Tae-Hwi Schwantes-An1, Rebecca Darlay2, Lawrence Lumeng3, Tatiana M Foroud1, Ann K Daly4, Heather J Cordell2, John B Whitfield5, Timothy R Morgan6, Devanshi Seth7,8,9, Philippe Mathurin10, Steven Masson4, Suthat Liangpunsakul3, Sebastian Mueller11, Guruprasad P Aithal12, Florian Eyer13, Dermot Gleeson14, Andrew Thompson15, Beat Muellhaupt16, Felix Stickel16, Michael Soyka17,18, David Goldman19, Tiebing Liang3, Munir Pirmohamed15, Bertrand Nalpas20,21, Jean-Marc Jacquet20, Romain Moirand22, Pierre Nahon23,24,25, Sylvie Naveau26, Pascal Perney27, Greg Botwin6,28, Paul S Haber7,8, Helmut K Seitz11, Christopher P Day4. 1. Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN. 2. Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, United Kingdom. 3. Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN. 4. Faculty of Medical Sciences, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, United Kingdom. 5. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. 6. Medical and Research Services, VA Long Beach Healthcare System, Long Beach, CA. 7. Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. 8. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. 9. Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia. 10. CHRU de Lille, Hôpital Claude Huriez, Lille Cedex, France. 11. Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany. 12. NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham, United Kingdom. 13. Division of Clinical Toxicology, Department of Internal Medicine 2, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. 14. The Clinical Research Facility, The Royal Hallamshire Hospital, Sheffield, United Kingdom. 15. MRC Centre for Drug Safety Science, Liverpool Centre for Alcohol Research, University of Liverpool, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners, Liverpool, United Kingdom. 16. Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. 17. Psychiatric Hospital University of Munich, Munich, Germany. 18. Privatklinik Meiringen, Willigen, Meiringen, Switzerland. 19. Laboratory of Neurogenetics, NIAAA, Rockville, MD. 20. Service Addictologie, CHRU Caremeau, Nîmes, France. 21. DISC, Inserm, Paris, France. 22. University Rennes, INRAE, INSERM, CHU Rennes, Institute NUMECAN (Nutrition Metabolisms and Cancer), Rennes, France. 23. APHP, Liver Unit, Hospital Jean Verdier, Bondy, France. 24. University Paris 13, Bobigny, France. 25. Inserm U1162 "Functional Genomics of Solid Tumors,", Paris, France. 26. Hôpital Antoine-Béclère, Clamart, France. 27. Hôpital Universitaire Car_Emeau, Nîmes, France. 28. Translational Genomics Group, Inflammatory Bowel & Immunobiology Research Institute, Los Angeles, CA.
Abstract
BACKGROUND AND AIMS: Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. APPROACH AND RESULTS: We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10-17 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10-10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10-8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. CONCLUSIONS: Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
BACKGROUND AND AIMS: Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. APPROACH AND RESULTS: We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10-17 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10-10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10-8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. CONCLUSIONS: Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
Authors: Alexis C Edwards; Kristina Sundquist; Jan Sundquist; Kenneth S Kendler; Sara Larsson Lönn Journal: Alcohol Clin Exp Res Date: 2021-12-19 Impact factor: 3.455
Authors: Dongbing Lai; Tae-Hwi Schwantes-An; Marco Abreu; Grace Chan; Victor Hesselbrock; Chella Kamarajan; Yunlong Liu; Jacquelyn L Meyers; John I Nurnberger; Martin H Plawecki; Leah Wetherill; Marc Schuckit; Pengyue Zhang; Howard J Edenberg; Bernice Porjesz; Arpana Agrawal; Tatiana Foroud Journal: Transl Psychiatry Date: 2022-07-05 Impact factor: 7.989
Authors: John B Whitfield; Tae-Hwi Schwantes-An; Rebecca Darlay; Guruprasad P Aithal; Stephen R Atkinson; Ramon Bataller; Greg Botwin; Naga P Chalasani; Heather J Cordell; Ann K Daly; Christopher P Day; Florian Eyer; Tatiana Foroud; Dermot Gleeson; David Goldman; Paul S Haber; Jean-Marc Jacquet; Tiebing Liang; Suthat Liangpunsakul; Steven Masson; Philippe Mathurin; Romain Moirand; Andrew McQuillin; Christophe Moreno; Marsha Y Morgan; Sebastian Mueller; Beat Müllhaupt; Laura E Nagy; Pierre Nahon; Bertrand Nalpas; Sylvie Naveau; Pascal Perney; Munir Pirmohamed; Helmut K Seitz; Michael Soyka; Felix Stickel; Andrew Thompson; Mark R Thursz; Eric Trépo; Timothy R Morgan; Devanshi Seth Journal: J Hepatol Date: 2021-10-14 Impact factor: 30.083
Authors: Bernd Schnabl; Gavin E Arteel; Felix Stickel; Jan Hengstler; Nachiket Vartak; Ahmed Ghallab; Steven Dooley; Yujia Li; Robert F Schwabe Journal: Z Gastroenterol Date: 2022-01-18 Impact factor: 1.769