Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and erythrocyte morphology

The spleen plays a key role in iron homeostasis. It is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this role, spleen iron concentration has not been measured in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank using magnetic resonance imaging, and provide the first reference range for spleen iron in an unselected population. Through genome-wide association study, we identify associations between spleen iron and regulatory variation at two hereditary spherocytosis genes, ANK1 and SPTA1 . Spherocytosis-causing coding mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while these novel common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes that have been observed clinically. Our genetic study also identifies a signal which co-localizes with a splicing quantitative trait locus for MS4A7 , and we show this gene is abundantly expressed in the spleen and in macrophages. The combination of deep learning and efficient image processing enables non-invasive measurement of spleen iron and, in turn, characterization of genetic factors related to iron recycling and erythrocyte morphology. ### Competing Interest Statement EPS, RLC and MC are employees of Calico Life Sciences LLC. YL is a former employee of Calico Life Sciences LLC. NB, BW, JDB, and ELT have no competing interests. ### Funding Statement This study was funded by Calico Life Sciences LLC. ### 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: All raw data is made available from the UK Biobank ([www.ukbiobank.ac.uk][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Model weights for spleen segmentation are available via Github ([www.github.com/calico-ukbb-mri-sseg][2]) and code for resampling at [www.github.com/recoh/pipeline][3]. All summary statistics will be made available from the GWAS Catalog ([www.ebi.ac.uk/gwas][4]) upon publication. All derived data will be made available from the UK Biobank ([www.ukbiobank.ac.uk][1]). [1]: http://www.ukbiobank.ac.uk [2]: http://www.github.com/calico-ukbb-mri-sseg [3]: http://www.github.com/recoh/pipeline [4]: http://www.ebi.ac.uk/gwas