Abstract
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 language | English |
|---|---|
| Pages (from-to) | 594-602 |
| Number of pages | 9 |
| Journal | Journal of Hepatology |
| Volume | 71 |
| Issue number | 3 |
| Early online date | 19 Jun 2019 |
| DOIs | |
| Publication status | Published - 1 Sept 2019 |
Bibliographical note
Funding Information:This research has been conducted using the UK Biobank resource and carried out under UK Biobank project numbers 9914 and 31037. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/Summary-EGF-consultation.pdf . No patients were specifically involved in setting the research question or the outcome measures or in developing plans for recruitment, design, or implementation of this study. No patients were asked to advise on interpretation or drafting of results. There are no specific plans to disseminate the research results to study participants, but the UK Biobank disseminates key findings from projects on its website. H.Y. is funded by a Diabetes UK RD Lawrence fellowship ( 17/0005594 ). C.A.P is funded by a Wellcome Trust Clinical PhD Programme ( 206274/Z/17/Z ). H.W is funded by an Innovate UK Knowledge Transfer Partnership ( KTP10271 ). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742 . IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. H.H is a National Institute for Health Research (NIHR Senior Investigator).
Funding Information:
H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). C.A.P is funded by a Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). H.W is funded by an Innovate UK Knowledge Transfer Partnership (KTP10271). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n?115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007?2013) and EFPIA companies? in-kind contribution. H.H is a National Institute for Health Research (NIHR) Senior Investigator.This research has been conducted using the UK Biobank resource and carried out under UK Biobank project numbers 9914 and 31037. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/Summary-EGF-consultation.pdf. No patients were specifically involved in setting the research question or the outcome measures or in developing plans for recruitment, design, or implementation of this study. No patients were asked to advise on interpretation or drafting of results. There are no specific plans to disseminate the research results to study participants, but the UK Biobank disseminates key findings from projects on its website. H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). C.A.P is funded by a Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). H.W is funded by an Innovate UK Knowledge Transfer Partnership (KTP10271). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n?115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies? in-kind contribution. H.H is a National Institute for Health Research (NIHR Senior Investigator).
Funding Information:
H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). C.A.P is funded by a Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). H.W is funded by an Innovate UK Knowledge Transfer Partnership (KTP10271). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. H.H is a National Institute for Health Research (NIHR) Senior Investigator.This research has been conducted using the UK Biobank resource and carried out under UK Biobank project numbers 9914 and 31037. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/Summary-EGF-consultation.pdf. No patients were specifically involved in setting the research question or the outcome measures or in developing plans for recruitment, design, or implementation of this study. No patients were asked to advise on interpretation or drafting of results. There are no specific plans to disseminate the research results to study participants, but the UK Biobank disseminates key findings from projects on its website. H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). C.A.P is funded by a Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). H.W is funded by an Innovate UK Knowledge Transfer Partnership (KTP10271). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. H.H is a National Institute for Health Research (NIHR Senior Investigator).
Funding Information:
M.K and R.B. are employees and shareholders of Perspectum Diagnostics. H.W. and S.N. are shareholders in Perspectum Diagnostics. The IMI DIRECT study was funded in part by Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi Aventis, and Servier. No other potential conflicts of interest relevant to this article were reported.
Funding Information:
H.Y. is funded by a Diabetes UK RD Lawrence fellowship ( 17/0005594 ). C.A.P is funded by a Wellcome Trust Clinical PhD Programme ( 206274/Z/17/Z ). H.W is funded by an Innovate UK Knowledge Transfer Partnership ( KTP10271 ). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. H.H is a National Institute for Health Research (NIHR) Senior Investigator.
Publisher Copyright:
© 2019 European Association for the Study of the Liver
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
Funding
This research has been conducted using the UK Biobank resource and carried out under UK Biobank project numbers 9914 and 31037. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/Summary-EGF-consultation.pdf . No patients were specifically involved in setting the research question or the outcome measures or in developing plans for recruitment, design, or implementation of this study. No patients were asked to advise on interpretation or drafting of results. There are no specific plans to disseminate the research results to study participants, but the UK Biobank disseminates key findings from projects on its website. H.Y. is funded by a Diabetes UK RD Lawrence fellowship ( 17/0005594 ). C.A.P is funded by a Wellcome Trust Clinical PhD Programme ( 206274/Z/17/Z ). H.W is funded by an Innovate UK Knowledge Transfer Partnership ( KTP10271 ). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742 . IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. H.H is a National Institute for Health Research (NIHR Senior Investigator). H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). C.A.P is funded by a Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). H.W is funded by an Innovate UK Knowledge Transfer Partnership (KTP10271). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n?115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007?2013) and EFPIA companies? in-kind contribution. H.H is a National Institute for Health Research (NIHR) Senior Investigator.This research has been conducted using the UK Biobank resource and carried out under UK Biobank project numbers 9914 and 31037. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/Summary-EGF-consultation.pdf. No patients were specifically involved in setting the research question or the outcome measures or in developing plans for recruitment, design, or implementation of this study. No patients were asked to advise on interpretation or drafting of results. There are no specific plans to disseminate the research results to study participants, but the UK Biobank disseminates key findings from projects on its website. H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). C.A.P is funded by a Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). H.W is funded by an Innovate UK Knowledge Transfer Partnership (KTP10271). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n?115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies? in-kind contribution. H.H is a National Institute for Health Research (NIHR Senior Investigator). H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). C.A.P is funded by a Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). H.W is funded by an Innovate UK Knowledge Transfer Partnership (KTP10271). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. H.H is a National Institute for Health Research (NIHR) Senior Investigator.This research has been conducted using the UK Biobank resource and carried out under UK Biobank project numbers 9914 and 31037. Details on patient and public involvement in the UK Biobank are available online at www.ukbiobank.ac.uk/about-biobank-uk and www.ukbiobank.ac.uk/wp-content/uploads/2011/07/Summary-EGF-consultation.pdf. No patients were specifically involved in setting the research question or the outcome measures or in developing plans for recruitment, design, or implementation of this study. No patients were asked to advise on interpretation or drafting of results. There are no specific plans to disseminate the research results to study participants, but the UK Biobank disseminates key findings from projects on its website. H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). C.A.P is funded by a Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). H.W is funded by an Innovate UK Knowledge Transfer Partnership (KTP10271). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. H.H is a National Institute for Health Research (NIHR Senior Investigator). M.K and R.B. are employees and shareholders of Perspectum Diagnostics. H.W. and S.N. are shareholders in Perspectum Diagnostics. The IMI DIRECT study was funded in part by Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi Aventis, and Servier. No other potential conflicts of interest relevant to this article were reported. H.Y. is funded by a Diabetes UK RD Lawrence fellowship ( 17/0005594 ). C.A.P is funded by a Wellcome Trust Clinical PhD Programme ( 206274/Z/17/Z ). H.W is funded by an Innovate UK Knowledge Transfer Partnership ( KTP10271 ). The work undertaken by P.W.F was supported in part by ERC-2015-CoG_NASCENT_681742. IMI DIRECT was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. H.H is a National Institute for Health Research (NIHR) Senior Investigator.
Keywords
- Genetics
- Genome-wide association study
- Iron
- Magnetic resonance imaging
- Metabolic syndrome
- Metabolism
ASJC Scopus subject areas
- Hepatology
