Vincent L Chen1,2, Yanhua Chen1, Xiaomeng Du1, Samuel K Handelman1,2, Elizabeth K Speliotes1,2. 1. Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA. 2. Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
Abstract
BACKGROUND AND AIMS: Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS: We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS: Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS: We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.
BACKGROUND AND AIMS: Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS: We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS: Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS: We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.
Authors: R G Kim; P Nguyen; R Bettencourt; P S Dulai; W Haufe; J Hooker; J Minocha; M A Valasek; H Aryafar; D A Brenner; C B Sirlin; R Loomba Journal: Aliment Pharmacol Ther Date: 2016-06-09 Impact factor: 8.171
Authors: S Rüeger; P-Y Bochud; J-F Dufour; B Müllhaupt; D Semela; M H Heim; D Moradpour; A Cerny; R Malinverni; D R Booth; V Suppiah; J George; L Argiro; P Halfon; M Bourlière; A H Talal; I M Jacobson; E Patin; B Nalpas; T Poynard; S Pol; L Abel; Z Kutalik; F Negro Journal: Gut Date: 2014-09-11 Impact factor: 23.059
Authors: Karim Hamesch; Mattias Mandorfer; Vítor M Pereira; Linda S Moeller; Monica Pons; Grace E Dolman; Matthias C Reichert; Carolin V Schneider; Vivien Woditsch; Jessica Voss; Cecilia Lindhauer; Malin Fromme; Igor Spivak; Nurdan Guldiken; Biaohuan Zhou; Anita Arslanow; Benedikt Schaefer; Heinz Zoller; Elmar Aigner; Thomas Reiberger; Martin Wetzel; Britta Siegmund; Carolina Simões; Rui Gaspar; Luís Maia; Dalila Costa; Mário Bento-Miranda; Josef van Helden; Eray Yagmur; Danilo Bzdok; Jan Stolk; Wolfgang Gleiber; Verena Knipel; Wolfram Windisch; Ravi Mahadeva; Robert Bals; Rembert Koczulla; Miriam Barrecheguren; Marc Miravitlles; Sabina Janciauskiene; Felix Stickel; Frank Lammert; Rodrigo Liberal; Joan Genesca; William J Griffiths; Michael Trauner; Aleksander Krag; Christian Trautwein; Pavel Strnad Journal: Gastroenterology Date: 2019-05-20 Impact factor: 22.682
Authors: Felix Stickel; Stephan Buch; Heinz Zoller; Rolf Hultcrantz; Sabina Gallati; Christoph Österreicher; Armin Finkenstedt; Andreas Stadlmayr; Elmar Aigner; Enijad Sahinbegovic; Christoph Sarrazin; Clemens Schafmayer; Felix Braun; Wiebke Erhart; Michael Nothnagel; Markus M Lerch; Julia Mayerle; Henry Völzke; André Schaller; Wolfgang Kratzer; Bernhard O Boehm; Bence Sipos; Mauro D'Amato; Leif Torkvist; Per Stal; Alexander Arlt; Andre Franke; Thomas Becker; Michael Krawczak; Jochen Zwerina; Thomas Berg; Holger Hinrichsen; Elisabeth Krones; Christian Dejaco; Michael Strasser; Christian Datz; Jochen Hampe Journal: Hum Mol Genet Date: 2014-02-20 Impact factor: 6.150
Authors: Catherine M Greene; Stefan J Marciniak; Jeffrey Teckman; Ilaria Ferrarotti; Mark L Brantly; David A Lomas; James K Stoller; Noel G McElvaney Journal: Nat Rev Dis Primers Date: 2016-07-28 Impact factor: 52.329
Authors: Cathie Sudlow; John Gallacher; Naomi Allen; Valerie Beral; Paul Burton; John Danesh; Paul Downey; Paul Elliott; Jane Green; Martin Landray; Bette Liu; Paul Matthews; Giok Ong; Jill Pell; Alan Silman; Alan Young; Tim Sprosen; Tim Peakman; Rory Collins Journal: PLoS Med Date: 2015-03-31 Impact factor: 11.069
