Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

Abstract

Iron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron-related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron-binding capacity) in the Trøndelag Health Study (HUNT), the Michigan Genomics Initiative (MGI), and the SardiNIA study, followed by their meta-analysis with publicly available summary statistics, analyzing up to 257,953 individuals. We identify 123 genetic loci associated with iron traits. Among 19 novel protein-altering variants, we observe a rare missense variant (rs367731784) in HUNT, which suggests a role for DNAJC13 in transferrin recycling. We further validate recently published results using genetic risk scores for each biomarker in HUNT (6% variance in serum iron explained) and present linear and non-linear Mendelian randomization analyses of the traits on all-cause mortality. We find evidence of a harmful effect of increased serum iron and transferrin saturation in linear analyses that estimate population-averaged effects. However, there was weak evidence of a protective effect of increasing serum iron at the very low end of its distribution. Our findings contribute to our understanding of the genes affecting iron status and its consequences on human health.

Fig. 1. Phenome-wide associations between GRSs for iron status biomarkers and 1473 phecodes, blood biomarkers, and continuous traits in the UK Biobank.

Phenome-wide associations between the GRS for each biomarker (serum iron [a], serum ferritin [b], total iron-binding capacity [c], and transferrin saturation percentage [d]) and 1473 phecodes, blood biomarkers, and continuous traits in the UK Biobank. Triangles pointing upwards indicate a positive association between the phenotype and the GRS (where a higher GRS score represents higher level of the biomarker) and vice versa. Associations with p-values < 10⁻³²⁴ are plotted at 10⁻³²⁴. The Bonferroni corrected p-value cut-off (2.3 × 10⁻⁷) is given as a red dotted line. Biological domains are indicated by color; for the significant associations, these are: hematopoietic (orange), anthropometric (dark blue), circulatory system (red), respiratory (brown), digestive (light green), genitourinary (yellow), musculoskeletal (dark green), endocrine/metabolic (magenta), symptoms (light blue). Abbreviations: MCV mean corpuscular volume, MCH mean corpuscular hemoglobin, MCHC mean corpuscular hemoglobin concentration, dist. distribution, Cong. def. congenital deficiencies, HbA1c glycated hemoglobin, SHBG sex hormone-binding globulin, LDL low-density lipoproteins, Apo B apolipoprotein B, IGF-1 insulin-like growth factor 1, FEV1 forced expiratory volume (1 s), FVC forced vital capacity, ALP alkaline phosphatase, ASAT aspartate aminotransferase, ALAT alanine aminotransferase, GGT gamma-glutamyl transferase. a: ¹Other anemias, ²Impedance, ³FEV1, ⁴FVC, ⁵Total protein, ⁶Cystatin C, ⁷Phosphate, ⁸Apo B, ⁹Testosterone, ¹⁰IGF-1, ¹¹Cholesterol, ¹²LDL. b: ¹Anemias (iron deficiency and other anemias), ²Platelet indices (platelet count, platelet crit, platelet dist. width), ³White blood cell counts (lymphocytes, leukocytes, monocytes), ⁴Seated height, ⁵Water mass, ⁶Fat-free mass, ⁷Phlebitis and thrombophlebitis, ⁸Non-alcoholic liver disease, ⁹Gamma-glutamyl Transferase, ¹⁰Direct bilirubin, ¹¹Urate, ¹²Creatinine. c: ¹Mean platelet volume, ²Platelet crit, ³Platelet dist. width., ⁴FEV1, ⁵FVC, ⁶Liver cirrhosis, ⁷Cystatin C, ⁸Phosphate. d: ¹Other anemias, ²Monocyte percentage, ³Congenital deficiency of other clotting factors, ⁴FEV1, ⁵FVC, ⁶ALAT, ⁷Cystatin C, ⁸Phosphate, ⁹LDL, ¹⁰Apo B, ¹¹IGF-1, ¹²Cholesterol, ¹³Testosterone.

Fig. 2. Non-linear Mendelian Randomization: causal associations between iron status biomarkers and all-cause mortality.

Dose-response curves (black) between iron traits and all-cause mortality in HUNT (gray lines give 95% confidence interval). The x-axis gives a: serum iron levels (µmol/L) [N = 56,654], b: serum ferritin (µg L⁻¹) [N = 2335], c: transferrin saturation (%) [N = 56,651] and d: total iron-binding capacity (TIBC) (µmol L⁻¹) [N = 56,654]. The y-axis gives the hazard ratios for all-cause mortality with respect to the reference values (red dot), which represent the established target values (iron, TIBC, TSP) or median value (ferritin) for the traits. The curve gradients represent the localized average causal effect at each point. N = sample size.