Other MR methods confirmed the findings of the main analyses. Finally, genetically predicted CKD conferred a 0.05 increase in standardized log-transformed 25(OH)D level (95% CI 0.04, 0.06 P = 1.06 × 10-13). Increased BUN was associated with increased 25(OH)D (β = 0.25, 95% CI 0.15, 0.36 P = 4.12 × 10-6 per unit increase in log-transformed BUN). Our inverse variance weighted MR demonstrated a 0.56 decrease in standardized log-transformed 25(OH)D (95% CI -0.73, -0.41 P = 2.89 × 10-12) per unit increase in log-transformed eGFR.

We did not find robust evidence supporting effects of 25(OH)D on eGFR, BUN, and CKD or its progression.

We performed a reverse MR, using SNPs for the above indices of renal function to study causal effects on 25(OH)D levels. To control for pleiotropy, we also used SNPs solely in DHCR7, CYP2R1, and GC, all genes with known roles in vitamin D metabolism. In this two-sample MR study, we used single nucleotide polymorphisms (SNP) associated with 25(OH)D in 443 734 Europeans and evaluated their effects on estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), chronic kidney disease (CKD) risk and progression in genome-wide association studies totaling over 1 million Europeans. We tested whether 25-hydroxyvitamin D (25D) serum levels are associated with renal function, and inversely, whether altered renal function causes changes in 25(OH)D, using Mendelian randomization (MR). Observational studies investigating the role of vitamin D in renal function have yielded inconsistent results.

Downie 3