Authors: Lillias H Maguire; Samuel K Handelman; Xiaomeng Du; Yanhua Chen; Tune H Pers; Elizabeth K Speliotes Journal: Nat Genet Date: 2018-09-03 Impact factor: 38.330
Authors: Johannes Kettunen; Ayşe Demirkan; Peter Würtz; Harmen H M Draisma; Toomas Haller; Rajesh Rawal; Anika Vaarhorst; Antti J Kangas; Leo-Pekka Lyytikäinen; Matti Pirinen; René Pool; Antti-Pekka Sarin; Pasi Soininen; Taru Tukiainen; Qin Wang; Mika Tiainen; Tuulia Tynkkynen; Najaf Amin; Tanja Zeller; Marian Beekman; Joris Deelen; Ko Willems van Dijk; Tõnu Esko; Jouke-Jan Hottenga; Elisabeth M van Leeuwen; Terho Lehtimäki; Evelin Mihailov; Richard J Rose; Anton J M de Craen; Christian Gieger; Mika Kähönen; Markus Perola; Stefan Blankenberg; Markku J Savolainen; Aswin Verhoeven; Jorma Viikari; Gonneke Willemsen; Dorret I Boomsma; Cornelia M van Duijn; Johan Eriksson; Antti Jula; Marjo-Riitta Järvelin; Jaakko Kaprio; Andres Metspalu; Olli Raitakari; Veikko Salomaa; P Eline Slagboom; Melanie Waldenberger; Samuli Ripatti; Mika Ala-Korpela Journal: Nat Commun Date: 2016-03-23 Impact factor: 14.919
Authors: Yingchang Lu; Felix R Day; Stefan Gustafsson; Martin L Buchkovich; Jianbo Na; Veronique Bataille; Diana L Cousminer; Zari Dastani; Alexander W Drong; Tõnu Esko; David M Evans; Mario Falchi; Mary F Feitosa; Teresa Ferreira; Åsa K Hedman; Robin Haring; Pirro G Hysi; Mark M Iles; Anne E Justice; Stavroula Kanoni; Vasiliki Lagou; Rui Li; Xin Li; Adam Locke; Chen Lu; Reedik Mägi; John R B Perry; Tune H Pers; Qibin Qi; Marianna Sanna; Ellen M Schmidt; William R Scott; Dmitry Shungin; Alexander Teumer; Anna A E Vinkhuyzen; Ryan W Walker; Harm-Jan Westra; Mingfeng Zhang; Weihua Zhang; Jing Hua Zhao; Zhihong Zhu; Uzma Afzal; Tarunveer Singh Ahluwalia; Stephan J L Bakker; Claire Bellis; Amélie Bonnefond; Katja Borodulin; Aron S Buchman; Tommy Cederholm; Audrey C Choh; Hyung Jin Choi; Joanne E Curran; Lisette C P G M de Groot; Philip L De Jager; Rosalie A M Dhonukshe-Rutten; Anke W Enneman; Elodie Eury; Daniel S Evans; Tom Forsen; Nele Friedrich; Frédéric Fumeron; Melissa E Garcia; Simone Gärtner; Bok-Ghee Han; Aki S Havulinna; Caroline Hayward; Dena Hernandez; Hans Hillege; Till Ittermann; Jack W Kent; Ivana Kolcic; Tiina Laatikainen; Jari Lahti; Irene Mateo Leach; Christine G Lee; Jong-Young Lee; Tian Liu; Youfang Liu; Stéphane Lobbens; Marie Loh; Leo-Pekka Lyytikäinen; Carolina Medina-Gomez; Karl Michaëlsson; Mike A Nalls; Carrie M Nielson; Laticia Oozageer; Laura Pascoe; Lavinia Paternoster; Ozren Polašek; Samuli Ripatti; Mark A Sarzynski; Chan Soo Shin; Nina Smolej Narančić; Dominik Spira; Priya Srikanth; Elisabeth Steinhagen-Thiessen; Yun Ju Sung; Karin M A Swart; Leena Taittonen; Toshiko Tanaka; Emmi Tikkanen; Nathalie van der Velde; Natasja M van Schoor; Niek Verweij; Alan F Wright; Lei Yu; Joseph M Zmuda; Niina Eklund; Terrence Forrester; Niels Grarup; Anne U Jackson; Kati Kristiansson; Teemu Kuulasmaa; Johanna Kuusisto; Peter Lichtner; Jian'an Luan; Anubha Mahajan; Satu Männistö; Cameron D Palmer; Janina S Ried; Robert A Scott; Alena Stancáková; Peter J Wagner; Ayse Demirkan; Angela Döring; Vilmundur Gudnason; Douglas P Kiel; Brigitte Kühnel; Massimo Mangino; Barbara Mcknight; Cristina Menni; Jeffrey R O'Connell; Ben A Oostra; Alan R Shuldiner; Kijoung Song; Liesbeth Vandenput; Cornelia M van