A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis (original) (raw)

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Acknowledgements

This study was supported by the German Ministry of Education and Research through the Virtual Liver Network (to J.H.), the PopGen 2.0 network biobank (grant 01EY1103) and institutional funds from the medical faculties of TU Dresden and Christian Albrechts University Kiel and by Swiss National Funds (grant 310030_138747 to F.S.). The Community Medicine Research network of the University of Greifswald, Germany, is funded by the Federal Ministry of Education and Research, the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg–West Pomerania. M.M.L. and J.M. were supported by the Federal Ministry of Education and Research (BMBF GANI-MED 03152061A and BMBF 0314107), the European Union (EU-FP-7: EPC-TM and EU-FP-7-REGPOT-2010-1) and the EFRE–State Ministry of Economics (V-630-S-150-2012/132/133). S.C., M.M.N. and M. Rietschel were supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Networks IntegraMent and Sysmed Alcohol under the auspices of the e:Med Programme (grant 01ZX1314A to M.M.N. and S.C. and grant 01ZX1311A to M.M.N. and M. Rietschel). M.M.N. is a member of the DFG (Deutsche Forschungsgemeinschaft)-funded Excellence Cluster ImmunoSensation. Research by H.D.N. related to this project was funded by the Deutsche Krebshilfe (107865). The work of A.F. and D.E. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysInflame grant 01ZX1306A). This project received infrastructure support from DFG Excellence Cluster 306, 'Inflammation at Interfaces'. A.F. receives an endowment professorship from the Foundation for Experimental Medicine (Zurich, Switzerland). The UK research effort was funded by a PhD studentship award jointly funded by University College London and an anonymous donor. We thank colleagues from the following centers for obtaining samples from alcohol-dependent cases for genotyping: the Bexley Substance Misuse Service, South London and Maudsley National Health Service (NHS) Trust; the East Hertfordshire Community Drug Action Team; the Max Glatt Unit, Southall; Renfrew and Inverclyde Alcohol Services, Strathclyde; the Newcastle North Tyneside Drug and Alcohol Service, Tyne and Wear; and the Acute Admissions Unit and the Centre for Hepatology at the Royal Free Hospital, London. We also thank colleagues associated with the National Institute for Health Research (NIHR) Mental Health Research Network for their assistance in identifying cases, obtaining consent and collecting samples at the following NHS trusts: Sandwell Mental Health and Social Care; Northamptonshire Healthcare; Avon and Wiltshire Mental Health Partnership, Sheffield Health and Social Care; Tees Esk and Wear Valleys; Lincolnshire Partnership; Nottinghamshire Healthcare; Central and North West London; South Staffordshire and Shropshire Healthcare; Coventry and Warwickshire; and Dudley and Walsall Mental Health Partnership. We are grateful to J. Saini, K. Ruparelia, S. Montagnese, R. Kandaswamy, A. Jarram, G. Quadri and N. O'Brien for assisting with the collection and processing of samples and DNA extraction.

The Belgian research effort was supported by the Belgian Medical Genomics Initiative (BeMGI) funded by the phase VII Interuniversity Attraction Poles (IAP) program of the Belgian Federal Science Policy Office (BELSPO) and the Fund for Scientific Research–FNRS (F.R.S.-FNRS). E.T. is a Postdoctoral Researcher of the F.R.S.-FNRS, and D.F. is a Research Director of the F.R.S.-FNRS. We are grateful to O. Lemoine, D. Degré, A. Lemmers and M. Amrani for identifying cases and controls, obtaining consent and collecting samples at CUB Hôpital Erasme, Université Libre de Bruxelles. We also thank E. Quertinmont at the Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, for his help with the collection and processing of samples and DNA extraction.

We are also grateful to the Center for Information Services and High-Performance Computing (ZIH) at TU Dresden where the computations were performed on a PC cluster.

Author information

Author notes

  1. Stephan Buch, Felix Stickel and Eric Trépo: These authors contributed equally to this work.
  2. Denis Franchimont, Marsha Y Morgan and Jochen Hampe: These authors jointly supervised this work.

