William P Bone1, Katherine M Siewert1, Anupama Jha2, Derek Klarin3,4,5, Scott M Damrauer6,7,8, Kyong-Mi Chang7,8, Philip S Tsao9,10, Themistocles L Assimes9,10, Marylyn D Ritchie11,12,13, Benjamin F Voight14,15,16,17,18. 1. Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. 2. Department of Computer and Information Science, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104, USA. 3. Boston VA Healthcare System, Boston, MA, 02130, USA. 4. Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. 5. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. 6. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, PA, 19104, Philadelphia, USA. 7. Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, 19104, USA. 8. Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. 9. VA Palo Alto Health Care System, Palo Alto, CA, 94550, USA. 10. Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA. 11. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. 12. Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. 13. Center for Precision Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. 14. Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu. 15. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu. 16. Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu. 17. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu. 18. Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. bvoight@pennmedicine.upenn.edu.
Abstract
BACKGROUND: Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. METHODS: We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. RESULTS: We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. CONCLUSION: Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.
BACKGROUND: Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. METHODS: We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. RESULTS: We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. CONCLUSION: Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.
Authors: Loic Yengo; Julia Sidorenko; Kathryn E Kemper; Zhili Zheng; Andrew R Wood; Michael N Weedon; Timothy M Frayling; Joel Hirschhorn; Jian Yang; Peter M Visscher Journal: Hum Mol Genet Date: 2018-10-15 Impact factor: 6.150
Authors: Donald J Lehmann; Mario Cortina-Borja; Donald R Warden; A David Smith; Kristel Sleegers; Jonathan A Prince; Cornelia M van Duijn; Patrick G Kehoe Journal: Am J Epidemiol Date: 2005-07-20 Impact factor: 4.897
Authors: Annalisa Buniello; Jacqueline A L MacArthur; Maria Cerezo; Laura W Harris; James Hayhurst; Cinzia Malangone; Aoife McMahon; Joannella Morales; Edward Mountjoy; Elliot Sollis; Daniel Suveges; Olga Vrousgou; Patricia L Whetzel; Ridwan Amode; Jose A Guillen; Harpreet S Riat; Stephen J Trevanion; Peggy Hall; Heather Junkins; Paul Flicek; Tony Burdett; Lucia A Hindorff; Fiona Cunningham; Helen Parkinson Journal: Nucleic Acids Res Date: 2019-01-08 Impact factor: 16.971
Authors: Evangelos Evangelou; Helen R Warren; David Mosen-Ansorena; Borbala Mifsud; Raha Pazoki; He Gao; Georgios Ntritsos; Niki Dimou; Claudia P Cabrera; Ibrahim Karaman; Fu Liang Ng; Marina Evangelou; Katarzyna Witkowska; Evan Tzanis; Jacklyn N Hellwege; Ayush Giri; Digna R Velez Edwards; Yan V Sun; Kelly Cho; J Michael Gaziano; Peter W F Wilson; Philip S Tsao; Csaba P Kovesdy; Tonu Esko; Reedik Mägi; Lili Milani; Peter Almgren; Thibaud Boutin; Stéphanie Debette; Jun Ding; Franco Giulianini; Elizabeth G Holliday; Anne U Jackson; Ruifang Li-Gao; Wei-Yu Lin; Jian'an Luan; Massimo Mangino; Christopher Oldmeadow; Bram Peter Prins; Yong Qian; Muralidharan Sargurupremraj; Nabi Shah; Praveen Surendran; Sébastien Thériault; Niek Verweij; Sara M Willems; Jing-Hua Zhao; Philippe Amouyel; John Connell; Renée de Mutsert; Alex S F Doney; Martin Farrall; Cristina Menni; Andrew D Morris; Raymond Noordam; Guillaume Paré; Neil R Poulter; Denis C Shields; Alice