Genetic Association of eGFR with BMD: A Mendelian Randomization Study Public

Abstract

Background: Both chronic kidney disease (CKD) and osteoporosis are important public health issues worldwide with high prevalence especially among the older population. These two diseases have high comorbidity and share multiple risk factors. The estimated glomerular filtration rate (eGFR) is the primary measurement of the filtration function of kidney. A low bone mineral density (BMD) is often used to diagnose osteoporosis and predict future osteoporotic fractures. Several observational epidemiologic studies have reported strong association between eGFR and BMD among older populations. Understanding whether the associations reflect a causal relationship or mere correlation may inform whether targeting renal treatment could reduce risk for osteoporosis, or vice versa.

Methods: We performed a bidirectional two-sample Mendelian randomization (MR) analysis using publicly available summary-level data from a genome-wide association study (GWAS) of eGFR (n= 567,460), and a GWAS of BMD (n = 395,929) among participants of European ancestry to test the hypothesis that the association between eGFR and BMD is potentially causal. The two-sample MR analyses included inverse-variance-weighted (IVW) regression for estimating the causal effects, and MR-Egger regression for the sensitivity analyses.

Results: We found no evidence of causal effect of eGFR on BMD (225 SNPs; causal effect estimate per 1-unit increase in log(eGFR)=-0.0950, p-value=0.68). The intercept obtained from MR-Egger regression was 0.001 (p-value=0.53), suggesting no evidence of horizontal pleiotropy. Evaluation of the inverse direction of causality showed that there is no evidence of causal effect of BMD on eGFR either (878 SNPs; causal effect estimate per 1-SD increase in BMD=-2.99×10^(-5), p-value=0.98). Results obtained from MR-Egger regression (intercept=0.000, p-value=0.054) suggested no evidence of horizontal pleiotropy.

Conclusion: In summary, our bidirectional MR analyses did not support the causal relationship between eGFR and BMD in either direction among the European ancestry. However, MR analysis does not exclusively address the causal relationship by itself, and further work would be needed to investigate such causal relationship among specific subgroups, or common risk factors underlying the observed association between eGFR and BMD.

Table of Contents

Introduction

Methods

- Genetic variant instruments for eGFR

- Genetic variant instruments for BMD

- Bidirectional Two-sample Mendelian Randomization

Results

- Causal assocation of eGFR on BMD

- Causal association of BMD on eGFR

Discussion

References

Tables and Figures

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Epidemiology - MPH & MSPH
Degree	M.S.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Epidemiology
Mot-clé	BMD Mendelian Randomization eGFR
Committee Chair / Thesis Advisor	Yan Sun, Emory University

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