The role of genetically predicted serum iron levels on neurodegenerative and cardiovascular traits

Abstract

Iron is an essential mineral that supports numerous biological functions. Studies have reported associations between iron dysregulation and certain cardiovascular and neurodegenerative diseases, but the direction of influence is not clear. Our goal was to use computational approaches to better understand the role of genetically predicted iron levels on disease risk. We meta-analyzed genome-wide association study summary statistics for serum iron levels from two cohorts and two previous meta-analyses. We then obtained summary statistics from 11 neurodegenerative, cerebrovascular, cardiovascular or lipid traits to assess global and regional genetic correlation between iron levels and these traits. We used two-sample Mendelian randomization (MR) to estimate causal effects. Sex-stratified analyses were also carried out to identify effects potentially differing by sex. Overall, we identified three significant global correlations between iron levels and (i) coronary heart disease, (ii) triglycerides, and (iii) high-density lipoprotein (HDL) cholesterol levels. A total of 194 genomic regions had significant (after correction for multiple testing) local correlations between iron levels and the 11 tested traits. MR analysis revealed two potential causal relationships, between genetically predicted iron levels and (i) total cholesterol or (ii) non-HDL cholesterol. Sex-stratified analyses suggested a potential protective effect of iron levels on Parkinson's disease risk in females, but not in males. Our results will contribute to a better understanding of the genetic basis underlying iron in cardiovascular and neurological health in aging, and to the eventual identification of new preventive interventions or therapeutic avenues for diseases which affect women and men worldwide.

Keywords: Cardiovascular; Genetic correlation; Mendelian randomization (MR); Neurodegeneration; Serum iron; Sex-stratified.

Fig. 1

Manhattan plot of the results from the GWAS meta-analysis of serum iron using a sample-size weighted z-score method resulting in a total sample size of 263,167 individuals of European-like genetic ancestry. The dashed line presents the threshold to denote genome-wide significance (5 × 10^–8). We replaced extremely significant values in our analysis with a minimum non-zero value that plotting libraries can handle. Note rescaling on the y-axis represented by two horizontal lines (“=”).

Fig. 2

Local genetic correlations between iron and NDD or CVD. Chromosomal visualization (created using PhenoGram) of significantly correlated regions between iron and the 11 neurodegenerative or cardiovascular traits tested as listed in Supplementary Table 1 (a). Illustration of selected significant shared regional correlations on chromosome 6 (either just upstream or within the major histocompatibility complex) between serum iron and lipid traits tested (b). **Significant local correlation after Bonferroni correction; s: p-value < 0.05 but not significant at the Bonferroni correction threshold; ns non-significant (p-value > 0.05), AD Alzheimer’s disease, PD Parkinson’s disease, ALS amyotrophic lateral sclerosis, CAD coronary artery disease, HF heart failure, TC total cholesterol, TG triglycerides, HDL high-density lipoprotein cholesterol, LDL low-density lipoprotein cholesterol, nonHDL non-high-density lipoprotein cholesterol.

Fig. 3

Mendelian randomization results with genetically predicted iron levels as the exposure and each of the 11 neurodegenerative, cardiovascular or cerebrovascular traits tested as the outcome with inverse-variance weighted (IVW) approach as the primary analysis and MR Egger, weighted median and weighted mode as secondary analyses. AD Alzheimer’s disease, PD Parkinson’s disease, ALS amyotrophic lateral sclerosis, CAD coronary artery disease, HF heart failure, TC total cholesterol, TG triglycerides, HDL high-density lipoprotein cholesterol, LDL low-density lipoprotein cholesterol, nonHDL non-high-density lipoprotein cholesterol.