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

Abstract Background & Aims Excess liver iron content is common and is linked to hepatic and extrahepatic disease risk. 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 in UK Biobank with MRI quantified liver iron, and validated our findings in an independent cohort (n=1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 29 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 anthropometric traits and diseases. Results We identified three 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 -8 ). The two 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 find that three genetic variants are linked to 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.