Polygenic Scores for Longitudinal Prediction of Incident Type 2 Diabetes in an Ancestrally and Medically Diverse Primary Care Network

OBJECTIVE The clinical utility of genetic information for type 2 diabetes (T2D) prediction with polygenic score (PGS) in ancestrally diverse, real-world US healthcare systems is unclear, especially for those at low clinical phenotypic risk for T2D. RESEARCH DESIGN AND METHODS We tested the association of PGS with T2D incidence in patients followed within a primary care practice network over 16 years in four hypothetical scenarios that varied by clinical data availability (N = 14,712): 1) age and sex, 2) age, sex, BMI, systolic blood pressure, and family history of diabetes; 3) all variables in (2) and random glucose; 4) all variables in (3), HDL, total cholesterol, and triglycerides, combined in a clinical risk score (CRS). To determine whether genetic effects differed by baseline clinical risk, we tested for interaction with the CRS. RESULTS PGS was associated with incident diabetes in all models. Adjusting for age and sex only, the Hazard Ratio (HR) per PGS standard deviation (SD) was 1.76 (95% CI 1.68, 1.84) and the HR of top 5% of PGS vs interquartile range (IQR) was 2.80 (2.39, 3.28). Adjusting for the CRS, the HR per SD was 1.48 (1.40, 1.57) and HR of top 5% of PGS vs IQR was 2.09 (1.72, 2.55). Genetic effects differed by baseline clinical risk [(PGS-CRS interaction p =0.05; CRS below the median: HR 1.60 (1.43, 1.79); CRS above the median: HR 1.45 (1.35, 1.55)]. CONCLUSIONS Genetic information can help identify high-risk patients even among those perceived to be low risk in a clinical evaluation. ### Competing Interest Statement J.B.M. is an Academic Associate for Quest Diagnostics inc. Endocrine R&D. ### Funding Statement J.M.M. and R.M. is supported by American Diabetes Association Innovative and Clinical Translational Award 1-19-ICTS-068, American Diabetes Association grant #11-22-ICTSPM-16 and by NHGRI U01HG011723. A.L. is supported by grant 2020096 from the Doris Duke Foundation and the American Diabetes Association Grant 7-22-ICTSPM-23. J.B.M. is supported by NIDDK U01 DK078616 and R01 HL151855. ### 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 IRB of Massachusetts General Hospital gave ethnical 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 Datasets analyzed in this study are not publicly available but on reasonable request may be made available from the corresponding author after detailing any restrictions that may apply to preserve patient confidentiality.