Alexis C Wood1, Amit Arora2, Michelle Newell2, Victoria L Bland3, Jin Zhou4, Nicola Pirastu5, Jose M Ordovas6, Yann C Klimentidis7. 1. USDA/ARS Children's Nutrition Research Center, 1100 Bates Avenue, Houston, TX, USA. Electronic address: lekkiwood@gmail.com. 2. Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA. 3. Division of Geriatric Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 4. Department of Biostatistics, University of California, Los Angeles, CA, USA. 5. Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland, UK. 6. Nutrition and Genomics Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA; IMDEA-Food, Madrid, Spain. 7. Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA; BIO5 Institute, University of Arizona, Tucson, AZ, USA.
Abstract
BACKGROUND AND AIMS: Cardiometabolic disorders (CMD) arise from a constellation of features such as increased adiposity, hyperlipidemia, hypertension and compromised glucose control. Many genetic loci have shown associations with individual CMD-related traits, but no investigations have focused on simultaneously identifying loci showing associations across all domains. We therefore sought to identify loci associated with risk across seven continuous CMD-related traits. METHODS AND RESULTS: We conducted separate genome-wide association studies (GWAS) for systolic and diastolic blood pressure (SBP/DBP), hemoglobin A1c (HbA1c), low- and high- density lipoprotein cholesterol (LDL-C/HDL-C), waist-to-hip-ratio (WHR), and triglycerides (TGs) in the UK Biobank (N = 356,574-456,823). Multiple loci reached genome-wide levels of significance (N = 145-333) for each trait, but only four loci (in/near VEGFA, GRB14-COBLL1, KLF14, and RGS19-OPRL1) were associated with risk across all seven traits (P < 5 × 10-8). We sought replication of these four loci in an independent set of seven trait-specific GWAS meta-analyses. GRB14-COBLL1 showed the most consistent replication, revealing nominally significant associations (P < 0.05) with all traits except DBP. CONCLUSIONS: Our analyses suggest that very few loci are associated in the same direction of risk with traits representing the full spectrum of CMD features. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors that can be used to identify pathologic disturbances that represent broadly beneficial therapeutic targets.
BACKGROUND AND AIMS: Cardiometabolic disorders (CMD) arise from a constellation of features such as increased adiposity, hyperlipidemia, hypertension and compromised glucose control. Many genetic loci have shown associations with individual CMD-related traits, but no investigations have focused on simultaneously identifying loci showing associations across all domains. We therefore sought to identify loci associated with risk across seven continuous CMD-related traits. METHODS AND RESULTS: We conducted separate genome-wide association studies (GWAS) for systolic and diastolic blood pressure (SBP/DBP), hemoglobin A1c (HbA1c), low- and high- density lipoprotein cholesterol (LDL-C/HDL-C), waist-to-hip-ratio (WHR), and triglycerides (TGs) in the UK Biobank (N = 356,574-456,823). Multiple loci reached genome-wide levels of significance (N = 145-333) for each trait, but only four loci (in/near VEGFA, GRB14-COBLL1, KLF14, and RGS19-OPRL1) were associated with risk across all seven traits (P < 5 × 10-8). We sought replication of these four loci in an independent set of seven trait-specific GWAS meta-analyses. GRB14-COBLL1 showed the most consistent replication, revealing nominally significant associations (P < 0.05) with all traits except DBP. CONCLUSIONS: Our analyses suggest that very few loci are associated in the same direction of risk with traits representing the full spectrum of CMD features. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors that can be used to identify pathologic disturbances that represent broadly beneficial therapeutic targets.