Duijn; Peter Vollenweider; Charles C White; Michael Boehnke; Yvonne Boettcher; Richard S Cooper; Nita G Forouhi; Christian Gieger; Harald Grallert; Aroon Hingorani; Torben Jørgensen; Pekka Jousilahti; Mika Kivimaki; Meena Kumari; Markku Laakso; Claudia Langenberg; Allan Linneberg; Amy Luke; Colin A Mckenzie; Aarno Palotie; Oluf Pedersen; Annette Peters; Konstantin Strauch; Bamidele O Tayo; Nicholas J Wareham; David A Bennett; Lars Bertram; John Blangero; Matthias Blüher; Claude Bouchard; Harry Campbell; Nam H Cho; Steven R Cummings; Stefan A Czerwinski; Ilja Demuth; Rahel Eckardt; Johan G Eriksson; Luigi Ferrucci; Oscar H Franco; Philippe Froguel; Ron T Gansevoort; Torben Hansen; Tamara B Harris; Nicholas Hastie; Markku Heliövaara; Albert Hofman; Joanne M Jordan; Antti Jula; Mika Kähönen; Eero Kajantie; Paul B Knekt; Seppo Koskinen; Peter Kovacs; Terho Lehtimäki; Lars Lind; Yongmei Liu; Eric S Orwoll; Clive Osmond; Markus Perola; Louis Pérusse; Olli T Raitakari; Tuomo Rankinen; D C Rao; Treva K Rice; Fernando Rivadeneira; Igor Rudan; Veikko Salomaa; Thorkild I A Sørensen; Michael Stumvoll; Anke Tönjes; Bradford Towne; Gregory J Tranah; Angelo Tremblay; André G Uitterlinden; Pim van der Harst; Erkki Vartiainen; Jorma S Viikari; Veronique Vitart; Marie-Claude Vohl; Henry Völzke; Mark Walker; Henri Wallaschofski; Sarah Wild; James F Wilson; Loïc Yengo; D Timothy Bishop; Ingrid B Borecki; John C Chambers; L Adrienne Cupples; Abbas Dehghan; Panos Deloukas; Ghazaleh Fatemifar; Caroline Fox; Terrence S Furey; Lude Franke; Jiali Han; David J Hunter; Juha Karjalainen; Fredrik Karpe; Robert C Kaplan; Jaspal S Kooner; Mark I McCarthy; Joanne M Murabito; Andrew P Morris; Julia A N Bishop; Kari E North; Claes Ohlsson; Ken K Ong; Inga Prokopenko; J Brent Richards; Eric E Schadt; Tim D Spector; Elisabeth Widén; Cristen J Willer; Jian Yang; Erik Ingelsson; Karen L Mohlke; Joel N Hirschhorn; John Andrew Pospisilik; M Carola Zillikens; Cecilia Lindgren; Tuomas Oskari Kilpeläinen; Ruth J F Loos Journal: Nat Commun Date: 2016-02-01 Impact factor: 14.919
Authors: Janne Pott; Jesper R Gådin; Elizabeth Theusch; Marcus E Kleber; Graciela E Delgado; Holger Kirsten; Stefanie M Hauck; Ralph Burkhardt; Hubert Scharnagl; Ronald M Krauss; Markus Loeffler; Winfried März; Joachim Thiery; Angela Silveira; Ferdinand M Van't Hooft; Markus Scholz Journal: Hum Mol Genet Date: 2022-03-21 Impact factor: 6.150
Authors: Hyun-Seok Kim; Xiangjun Xiao; Jinyoung Byun; Goo Jun; Stacia M DeSantis; Han Chen; Aaron P Thrift; Hashem B El-Serag; Fasiha Kanwal; Christopher I Amos Journal: JAMA Netw Open Date: 2022-10-03
Authors: Aaron Hakim; Matthew Moll; Dandi Qiao; Jiangyuan Liu; Jessica A Lasky-Su; Edwin K Silverman; Silvia Vilarinho; Z Gordon Jiang; Brian D Hobbs; Michael H Cho Journal: Hepatol Commun Date: 2021-04-03
Authors: Vincent L Chen; Xiaomeng Du; Yanhua Chen; Annapurna Kuppa; Samuel K Handelman; Rishel B Vohnoutka; Patricia A Peyser; Nicholette D Palmer; Lawrence F Bielak; Brian Halligan; Elizabeth K Speliotes Journal: Nat Commun Date: 2021-02-05 Impact factor: 14.919
Authors: Magda Rybicka; Anna Woziwodzka; Alicja Sznarkowska; Tomasz Romanowski; Piotr Stalke; Marcin Dręczewski; Eloi R Verrier; Thomas F Baumert; Krzysztof Piotr Bielawski Journal: Cancers (Basel) Date: 2020-11-07 Impact factor: 6.639