Shared and Unique Clinical Effects of Five Circulating Minerals: A Comparative Phenome-Wide Mendelian-Randomization Study

Abstract Objectives To disentangle the shared and unique causal clinical effects of five circulating minerals – iron, zinc, copper, calcium, and magnesium. Methods Genetic instruments for circulating minerals were curated from existing genome-wide association studies. Candidate clinical outcomes were identified with a phenome-wide association study (PheWAS) between these genetic instruments and 853 phenotypes in 310,999 individuals from the UK Biobank. Two-sample Mendelian Randomization (MR) analyses were performed to evaluate the causal associations between genetically predicted circulating mineral levels and candidate clinical outcomes. Multiple sensitivity tests were applied to detect and correct for the presence of horizontal pleiotropy. Results Iron and copper were found to share the most clinical outcomes. Genetically predicted higher blood levels of iron and copper are associated with lower risks of iron deficiency anemia and lipid metabolism disorders, including hyperlipidemia and hypercholesterolemia. Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. On the other hand, osteoarthrosis (OA) and its subcategories are associated with the most minerals, including zinc, copper, and calcium. Genetically predicted higher blood levels of zinc and copper are associated with increased risk of OA, while calcium exhibits protective effects. Another five shared clinical effects were identified. For instance, zinc and magnesium are associated with a higher risk of bacterial infection; calcium and magnesium increase the risk of renal colic; iron increases while calcium decreases the risk of varicose veins. Unique clinical effects of each blood mineral were also pinpointed, such as iron enhancing the risk of glossitis and acquired foot deformities. Conclusions Our comparative PheWAS-MR study of five circulating minerals comprehensively characterized their shared and unique clinical effects, highlighting the causal roles of specific minerals in hyperlipidemia and OA. Our findings emphasize managing blood minerals, probably through dietary adjustments, for disease prevention. Funding Sources United States Department of Agriculture; National Institute of Food and Agriculture Hatch Funds; Allen Foundation Inc.; University of Georgia Research Foundation.