Background: Observational studies suggest that long-standing diabetes may be a cause of pancreatic cancer. To further support this observation, we aimed to determine whether the genetic risk of diabetes is associated with a family history of pancreatic cancer in persons without a personal history of pancreatic cancer. We hypothesized that if diabetes is a cause of pancreatic cancer, then persons with a family history of pancreatic cancer, reflecting both inheritance and lifestyle risk factors, will be enriched with a genetic propensity for diabetes. Our hypothesis assumes that the causal genes for diabetes and pancreatic cancer are not identical. Methods: We conducted a cross-sectional analysis of 3,911 participants without a personal history of pancreatic cancer using data from the All of Us Research Program. Family history of pancreatic cancer was assessed through structured electronic health record reviews and self-reported questionnaires capturing first-degree relatives cancer histories. A polygenic score (PGS) for type II diabetes was created using short-read whole genome sequencing (srWGS) data in All of Us. Logistic regression was used to test the association between family history (first degree relative) of pancreatic cancer and polygenic risk for diabetes, adjusting for relevant demographic and lifestyle variables. Results: Mean age was 65.7 years, with 64.8% women and 83.4% White participants. Among the 3,911 participants,173 individuals (4.4%) had a family history of pancreatic cancer. Diabetes PGS was not associated with a higher OR of a family history of pancreatic cancer; OR for higher PGS was 0.67 (95% CI 0.45-0.98) before adjustment and 0.67 (95% CI 0.44-0.97) after adjustment. Restricting to participants ≤ 50 years among whom we expected a lower likelihood of survival bias, the association was attenuated (OR= 0.75, 95% CI 0.47-1.18). In contrast, the OR was even more inverse in participants >50 years (OR= 0.60, 95% CI 0.38-0.94). Simulations further support the potential for survival bias. Conclusions: Contrary to the hypothesis, persons with a family history of pancreatic cancer were not enriched with genetic risk of diabetes. The observed inverse association may be partially due to survival bias. This work points to complexities in the conduct of etiologic research using a cross-sectional design. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### 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: Institutional Review Board of the Johns Hopkins Bloomberg School of Public Health waived ethical approval for this work. 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 Data used in this study are available to registered researchers through the All of Us Researcher Workbench (https://www.researchallofus.org/) following institutional registration and required training.
