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

Henry R. Wilman, Constantinos A. Parisinos, Naeimeh Atabaki-Pasdar, Matt Kelly, E. Louise Thomas, Stefan Neubauer, Christopher Jennison, Beate Ehrhardt, Patrick Baum, Corinna Schoelsch, Jan Freijer, Rolf Grempler, Ulrike Graefe-Mody, Anita Hennige, Christiane Dings, Thorsten Lehr, Nina Scherer, Iryna Sihinecich, Francois Pattou, Violeta RaverdiRobert Caiazzo, Fanelly Torres, Helene Verkindt, Andrea Mari, Andrea Tura, Toni Giorgino, Bizzotto, Philippe Froguel, Amelie Bonneford, Mickael Canouil, Veronique Dhennin, Caroline Brorsson, Soren Brunak, Federico de Masi, Valborg Gudmundsdóttir, Helle Pedersen, Karina Banasik, Cecilia Thomas, Peter Sackett, Hans-Henrik Staerfeldt, Agnete Lundgaard, Anitra Koopman, Femke Rutters, Joline Beulens, Lenka Groeneveld, IMI DIRECT Consortium, Anitra Koopman, Femke Rutters, Joline Beulens, Lenka Groeneveld, Anitra Koopman, Louise Thomas, Brandon Whitcher, Anubha Mahajan, Aroon D. Hingorani, Riyaz S. Patel, Harry Hemingway, Paul W. Franks, Jimmy D. Bell, Rajarshi Banerjee, Hanieh Yaghootkar

Research output: Contribution to journalArticleAcademicpeer-review


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
Pages (from-to)594-602
Number of pages9
JournalJournal of Hepatology
Issue number3
Publication statusPublished - 1 Sep 2019

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