Independent Effects of Family History and Polygenic Score in Predicting the Risk of CKD

Background: Family health history (FHH) and genetic predisposition contribute significantly to the risk of chronic kidney disease (CKD). However, their relative predictive values have not been systematically evaluated. Methods: We analyzed preliminary data from a multi-center eMERGE IV cohort (N=4104) using Poisson regression models with a log link function and robust standard errors to estimate recurrence risk ratios (RRRs) for CKD associated with FHH and polygenic risk score (PRS). The CKD diagnosis and staging was defined electronically using our published e-phenotype. The PRS used was previously validated by our group. FHH was collected by self-report using MeTree software, and stratified by the number of affected relatives (single vs. multiple) and relatedness type (maternal, paternal, 1st degree, 2nd degree). All models were adjusted for age, sex, BMI, diabetes, hyperlipidemia, and site. Results: Across all models, FHH was a strong and consistent predictor of CKD. Compared to individuals without a family history of CKD, those with at least one affected family member had a 1.56-fold to 6.73-fold increased risk of CKD across different definitions of FHH and CKD. The risk was similarly elevated or greater among those with two or more affected relatives, with RRRs ranging from 1.67 to 6.15 depending on CKD severity. Generally, the effect sizes for FHH became more pronounced for higher stages of CKD, suggesting that FHH is particularly predictive of more advanced disease. The PRS for CKD was also consistently associated with CKD, with statistically significant effects independent of FHH (RRR range: 1.05–1.11 per SD). We observed no significant interactions between the PRS and FHH. Conclusion: Both FHH and PRS are independently associated with CKD risk. FHH had larger effects on the risk of more advanced CKD. Our findings support incorporating both familial and genetic information into the CKD risk stratification models. Funding: Other NIH Support - National Human Genome Research Institute (NHGRI)