Associations of genetically determined iron status across the phenome: A mendelian randomization study

Abstract

Background Iron is integral to many physiological processes, and variations in its levels, even within the normal range, can have implications for health. The objective of this study was to explore the broad clinical effects of varying iron status. Methods and findings Genome-wide association study (GWAS) summary data obtained from 48,972 European individuals (55% female) across 19 cohorts in the Genetics of Iron Status Consortium were used to identify 3 genetic variants (rs1800562 and rs1799945 in the hemochromatosis gene [ HFE ] and rs855791 in the transmembrane protease serine 6 gene [ TMPRSS6 ]) that associate with increased serum iron, ferritin, and transferrin saturation and decreased transferrin levels, thus serving as instruments for systemic iron status. Phenome-wide association study (PheWAS) of these instruments was performed on 424,439 European individuals (54% female) in the UK Biobank who were aged 40–69 years when recruited from 2006 to 2010, with their genetic data linked to Hospital Episode Statistics (HES) from April, 1995 to March, 2016. Two-sample summary data mendelian randomization (MR) analysis was performed to investigate the effect of varying iron status on outcomes across the human phenome. MR–PheWAS analysis for the 3 iron status genetic instruments was performed separately and then pooled by meta-analysis. Correction was made for testing of multiple correlated phenotypes using a 5% false discovery rate (FDR) threshold. Heterogeneity between MR estimates for different instruments was used to indicate possible bias due to effects of the genetic variants through pathways unrelated to iron status. There were 904 distinct phenotypes included in the MR–PheWAS analyses. After correcting for multiple testing, the 3 genetic instruments for systemic iron status demonstrated consistent evidence of a causal effect of higher iron status on decreasing risk of traits related to anemia (iron deficiency anemia: odds ratio [OR] scaled to a standard deviation [SD] increase in genetically determined serum iron levels 0.72, 95% confidence interval [CI] 0.64–0.81, P = 4 × 10 −8 ) and hypercholesterolemia (hypercholesterolemia: OR 0.88, 95% CI 0.83–0.93, P = 2 × 10 −5 ) and increasing risk of traits related to infection of the skin and related structures (cellulitis and abscess of the leg: OR 1.25, 95% CI 1.10–1.42, P = 6 × 10 −4 ). The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and misclassification of diagnoses in the HES data. Furthermore, this work only investigated participants with European ancestry, and the findings may not be applicable to other ethnic groups. Conclusions Our findings offer novel, to our knowledge, insight into previously unr...

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

“…Other significant mineral–outcome relationships are also worth mentioning. We found that genetically predicted higher blood iron is associated with an increased risk of glossitis (i.e., tongue inflammation), which is consistent with what has been reported in a previous MR study [ 21 ]. However, it is fairly well established that patients of atrophic glossitis frequently suffer from deficiencies of nutrients, including iron, and corresponding nutrient supplementation is able to resolve oral symptoms [ 60 ].…”

“…Compared to these hypothesis-driven MR studies with an obvious bias toward cardiovascular diseases, a phenome-wide association study coupled with MR (PheWAS-MR) enables an unbiased and hypothesis-free scan through a wide range of phenotypes (i.e., phenome) and prioritized candidate clinical outcomes for MR causal inferences. PheWAS-MR has been conducted on iron, but not copper [ 21 ]. Most importantly, few existing studies simultaneously examine multiple blood minerals at a phenome-wide scale to disentangle their confounded clinical effects [ 22 ].…”

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Disease: Evidence from Phenome-wide Mendelian Randomization Study

“…Other significant mineral-outcome relationships are also worth attention. For iron, our finding of its status increases the risk of glossitis (i.e., tongue inflammation) has been reported in a previous MR study 49 . However, it is fairly well established that patients of atrophic glossitis frequently suffer from deficiencies of nutrients, including iron, and corresponding nutrient supplementation is able to resolve oral symptoms 50 .…”

Guidelines for performing Mendelian randomization investigations

“…If the aim of the investigation is to understand disease aetiology, then consideration of a limited set of exposures/outcomes as main analyses may be justified, whereas if the question relates to public health, then consideration of a broad range of outcomes influenced by an exposure may be worthwhile. At the extreme end of the spectrum is a phenome-wide Mendelian randomization investigation, in which very large numbers of exposure/outcome pairs are considered 15 – 17 . Such analyses are generally regarded as exploratory or “hypothesis-generating”, and results are typically treated as provisional until replicated in an independent dataset.…”