Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

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Henry R. Wilman, Constantinos A. Parisinos, Naeimeh Atabaki-Pasdar, Matt Kelly, E. Louise Thomas, Stefan Neubauer, Christopher Jennison, B. Ehrhardt, Patrick Baum, Corinna Schoelsch, Jan Freijer, Rolf Grempler, Ulrike Graefe-Mody, A. Hennige, Christiane Dings, Thorsten Lehr, Nina Scherer, I. Sihinecich, Francois Pattou, Violeta Raverdi & 31 others Robert Caiazzo, Fanelly Torres, Helene Verkindt, Andrea Mari, Andrea Tura, Toni Giorgino, Bizzotto, Philippe Froguel, Caroline Brorsson, S. Brunak, Federico De Masi, H. Pedersen, Karina Banasik, Cecilia Thomas, Agnete Lundgaard, A. Nielsen, Gianluca Mazzoni, T. Karaderi, S. Rasmussen, Joachim Johansen, Rosa Allesøe, Manimozhiyan Arumugam, Kristine Allin, Torben Hansen, Tue Hansen, Anna Jonsson, Oluf Pedersen, Avirup Dutta, J. Vogt, Henrik Vestergaard, IMI-DIRECT consortium

Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.

Original languageEnglish
JournalJournal of Hepatology
Volume71
Issue number3
Pages (from-to)594-602
Number of pages9
ISSN0168-8278
DOIs
Publication statusPublished - 2019

    Research areas

  • Genetics, Genome-wide association study, Iron, Magnetic resonance imaging, Metabolic syndrome, Metabolism

ID: 226394520