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.