • Nobutaka Hattori,
  • Kenya Nishioka,
  • Sun Ju Chung,
  • Yun Joong Kim,
  • Pierre Kolber,
  • Bart PC Van de Warrenburg,
  • Bastiaan R. Bloem,
  • Mathias Toft,
  • Lasse Pihlstrøm,
  • Leonor Correia Guedes,
  • Joaquim J. Ferreira,
  • Soraya Bardien,
  • Jonathan Carr,
  • Eduardo Tolosa,
  • Mario Ezquerra,
  • Pau Pastor,
  • Caroline Ran,
  • Andrea C. Belin,
  • Andreas Puschmann,
  • Carl E. Clarke,
  • Karen E. Morrison,
  • Manuela Tan,
  • Dimitri Krainc,
  • Matt J. Farrer,
  • Zied Landoulsi,
  • Rejko Kruger,
  • Thomas Gasser,
  • Alexis Elbaz,
  • Manu Sharma,
  • Karin Wirdefeldt

摘要

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.