Causal linkage between adult height and kidney function: An integrated population-scale observational analysis and Mendelian randomization study

As adult height is linked to various health outcomes, further investigation of its causal effects on kidney function later in life is warranted. This study involved a cross-sectional observational analysis and summary-level Mendelian randomization (MR) analysis. First, the observational association between height and estimated GFR determined by creatinine (eGFR(creatinine)) or cystatin C (eGFR(cystatinC)) was investigated in 467,182 individuals aged 40–69 using UK Biobank. Second, the genetic instrument for adult height, as reported by the GIANT consortium, was implemented, and summary-level MR of eGFR(creatinine) and CKD(creatinine) in a CKDGen genome-wide association study was performed (N = 567,460), with multivariable MR being adjusted for the effects of genetic predisposition on body mass index. To replicate the findings, additional two-sample MR using the summary statistics of eGFR(cystatinC) and CKD(cystatinC) in UK Biobank was performed (N = 321,405). In observational analysis, adult height was inversely associated with both eGFR(creatinine) (per 1 SD, adjusted beta -1.039, standard error 0.129, P < 0.001) and eGFR(cystatinC) (adjusted beta -1.769, standard error 0.161, P < 0.001) in a multivariable model adjusted for clinicodemographic, anthropometric, metabolic, and social factors. Moreover, multivariable summary-level MR showed that a taller genetically predicted adult height was causally linked to a lower log-eGFR(creatinine) (adjusted beta -0.007, standard error 0.001, P < 0.001) and a higher risk of CKD(creatinine) (adjusted beta 0.083, standard error 0.019, P < 0.001). Other pleiotropy-robust sensitivity MR analysis results supported the findings. In addition, similar results were obtained by two-sample MR of eGFR(cystatinC) (adjusted beta -1.303, standard error 0.140, P < 0.001) and CKD(cystatinC) (adjusted beta 0.153, standard error 0.025, P < 0.001) in UK Biobank. In conclusion, the results of this study suggest that a taller adult height is causally linked to worse kidney function in middle-aged to elderly individuals, independent of the effect of body mass index.