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

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Hansen, Ailin Falkmo 
Gagliano Taliun, Sarah A  ORCID logo


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.



Humans, Iron, Transferrin, Polymorphism, Single Nucleotide, Ferritins, Genome-Wide Association Study, Biomarkers

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Commun Biol

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Springer Science and Business Media LLC
Medical Research Council (MC_UU_00002/7)
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
National Institute for Health Research (IS-BRC-1215-20014)
Wellcome Trust and the Royal Society (204623/Z/16/Z). United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7). National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014)