Title | Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and hemolysis |
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Type | Journal article |
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Authors | Sorokin, E., Basty, N., Whitcher, B., Liu, Y., Bell, J.D., Cohen, R.L., Cule, M. and Thomas, E.L. |
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Abstract | 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 a 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 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 the lytic phase of the erythrocyte life cycle and iron reuptake in the spleen. |
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Keywords | spleen iron |
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| magnetic resonance imaging |
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| imaging-derived phenotype |
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| quantitative traits |
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| human iron economy |
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| iron homeostasis |
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| hereditary spherocytosis |
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| hemolytic anemia |
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| genome-wide association study |
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| rare variant association study |
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Journal | American Journal of Human Genetics |
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Journal citation | 109 (6), pp. P1092-1104 |
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ISSN | 1537-6605 |
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Year | 2022 |
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Publisher | Cell Press |
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Accepted author manuscript | File Access Level Open (open metadata and files) |
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Digital Object Identifier (DOI) | https://doi.org/10.1016/j.ajhg.2022.04.013 |
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Web address (URL) | https://www.cell.com/ajhg/fulltext/S0002-9297(22)00161-6 |
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Publication dates |
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Published online | 13 May 2022 |
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Published in print | 02 Jun 2022 |
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Supplemental file | File Access Level Open (open metadata and files) |
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Funder | Calico Life Sciences LLC |
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