Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT
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 Tr?ndelag 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 127 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 the latest 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.
Burgess Stephen、Nielsen Jonas B、Hveem Kristian、Graham Sarah E、Gagliano Taliun Sarah A、Wu Kuan-Han、Cucca Francesco、Schlessinger David、Abecasis Gon?alo R.、?svold Bj?rn Olav、Willer Cristen J、Gill Dipender、Thorstensen Ketil、Brumpton Ben M、Fritsche Lars G、Hansen Ailin Falkmo、Zhou Wei、Mason Amy、Moksnes Marta R
Department of Public Health and Primary Care, University of Cambridge||Medical Research Council Biostatistics Unit, University of CambridgeK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU ¨C Norwegian University of Science and Technology||Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan||Department of Epidemiology Research, Statens Serum Institute||Department of Cardiology, Copenhagen University HospitalK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU ¨C Norwegian University of Science and Technology||HUNT Research Centre, Department of Public Health and Nursing, NTNU ¨C Norwegian University of Science and TechnologyDivision of Cardiovascular Medicine, Department of Internal Medicine, University of MichiganFaculty of Medicine, University of Montr¨|al||Montr¨|al Heart InstituteDepartment of Computational Medicine and Bioinformatics, University of MichiganIstituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR)||Dipartimento di Scienze Biomediche, Universit¨¤ degli Studi di SassariLaboratory of Genetics, National Institute on Aging, US National Institutes of HealthCenter for Statistical Genetics, University of Michigan School of Public HealthK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU ¨C Norwegian University of Science and Technology||Department of Endocrinology, Clinic of Medicine, St. Olavs hospital Trondheim University Hospital||HUNT Research Centre, Department of Public Health and Nursing, NTNU ¨C Norwegian University of Science and TechnologyK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU ¨C Norwegian University of Science and Technology||Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan||Department of Computational Medicine and Bioinformatics, University of Michigan||Department of Human Genetics, University of MichiganDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London||Clinical Pharmacology and Therapeutics Section, Institute for Infection and Immunity, St George?ˉs, University of London||Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George?ˉs University Hospitals NHS Foundation Trust||Novo Nordisk Research Centre Oxford, Old Road CampusDepartment of Clinical Chemistry, St. Olavs hospital Trondheim University HospitalK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU ¨C Norwegian University of Science and Technology||HUNT Research Centre, Department of Public Health and Nursing, NTNU ¨C Norwegian University of Science and Technology||Clinic of Medicine, St. Olavs hospital Trondheim University HospitalDepartment of Biostatistics, University of Michigan School of Public Health||Center for Statistical Genetics, University of Michigan School of Public HealthK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU ¨C Norwegian University of Science and TechnologyAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardDepartment of Public Health and Primary Care, University of Cambridge||National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University HospitalsK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU ¨C Norwegian University of Science and Technology
基础医学遗传学生物科学研究方法、生物科学研究技术
Burgess Stephen,Nielsen Jonas B,Hveem Kristian,Graham Sarah E,Gagliano Taliun Sarah A,Wu Kuan-Han,Cucca Francesco,Schlessinger David,Abecasis Gon?alo R.,?svold Bj?rn Olav,Willer Cristen J,Gill Dipender,Thorstensen Ketil,Brumpton Ben M,Fritsche Lars G,Hansen Ailin Falkmo,Zhou Wei,Mason Amy,Moksnes Marta R.Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT[EB/OL].(2025-03-28)[2025-05-07].https://www.medrxiv.org/content/10.1101/2021.09.20.21262960.点此复制
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