Mendelian randomization study of diabetes and dementia in the Million Veteran Program

INTRODUCTION Diabetes and dementia are diseases of high healthcare burden worldwide. Individuals with diabetes have 1.4 to 2.2 times higher risk of dementia. Our objective was to evaluate evidence of causality between these two common diseases. METHODS We conducted a one-sample Mendelian randomization (MR) analysis in the U.S. Department of Veterans Affairs Million Veteran program. The study included 334,672 participants ≥65 years of age with type 2 diabetes and dementia case-control status and genotype data. RESULTS For each standard deviation increase in genetically-predicted diabetes, we found increased odds of three dementia diagnoses in non-Hispanic White participants (all-cause: OR=1.07[1.05-1.08], P =3.40E-18; vascular: OR=1.11[1.07-1.15], P =3.63E-09, Alzheimer’s: OR=1.06[1.02-1.09], P =6.84E-04) and non-Hispanic Black participants (all-cause: OR=1.06[1.02-1.10], P =3.66E-03, vascular: OR=1.11[1.04-1.19], P =2.20E-03, Alzheimer’s: OR=1.12 [1.02-1.23], P =1.60E-02) but not in Hispanic participants (all P >.05). DISCUSSION We found evidence of causality between diabetes and dementia using a one-sample MR study, with access to individual level data, overcoming limitations of prior studies utilizing two-sample MR techniques. ### Competing Interest Statement Within the past several years, LSP has served on Scientific Advisory Boards for Janssen, and the Profil Institute for Clinical Research, and has or had research support from Merck, Amylin, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, Abbvie, Vascular Pharmaceuticals, Janssen, Glaxo SmithKline, Pfizer, and the Cystic Fibrosis Foundation. In the past, LSP was a speaker for Novartis and Merck, but not for the last five years. LSP is also a cofounder and Officer and Board member and stockholder of a company, DIASYST, Inc., which is developing software aimed to help improve diabetes management. SR has previously received research grant funding from the American Heart Association. EML, MWL, RZ, BRC, EML(2), JEH, JAL, MV, LAL, RLH have no conflicts to disclose. ### Funding Statement Funding: EML is supported by US National Institutes of Health award P30DK116073, and by funds from the Boettcher Foundation Webb-Waring Biomedical Research Program. Phenotype development in MVP was supported by US Department of Veterans Affairs award BLR&D 1 I01BX004192 (MWL PI). LSP 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. RLH is supported by the Million Veteran Program MVP022 award # I01 CX001727, VISN-22 VA Center of Excellence for Stress and Mental Health (CESAMH), and National Institute of Aging RO1 grants AG050595 (The VETSA Longitudinal Twin Study of Cognition and Aging VETSA 4), AG05064 (Effects of Androgen Deprivation Therapy on Preclinical Symptoms of Alzheimers Disease), SR is supported by US Department of Veterans Affairs award IK2-CX001907, by US National Institutes of Health award P30DK116073, and by funds from the Boettcher Foundation Webb-Waring Biomedical Research Program. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards MVP003, MVP009, MVP015, and MVP022. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Veterans Affairs Central Institutional Review Board provided approval for the study protocol in accordance with the principles of the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Summary data produced in the present study are available upon reasonable request to the authors