Authors: Ellen W Demerath; Derek Reed; Nikki Rogers; Shumei S Sun; Miryoung Lee; Audrey C Choh; William Couch; Stefan A Czerwinski; W Cameron Chumlea; Roger M Siervogel; Bradford Towne Journal: Am J Clin Nutr Date: 2008-11 Impact factor: 7.045
Authors: Rachel P Wildman; Paul Muntner; Kristi Reynolds; Aileen P McGinn; Swapnil Rajpathak; Judith Wylie-Rosett; MaryFran R Sowers Journal: Arch Intern Med Date: 2008-08-11
Authors: Iris M Heid; Anne U Jackson; Joshua C Randall; Thomas W Winkler; Lu Qi; Valgerdur Steinthorsdottir; Gudmar Thorleifsson; M Carola Zillikens; Elizabeth K Speliotes; Reedik Mägi; Tsegaselassie Workalemahu; Charles C White; Nabila Bouatia-Naji; Tamara B Harris; Sonja I Berndt; Erik Ingelsson; Cristen J Willer; Michael N Weedon; Jian'an Luan; Sailaja Vedantam; Tõnu Esko; Tuomas O Kilpeläinen; Zoltán Kutalik; Shengxu Li; Keri L Monda; Anna L Dixon; Christopher C Holmes; Lee M Kaplan; Liming Liang; Josine L Min; Miriam F Moffatt; Cliona Molony; George Nicholson; Eric E Schadt; Krina T Zondervan; Mary F Feitosa; Teresa Ferreira; Hana Lango Allen; Robert J Weyant; Eleanor Wheeler; Andrew R Wood; Karol Estrada; Michael E Goddard; Guillaume Lettre; Massimo Mangino; Dale R Nyholt; Shaun Purcell; Albert Vernon Smith; Peter M Visscher; Jian Yang; Steven A McCarroll; James Nemesh; Benjamin F Voight; Devin Absher; Najaf Amin; Thor Aspelund; Lachlan Coin; Nicole L Glazer; Caroline Hayward; Nancy L Heard-Costa; 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Karen L Mohlke; Cecilia M Lindgren Journal: Nat Genet Date: 2010-10-10 Impact factor: 38.330
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Authors: Cristen J Willer; Ellen M Schmidt; Sebanti Sengupta; Michael Boehnke; Panos Deloukas; Sekar Kathiresan; Karen L Mohlke; Erik Ingelsson; Gonçalo R Abecasis; Gina M Peloso; Stefan Gustafsson; Stavroula Kanoni; Andrea Ganna; Jin Chen; Martin L Buchkovich; Samia Mora; Jacques S Beckmann; Jennifer L Bragg-Gresham; Hsing-Yi Chang; Ayşe Demirkan; Heleen M Den Hertog; Ron Do; Louise A Donnelly; Georg B Ehret; Tõnu Esko; Mary F Feitosa; Teresa Ferreira; Krista Fischer; Pierre Fontanillas; Ross M Fraser; Daniel F Freitag; Deepti Gurdasani; Kauko Heikkilä; Elina Hyppönen; Aaron Isaacs; Anne U Jackson; Åsa Johansson; Toby Johnson; Marika Kaakinen; Johannes Kettunen; Marcus E Kleber; Xiaohui Li; Jian'an Luan; Leo-Pekka Lyytikäinen; Patrik K E Magnusson; Massimo Mangino; Evelin Mihailov; May E Montasser; Martina Müller-Nurasyid; Ilja M Nolte; Jeffrey R O'Connell; Cameron D Palmer; Markus Perola; Ann-Kristin Petersen; Serena Sanna; Richa Saxena; Susan K Service; Sonia Shah; Dmitry Shungin; Carlo Sidore; Ci Song; Rona J Strawbridge; Ida Surakka; Toshiko Tanaka; Tanya M Teslovich; Gudmar Thorleifsson; Evita G Van den Herik; Benjamin F Voight; Kelly A Volcik; Lindsay L Waite; Andrew Wong; Ying Wu; Weihua Zhang; Devin Absher; Gershim Asiki; Inês Barroso; Latonya F Been; Jennifer L Bolton; Lori L Bonnycastle; Paolo Brambilla; Mary S Burnett; Giancarlo Cesana; Maria Dimitriou; Alex S F Doney; Angela Döring; Paul Elliott; Stephen