Stanton; Simon Thom; Gonçalo Abecasis; Najaf Amin; Dan E Arking; Kristin L Ayers; Caterina M Barbieri; Chiara Batini; Joshua C Bis; Tineka Blake; Murielle Bochud; Michael Boehnke; Eric Boerwinkle; Dorret I Boomsma; Erwin P Bottinger; Peter S Braund; Marco Brumat; Archie Campbell; Harry Campbell; Aravinda Chakravarti; John C Chambers; Ganesh Chauhan; Marina Ciullo; Massimiliano Cocca; Francis Collins; Heather J Cordell; Gail Davies; Martin H de Borst; Eco J de Geus; Ian J Deary; Joris Deelen; Fabiola Del Greco M; Cumhur Yusuf Demirkale; Marcus Dörr; Georg B Ehret; Roberto Elosua; Stefan Enroth; A Mesut Erzurumluoglu; Teresa Ferreira; Mattias Frånberg; Oscar H Franco; Ilaria Gandin; Paolo Gasparini; Vilmantas Giedraitis; Christian Gieger; Giorgia Girotto; Anuj Goel; Alan J Gow; Vilmundur Gudnason; Xiuqing Guo; Ulf Gyllensten; Anders Hamsten; Tamara B Harris; Sarah E Harris; Catharina A Hartman; Aki S Havulinna; Andrew A Hicks; Edith Hofer; Albert Hofman; Jouke-Jan Hottenga; Jennifer E Huffman; Shih-Jen Hwang; Erik Ingelsson; Alan James; Rick Jansen; Marjo-Riitta Jarvelin; Roby Joehanes; Åsa Johansson; Andrew D Johnson; Peter K Joshi; Pekka Jousilahti; J Wouter Jukema; Antti Jula; Mika Kähönen; Sekar Kathiresan; Bernard D Keavney; Kay-Tee Khaw; Paul Knekt; Joanne Knight; Ivana Kolcic; Jaspal S Kooner; Seppo Koskinen; Kati Kristiansson; Zoltan Kutalik; Maris Laan; Marty Larson; Lenore J Launer; Benjamin Lehne; Terho Lehtimäki; David C M Liewald; Li Lin; Lars Lind; Cecilia M Lindgren; YongMei Liu; Ruth J F Loos; Lorna M Lopez; Yingchang Lu; Leo-Pekka Lyytikäinen; Anubha Mahajan; Chrysovalanto Mamasoula; Jaume Marrugat; Jonathan Marten; Yuri Milaneschi; Anna Morgan; Andrew P Morris; Alanna C Morrison; Peter J Munson; Mike A Nalls; Priyanka Nandakumar; Christopher P Nelson; Teemu Niiranen; Ilja M Nolte; Teresa Nutile; Albertine J Oldehinkel; Ben A Oostra; Paul F O'Reilly; Elin Org; Sandosh Padmanabhan; Walter Palmas; Aarno Palotie; Alison Pattie; Brenda W J H Penninx; Markus Perola; Annette Peters; Ozren Polasek; Peter P Pramstaller; Quang Tri Nguyen; Olli T Raitakari; Meixia Ren; Rainer Rettig; Kenneth Rice; Paul M Ridker; Janina S Ried; Harriëtte Riese; Samuli Ripatti; Antonietta Robino; Lynda M Rose; Jerome I Rotter; Igor Rudan; Daniela Ruggiero; Yasaman Saba; Cinzia F Sala; Veikko Salomaa; Nilesh J Samani; Antti-Pekka Sarin; Reinhold Schmidt; Helena Schmidt; Nick Shrine; David Siscovick; Albert V Smith; Harold Snieder; Siim Sõber; Rossella Sorice; John M Starr; David J Stott; David P Strachan; Rona J Strawbridge; Johan Sundström; Morris A Swertz; Kent D Taylor; Alexander Teumer; Martin D Tobin; Maciej Tomaszewski; Daniela Toniolo; Michela Traglia; Stella Trompet; Jaakko Tuomilehto; Christophe Tzourio; André G Uitterlinden; Ahmad Vaez; Peter J van der Most; Cornelia M van Duijn; Anne-Claire Vergnaud; Germaine C Verwoert; Veronique Vitart; Uwe Völker; Peter Vollenweider; Dragana Vuckovic; Hugh Watkins; Sarah H Wild; Gonneke Willemsen; James F Wilson; Alan F Wright; Jie Yao; Tatijana Zemunik; Weihua Zhang; John R Attia; Adam S Butterworth; Daniel I Chasman; David Conen; Francesco Cucca; John Danesh; Caroline Hayward; Joanna M M Howson; Markku Laakso; Edward G Lakatta; Claudia Langenberg; Olle Melander; Dennis O Mook-Kanamori; Colin N A Palmer; Lorenz Risch; Robert A Scott; Rodney J Scott; Peter Sever; Tim D Spector; Pim van der Harst; Nicholas J Wareham; Eleftheria Zeggini; Daniel Levy; Patricia B Munroe; Christopher Newton-Cheh; Morris J Brown; Andres Metspalu; Adriana M Hung; Christopher J O'Donnell; Todd L Edwards; Bruce M Psaty; Ioanna Tzoulaki; Michael R Barnes; Louise V Wain; Paul Elliott; Mark J Caulfield Journal: Nat Genet Date: 2018-09-17 Impact factor: 41.307
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
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