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; 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; Robert Caiazzo; Fanelly Torres; Helene Verkindt; Andrea Mari; Andrea Tura; Toni Giorgino; null 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

doi:10.1016/j.jhep.2019.05.032

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, 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 RaverdiRobert 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

^*Corresponding author af dette arbejde

Disease Systems Biology Program

5 Citationer (Scopus)

13 Downloads (Pure)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Hepatology
Vol/bind	71
Udgave nummer	3
Sider (fra-til)	594-602
Antal sider	9
ISSN	0168-8278
DOI	https://doi.org/10.1016/j.jhep.2019.05.032
Status	Udgivet - 1 sep. 2019

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10.1016/j.jhep.2019.05.032Licens: CC BY

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentrationForlagets udgivne version, 944 KBLicens: CC BY

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Wilman, H. R., Parisinos, C. A., Atabaki-Pasdar, N., Kelly, M., Thomas, E. L., Neubauer, S., Jennison, C., Ehrhardt, B., Baum, P., Schoelsch, C., Freijer, J., Grempler, R., Graefe-Mody, U., Hennige, A., Dings, C., Lehr, T., Scherer, N., Sihinecich, I., Pattou, F., ... IMI-DIRECT consortium (2019). Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration. Journal of Hepatology, 71(3), 594-602. https://doi.org/10.1016/j.jhep.2019.05.032

Wilman, HR, Parisinos, CA, Atabaki-Pasdar, N, Kelly, M, Thomas, EL, Neubauer, S, Jennison, C, Ehrhardt, B, Baum, P, Schoelsch, C, Freijer, J, Grempler, R, Graefe-Mody, U, Hennige, A, Dings, C, Lehr, T, Scherer, N, Sihinecich, I, Pattou, F, Raverdi, V, Caiazzo, R, Torres, F, Verkindt, H, Mari, A, Tura, A, Giorgino, T, Bizzotto, Froguel, P, Brorsson, C , Brunak, S, De Masi, F, Pedersen, H, Banasik, K , Thomas, C , Lundgaard, A, Nielsen, A, Mazzoni, G , Karaderi, T , Rasmussen, S , Johansen, J , Allesøe, R , Arumugam, M , Allin, K , Hansen, T, Hansen, T, Jonsson, A, Pedersen, O, Dutta, A, Vogt, J, Vestergaard, H & IMI-DIRECT consortium 2019, 'Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration', Journal of Hepatology, bind 71, nr. 3, s. 594-602. https://doi.org/10.1016/j.jhep.2019.05.032

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title = "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 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.",

keywords = "Genetics, Genome-wide association study, Iron, Magnetic resonance imaging, Metabolic syndrome, Metabolism",

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

year = "2019",

month = sep,

day = "1",

doi = "10.1016/j.jhep.2019.05.032",

language = "English",

volume = "71",

pages = "594--602",

journal = "Journal of Hepatology, Supplement",

issn = "0169-5185",

publisher = "Elsevier",

number = "3",

}

TY - JOUR

T1 - Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

AU - Wilman, Henry R.

AU - Parisinos, Constantinos A.

AU - Atabaki-Pasdar, Naeimeh

AU - Kelly, Matt

AU - Thomas, E. Louise

AU - Neubauer, Stefan

AU - Jennison, Christopher

AU - Ehrhardt, B.

AU - Baum, Patrick

AU - Schoelsch, Corinna

AU - Freijer, Jan

AU - Grempler, Rolf

AU - Graefe-Mody, Ulrike

AU - Hennige, A.

AU - Dings, Christiane

AU - Lehr, Thorsten

AU - Scherer, Nina

AU - Sihinecich, I.

AU - Pattou, Francois

AU - Raverdi, Violeta

AU - Caiazzo, Robert

AU - Torres, Fanelly

AU - Verkindt, Helene

AU - Mari, Andrea

AU - Tura, Andrea

AU - Giorgino, Toni

AU - Bizzotto, null

AU - Froguel, Philippe

AU - Brorsson, Caroline

AU - Brunak, S.

AU - De Masi, Federico

AU - Pedersen, H.

AU - Banasik, Karina

AU - Thomas, Cecilia

AU - Lundgaard, Agnete

AU - Nielsen, A.

AU - Mazzoni, Gianluca

AU - Karaderi, T.

AU - Rasmussen, S.

AU - Johansen, Joachim

AU - Allesøe, Rosa

AU - Arumugam, Manimozhiyan

AU - Allin, Kristine

AU - Hansen, Torben

AU - Hansen, Tue

AU - Jonsson, Anna

AU - Pedersen, Oluf

AU - Dutta, Avirup

AU - Vogt, J.

AU - Vestergaard, Henrik

AU - IMI-DIRECT consortium

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

KW - Genetics

KW - Genome-wide association study

KW - Iron

KW - Magnetic resonance imaging

KW - Metabolic syndrome

KW - Metabolism

U2 - 10.1016/j.jhep.2019.05.032

DO - 10.1016/j.jhep.2019.05.032

M3 - Journal article

C2 - 31226389

AN - SCOPUS:85068854139

SN - 0169-5185

VL - 71

SP - 594

EP - 602

JO - Journal of Hepatology, Supplement

JF - Journal of Hepatology, Supplement

IS - 3

ER -

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

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