Authors and Affiliations

  1. Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany
    Stephan Buch, Alexander Herrmann, Mario Brosch, Renate Schmelz, Stefan Brückner, Sebastian Zeissig, Anna-Magdalena Stephan & Jochen Hampe
  2. Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
    Felix Stickel
  3. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
    Eric Trépo, Jacques Devière, Thierry Gustot, Pierre Deltenre, Christophe Moreno & Denis Franchimont
  4. Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
    Eric Trépo, Jacques Devière, Thierry Gustot, Christophe Moreno & Denis Franchimont
  5. Division of Medicine, UCL Institute for Liver and Digestive Health, Royal Free Campus, University College London, London, UK
    Michael Way & Marsha Y Morgan
  6. Division of Psychiatry, Molecular Psychiatry Laboratory, University College London, London, UK
    Michael Way & Andrew McQuillin
  7. Department of Internal Medicine I, University of Bonn, Bonn, Germany
    Hans Dieter Nischalke
  8. Section of Hepatology, University Hospital Leipzig, Leipzig, Germany
    Jonas Rosendahl & Thomas Berg
  9. Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany
    Monika Ridinger & Norbert Wodarz
  10. Psychiatric Health Care Aargau, Psychiatrische Dienste Aargau, Windisch, Switzerland.,
    Monika Ridinger
  11. Central Institute of Mental Health, University of Heidelberg, Faculty of Medicine Mannheim, Mannheim, Germany
    Marcella Rietschel, Josef Frank & Falk Kiefer
  12. Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
    Stefan Schreiber
  13. Institute of Epidemiology and Biobank PopGen, Christian Albrechts University Kiel, Kiel, Germany
    Wolfgang Lieb
  14. Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany
    Michael Soyka
  15. Department of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
    Nasser Semmo
  16. Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Salzburg, Austria
    Elmar Aigner & Christian Datz
  17. Centre Hospitalier Le Domaine, Université Libre de Bruxelles, Braine-l'Alleud, Belgium
    Nicolas Clumeck
  18. Department of Gastroenterology, University Hospital Frankfurt, Frankfurt, Germany
    Christoph Sarrazin
  19. Department of Medicine II, Saarland University Hospital, Homburg, Germany
    Frank Lammert
  20. Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium
    Pierre Deltenre
  21. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
    Pierre Deltenre
  22. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
    Henry Völzke
  23. Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany
    Markus M Lerch & Julia Mayerle
  24. Department of Clinical Toxicology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
    Florian Eyer
  25. Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.,
    Clemens Schafmayer
  26. Department of Biomedicine, University Hospital Basel, Basel, Switzerland
    Sven Cichon
  27. Institute of Human Genetics, University of Bonn, Bonn, Germany
    Markus M Nöthen
  28. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
    Markus M Nöthen
  29. Cologne Center for Genomics, University of Cologne, Cologne, Germany
    Michael Nothnagel
  30. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
    David Ellinghaus & Andre Franke
  31. Fritz Lipmann Institute of Age Research (FLI), Jena, Germany
    Klaus Huse
  32. Department of Internal Medicine 1, University Hospital Erlangen, Erlangen, Germany
    Steffen Zopf
  33. Department of Internal Medicine 1, University Hospital Regensburg, Regensburg, Germany
    Claus Hellerbrand

Authors

  1. Stephan Buch
  2. Felix Stickel
  3. Eric Trépo
  4. Michael Way
  5. Alexander Herrmann
  6. Hans Dieter Nischalke
  7. Mario Brosch
  8. Jonas Rosendahl
  9. Thomas Berg
  10. Monika Ridinger
  11. Marcella Rietschel
  12. Andrew McQuillin
  13. Josef Frank
  14. Falk Kiefer
  15. Stefan Schreiber
  16. Wolfgang Lieb
  17. Michael Soyka
  18. Nasser Semmo
  19. Elmar Aigner
  20. Christian Datz
  21. Renate Schmelz
  22. Stefan Brückner
  23. Sebastian Zeissig
  24. Anna-Magdalena Stephan
  25. Norbert Wodarz
  26. Jacques Devière
  27. Nicolas Clumeck
  28. Christoph Sarrazin
  29. Frank Lammert
  30. Thierry Gustot
  31. Pierre Deltenre
  32. Henry Völzke
  33. Markus M Lerch
  34. Julia Mayerle
  35. Florian Eyer
  36. Clemens Schafmayer
  37. Sven Cichon
  38. Markus M Nöthen
  39. Michael Nothnagel
  40. David Ellinghaus
  41. Klaus Huse
  42. Andre Franke
  43. Steffen Zopf
  44. Claus Hellerbrand
  45. Christophe Moreno
  46. Denis Franchimont
  47. Marsha Y Morgan
  48. Jochen Hampe

