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Herold, J.M.* ; Nano, J. ; Gorski, M.* ; Winkler, T.W.* ; Stanzick, K.J.* ; Zimmermann, M.E.* ; Brandl, C.* ; Peters, A. ; Koenig, W.* ; Burkhardt, R.* ; Gessner, A.* ; Heid, I.* ; Gieger, C. ; Stark, K.J.*

Polygenic scores for estimated glomerular filtration rate in a population of general adults and elderly - comparative results from the KORA and AugUR study.

BMC Genom Data 24:28 (2023)

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BACKGROUND: Polygenic scores (PGSs) combining genetic variants found to be associated with creatinine-based estimated glomerular filtration rate (eGFR_crea) have been applied in various study populations with different age ranges. This has shown that PGS explain less eGFR_crea variance in the elderly. Our aim was to understand how differences in eGFR variance and the percentage explained by PGS varies between population of general adults and elderly. RESULTS: We derived a PGS for cystatin-based eGFR (eGFR_cys) from published genome-wide association studies. We used the 634 variants known for eGFR_crea and the 204 variants identified for eGFR_cys to calculate the PGS in two comparable studies capturing a general adult and an elderly population, KORA S4 (n = 2,900; age 24-69 years) and AugUR (n = 2,272, age ≥ 70 years). To identify potential factors determining age-dependent differences on the PGS-explained variance, we evaluated the PGS variance, the eGFR variance, and the beta estimates of PGS association on eGFR. Specifically, we compared frequencies of eGFR-lowering alleles between general adult and elderly individuals and analyzed the influence of comorbidities and medication intake. The PGS for eGFR_crea explained almost twice as much (R² = 9.6%) of age-/sex adjusted eGFR variance in the general adults compared to the elderly (4.6%). This difference was less pronounced for the PGS for eGFR_cys (4.7% or 3.6%, respectively). The beta-estimate of the PGS on eGFR_crea was higher in the general adults compared to the elderly, but similar for the PGS on eGFR_cys. The eGFR variance in the elderly was reduced by accounting for comorbidities and medication intake, but this did not explain the difference in R²-values. Allele frequencies between general adult and elderly individuals showed no significant differences except for one variant near APOE (rs429358). We found no enrichment of eGFR-protective alleles in the elderly compared to general adults. CONCLUSIONS: We concluded that the difference in explained variance by PGS was due to the higher age- and sex-adjusted eGFR variance in the elderly and, for eGFR_crea, also by a lower PGS association beta-estimate. Our results provide little evidence for survival or selection bias.

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