E Epstein; Gudmundur Ingi Eyjolfsson; Bruna Gigante; Mark O Goodarzi; Harald Grallert; Martha L Gravito; Christopher J Groves; Göran Hallmans; Anna-Liisa Hartikainen; Caroline Hayward; Dena Hernandez; Andrew A Hicks; Hilma Holm; Yi-Jen Hung; Thomas Illig; Michelle R Jones; Pontiano Kaleebu; John J P Kastelein; Kay-Tee Khaw; Eric Kim; Norman Klopp; Pirjo Komulainen; Meena Kumari; Claudia Langenberg; Terho Lehtimäki; Shih-Yi Lin; Jaana Lindström; Ruth J F Loos; François Mach; Wendy L McArdle; Christa Meisinger; Braxton D Mitchell; Gabrielle Müller; Ramaiah Nagaraja; Narisu Narisu; Tuomo V M Nieminen; Rebecca N Nsubuga; Isleifur Olafsson; Ken K Ong; Aarno Palotie; Theodore Papamarkou; Cristina Pomilla; Anneli Pouta; Daniel J Rader; Muredach P Reilly; Paul M Ridker; Fernando Rivadeneira; Igor Rudan; Aimo Ruokonen; Nilesh Samani; Hubert Scharnagl; Janet Seeley; Kaisa Silander; Alena Stančáková; Kathleen Stirrups; Amy J Swift; Laurence Tiret; Andre G Uitterlinden; L Joost van Pelt; Sailaja Vedantam; Nicholas Wainwright; Cisca Wijmenga; Sarah H Wild; Gonneke Willemsen; Tom Wilsgaard; James F Wilson; Elizabeth H Young; Jing Hua Zhao; Linda S Adair; Dominique Arveiler; Themistocles L Assimes; Stefania Bandinelli; Franklyn Bennett; Murielle Bochud; Bernhard O Boehm; Dorret I Boomsma; Ingrid B Borecki; Stefan R Bornstein; Pascal Bovet; Michel Burnier; Harry Campbell; Aravinda Chakravarti; John C Chambers; Yii-Der Ida Chen; Francis S Collins; Richard S Cooper; John Danesh; George Dedoussis; Ulf de Faire; Alan B Feranil; Jean Ferrières; Luigi Ferrucci; Nelson B Freimer; Christian Gieger; Leif C Groop; Vilmundur Gudnason; Ulf Gyllensten; Anders Hamsten; Tamara B Harris; Aroon Hingorani; Joel N Hirschhorn; Albert Hofman; G Kees Hovingh; Chao Agnes Hsiung; Steve E Humphries; Steven C Hunt; Kristian Hveem; Carlos Iribarren; Marjo-Riitta Järvelin; Antti Jula; Mika Kähönen; Jaakko Kaprio; Antero Kesäniemi; Mika Kivimaki; Jaspal S Kooner; Peter J Koudstaal; Ronald M Krauss; Diana Kuh; Johanna Kuusisto; Kirsten O Kyvik; Markku Laakso; Timo A Lakka; Lars Lind; Cecilia M Lindgren; Nicholas G Martin; Winfried März; Mark I McCarthy; Colin A McKenzie; Pierre Meneton; Andres Metspalu; Leena Moilanen; Andrew D Morris; Patricia B Munroe; Inger Njølstad; Nancy L Pedersen; Chris Power; Peter P Pramstaller; Jackie F Price; Bruce M Psaty; Thomas Quertermous; Rainer Rauramaa; Danish Saleheen; Veikko Salomaa; Dharambir K Sanghera; Jouko Saramies; Peter E H Schwarz; Wayne H-H Sheu; Alan R Shuldiner; Agneta Siegbahn; Tim D Spector; Kari Stefansson; David P Strachan; Bamidele O Tayo; Elena Tremoli; Jaakko Tuomilehto; Matti Uusitupa; Cornelia M van Duijn; Peter Vollenweider; Lars Wallentin; Nicholas J Wareham; John B Whitfield; Bruce H R Wolffenbuttel; Jose M Ordovas; Eric Boerwinkle; Colin N A Palmer; Unnur Thorsteinsdottir; Daniel I Chasman; Jerome I Rotter; Paul W Franks; Samuli Ripatti; L Adrienne Cupples; Manjinder S Sandhu; Stephen S Rich Journal: Nat Genet Date: 2013-10-06 Impact factor: 38.330
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