New insights into the genetic etiology of 57 essential and non-essential trace elements in humans

Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study (GWAS) of 57 essential and non-essential trace elements. We performed GWA meta-analyses of 14 trace elements in up to 6580 Scandinavian whole-blood samples, and GWASs of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identified 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide meta-analyses. In HUNT, several genome-wide significant loci were also indicated for other trace elements. Using two-sample Mendelian randomization, we found several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our new understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Center (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St Olav's hospital and the Faculty of Medicine and Health Sciences, NTNU. The genetic investigations of the HUNT Study are a collaboration between researchers from the K.G. Jebsen Center for Genetic Epidemiology, NTNU, and the University of Michigan Medical School and the University of Michigan School of Public Health. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norway. We thank HUNT participants for donating their time, samples, and information to help others. The Norwegian Mother, Father and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities. The NIPH has contributed to funding of the Norwegian Environmental Biobank (NEB). The laboratory measurements have partly been funded by the Research Council of Norway through research projects (275903 and 268465), and the human biomonitoring project HBM4EU, funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No 733032. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The current study has been approved by the Norwegian Data Protection Authority and approved by the Regional Ethics Committee for Medical and Health Research Ethics in Northern Norway (REK Reference Number: 51604). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Summary level data supporting the findings are available in the Supplementary materials and upon request. The consent given by the participants in HUNT and MoBa does not open for storage of individual level data in repositories or journals. Researchers associated with Norwegian research institutes can apply for the use of HUNT data. Researchers from other countries may apply if collaborating with a Norwegian Principal Investigator. Information for data access can be found at https://www.ntnu.edu/hunt/data. Researchers who want access to MoBa data sets for replication should apply to helsedata.no. Access to data from either HUNT or MoBa requires approval from The Regional Committees for Medical and Health Research Ethics in Norway.