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Additive value of polygenic risk score to family history for type 2 diabetes prediction: Results from the All of US Research Database

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posted on 2025-01-22, 20:18 authored by Emily Drzymalla, Laura Raffield, Katherine Kolor, Alain Koyama, Ramal Moonesinghe, Meda E. Pavkov, Cassandra N. Spracklen, Muin J. Khoury

Objective: The goal of this study is to assess the additive value of considering type 2 diabetes (T2D) polygenic risk score (PRS) in addition to family history for T2D prediction.

Research Design and Methods: Data were obtained from the All of Us (AoU) research database. First degree T2D family history was self-report from the personal family history health questionnaire. A PRS was constructed from 1,289 variants identified from a large multi-ancestry GWAS meta-analysis for T2D. Logistic regression models were run to generate odds ratios (OR) and 95% confidence intervals (95% CI) for T2D. All models were adjusted for age, sex, and body mass index (BMI).

Results: A total of 109,958 AoU research participants were included in the analysis. The odds for T2D increased with 1 standard deviation (SD) PRS (OR: 1.75, 95% CI 1.71-1.79) and positive T2D family history (OR: 2.32, 95% CI 2.20-2.43). In the joint model, both the 1 SD PRS (OR: 1.69, 95% CI 1.65-1.72) and family history (OR: 2.06, 95% CI 1.98-2.15) were significantly associated with T2D, though the OR were slightly attenuated. Predictive models that included both PRS and family history (AUC=0.794) performed better than models including family history (AUC=0.763) or PRS (AUC=0.785).

Conclusions: In predicting T2D, inclusion of a T2D PRS in addition to family history of T2D (first degree relatives) has added statistical value. Further study is needed to determine whether consideration of both family history and PRS would be useful for clinical T2D prediction.

Funding

CNS was supported by the NIH (R01DK118011 and R01DK136671) and the American Diabetes Association (11-22-JDFPM-06). The All of Us Research Program is supported by the Federally Qualified Health Centers: HHSN 263201600085U; Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; and Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206.

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