Contributions

S. Buch performed genotyping, meta-analysis and in silico analysis, and drafted and revised the manuscript. F.S. conceptualized the study, recruited subjects, and wrote and revised the manuscript. E.T. recruited subjects, validated the study, provided replication data, and wrote and revised the manuscript. M.W. recruited subjects, performed genotyping for the validation study and revised the manuscript. A.H. performed bioinformatics work. H.D.N. recruited and phenotyped subjects. M.B. performed expression analysis. J.R. and T.B. recruited subjects. M. Ridinger, M. Rietschel, A.M., J.F. and F.K. recruited subjects and performed phenotyping and recruitment of alcoholic controls. S.S. provided technical support and critically revised the manuscript. W.L. helped with population genetic statistics. M.S. recruited subjects and phenotyped alcoholic controls. N.S., E.A., C.D., R.S., S. Brückner, S. Zeissig and A.-M.S. recruited subjects. N.W. recruited subjects and performed phenotyping of alcoholic controls. J.D., N.C., C. Sarrazin, F.L., T.G. and P.D. recruited and phenotyped subjects. H.V. recruited the population cohort. M.M.L., J.M., F.E. and C. Schafmayer recruited and phenotyped subjects. S.C. and M.M.N. performed phenotyping and recruitment of alcoholic controls. M.N. supervised and reviewed statistical analysis. D.E. assisted with bioinformatics analysis. K.H. performed expression analysis. A.F. gave conceptual advice and bioinformatics support. S. Zopf, C.H. and C.M. recruited subjects. D.F. and M.Y.M. recruited subjects and drafted and critically revised the manuscript. J.H. conceptualized the study and analytical design, and drafted and revised the manuscript. All authors critically revised and contributed to the final manuscript.

Corresponding author

Correspondence toFelix Stickel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 4 Fine-mapping analysis of the TM6SF2 association signals.

The –log10 (P values) are plotted against SNP genomic position based on NCBI Build 37. The known coding variant of likely functional significance, rs58542926 is highlighted in purple. The squares denote genotyped SNPs; the circles denote imputed SNPs (using 1000 Genomes Project–based imputation). SNPs are colored to reflect correlation with the most significant SNP, with red denoting the highest LD (_r_2 >0.8) to the lead SNP. Estimated recombination rates from 1000 Genomes Project (hg19/genomes March 2012 EUR) are plotted in blue to reflect the local LD structure. Gene annotations were obtained from the UCSC Genome Browser. The plot was generated using LocusZoom.

Supplementary Figure 5 Tissue expression of MBOAT7 and TMC4 mRNA.

Expression was tested by PCR in the human cDNA tissue panel from Takara Clontech (636742 and 636743) using transcript-specific primer pairs (MBOAT7: 5′-TCCTTGTGTCTTTCGCTCC-3′ and 5′-TACACACGGTGACCTGTCA-3′; TMC4: 5′-TGAGACCACCCAGAATTTCC-3′ and 5′-CTAGGCTTACAATGGGCCTG-3′). MBOAT7 shows a ubiquitous expression pattern in the tissues tested, albeit with lower expression in skeletal muscle. Expression of TMC4 is more selective, with no expression detected in brain or skeletal muscle.

No significant change in transcript abundance was seen for TMC4 across genotypes, whereas a significant increase in transcript abundance was detected for MBOAT7 in the homozygous mutant genotype (Mann-Whitney U test P = 0.0087).

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 2, 3 and 5–7. (PDF 887 kb)

Supplementary Table 1: Results of the primary GWAS meta-analysis (Germany/UK).

Results of the GWAS meta-analysis of 712 cases with alcohol-related cirrhosis and 1,466 controls. Variants that entered replication genotyping are marked "SNP1" to "SNP10". SNPs are ranked by combined P value, and data are provided for the top variants through SNP10. (XLSX 534 kb)

Supplementary Table 4: Results of the secondary GWAS meta-analysis (Germany/UK) adjusted for sex, age, BMI and type 2 diabetes status.

Results of the GWAS meta-analysis adjusted for age, sex, BMI and type 2 diabetes status. Variants that entered replication genotyping are marked "SNP1" to "SNP10". SNPs are ranked by combined P value, and data are provided for the top variants through SNP10. Adjusted meta-analysis results for the replicating variants of the primary analysis are as follows: TM6SF2 (rs10401969), _P_meta = 0.000667, ORmeta = 1.87 (1.30–2.69); MBOAT7 (rs626283), _P_meta = 0.0173, ORmeta = 1.28 (1.04–1.56). These rank below SNP10 in this analysis. (XLSX 153 kb)

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Buch, S., Stickel, F., Trépo, E. et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis.Nat Genet 47, 1443–1448 (2015). https://doi.org/10.1038/ng.3417

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