Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Frank J A van Rooij; Rehan Qayyum; Albert V Smith; Yi Zhou; Stella Trompet; Toshiko Tanaka; Margaux F Keller; Li-Ching Chang; Helena Schmidt; Min-Lee Yang; Ming-Huei Chen; James Hayes; Andrew D Johnson; Lisa R Yanek; Christian Mueller; Leslie Lange; James S Floyd; Mohsen Ghanbari; Alan B Zonderman; J Wouter Jukema; Albert Hofman; Cornelia M van Duijn; Karl C Desch; Yasaman Saba; Ayse B Ozel; Beverly M Snively; Jer-Yuarn Wu; Reinhold Schmidt; Myriam Fornage; Robert J Klein; Caroline S Fox; Koichi Matsuda; Naoyuki Kamatani; Philipp S Wild; David J Stott; Ian Ford; P Eline Slagboom; Jaden Yang; Audrey Y Chu; Amy J Lambert; André G Uitterlinden; Oscar H Franco; Edith Hofer; David Ginsburg; Bella Hu; Brendan Keating; Ursula M Schick; Jennifer A Brody; Jun Z Li; Zhao Chen; Tanja Zeller; Jack M Guralnik; Daniel I Chasman; Luanne L Peters; Michiaki Kubo; Diane M Becker; Jin Li; Gudny Eiriksdottir; Jerome I Rotter; Daniel Levy; Vera Grossmann; Kushang V Patel; Chien-Hsiun Chen; BioBank Japan Project; Paul M Ridker; Hua Tang; Lenore J Launer; Kenneth M Rice; Ruifang Li-Gao; Luigi Ferrucci; Michelle K Evans; Avik Choudhuri; Eirini Trompouki; Brian J Abraham; Song Yang; Atsushi Takahashi; Yoichiro Kamatani; Charles Kooperberg; Tamara B Harris; Sun Ha Jee; Josef Coresh; Fuu-Jen Tsai; Dan L Longo; Yuan-Tsong Chen; Janine F Felix; Qiong Yang; Bruce M Psaty; Eric Boerwinkle; Lewis C Becker; Dennis O Mook-Kanamori; James G Wilson; Vilmundur Gudnason; Christopher J O'Donnell; Abbas Dehghan; L Adrienne Cupples; Michael A Nalls; Andrew P Morris; Yukinori Okada; Alexander P Reiner; Leonard I Zon; Santhi K Ganesh

doi:10.1016/j.ajhg.2016.11.016

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Am J Hum Genet. 2017 Jan 5;100(1):51-63. doi: 10.1016/j.ajhg.2016.11.016. Epub 2016 Dec 22.

Authors

Frank J A van Rooij¹, Rehan Qayyum², Albert V Smith³, Yi Zhou⁴, Stella Trompet⁵, Toshiko Tanaka⁶, Margaux F Keller⁷, Li-Ching Chang⁸, Helena Schmidt⁹, Min-Lee Yang¹⁰, Ming-Huei Chen¹¹, James Hayes¹², Andrew D Johnson¹³, Lisa R Yanek², Christian Mueller¹⁴, Leslie Lange¹⁵, James S Floyd¹⁶, Mohsen Ghanbari¹⁷, Alan B Zonderman¹⁸, J Wouter Jukema¹⁹, Albert Hofman²⁰, Cornelia M van Duijn¹, Karl C Desch²¹, Yasaman Saba⁹, Ayse B Ozel²¹, Beverly M Snively²², Jer-Yuarn Wu²³, Reinhold Schmidt²⁴, Myriam Fornage²⁵, Robert J Klein¹², Caroline S Fox¹³, Koichi Matsuda²⁶, Naoyuki Kamatani²⁷, Philipp S Wild²⁸, David J Stott²⁹, Ian Ford³⁰, P Eline Slagboom³¹, Jaden Yang³², Audrey Y Chu³³, Amy J Lambert³⁴, André G Uitterlinden³⁵, Oscar H Franco¹, Edith Hofer³⁶, David Ginsburg²¹, Bella Hu⁴, Brendan Keating³⁷, Ursula M Schick³⁸, Jennifer A Brody¹⁶, Jun Z Li²¹, Zhao Chen³⁹, Tanja Zeller¹⁴, Jack M Guralnik⁴⁰, Daniel I Chasman⁴¹, Luanne L Peters³⁴, Michiaki Kubo⁴², Diane M Becker², Jin Li⁴³, Gudny Eiriksdottir⁴⁴, Jerome I Rotter⁴⁵, Daniel Levy¹³, Vera Grossmann⁴⁶, Kushang V Patel¹⁸, Chien-Hsiun Chen²³; BioBank Japan Project; Paul M Ridker⁴⁷, Hua Tang⁴⁸, Lenore J Launer⁴⁹, Kenneth M Rice⁵⁰, Ruifang Li-Gao⁵¹, Luigi Ferrucci⁶, Michelle K Evans⁵², Avik Choudhuri⁴, Eirini Trompouki⁵³, Brian J Abraham⁵⁴, Song Yang⁴, Atsushi Takahashi²⁷, Yoichiro Kamatani²⁷, Charles Kooperberg⁵⁵, Tamara B Harris⁴⁹, Sun Ha Jee⁵⁶, Josef Coresh⁵⁷, Fuu-Jen Tsai⁵⁸, Dan L Longo⁵⁹, Yuan-Tsong Chen⁸, Janine F Felix¹, Qiong Yang⁶⁰, Bruce M Psaty⁶¹, Eric Boerwinkle²⁵, Lewis C Becker², Dennis O Mook-Kanamori⁶², James G Wilson⁶³, Vilmundur Gudnason³, Christopher J O'Donnell¹³, Abbas Dehghan⁶⁴, L Adrienne Cupples⁶⁰, Michael A Nalls⁷, Andrew P Morris⁶⁵, Yukinori Okada⁶⁶, Alexander P Reiner⁶⁷, Leonard I Zon⁴, Santhi K Ganesh⁶⁸

Affiliations

¹ Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
² GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
³ Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland; Icelandic Heart Association, 210 Kopavogur, Iceland.
⁴ Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Pediatric Hematology/Oncology at DFCI, Harvard Stem Cell Institute, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
⁵ Department of Cardiology, Leiden University Medical Center, 2300 AC Leiden, the Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 AC Leiden, the Netherlands.
⁶ National Institute on Aging, NIH, Baltimore, MD 21224, USA.
⁷ Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
⁸ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
⁹ Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
¹⁰ Division of Cardiovascular Medicine, Department of Internal Medicine, Department of Human Genetics, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
¹¹ Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
¹² Icahn Institute for Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹³ Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
¹⁴ Department of General and Interventional Cardiology, University Heart Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg, Lübeck, Kiel, Hamburg 20246, Germany.
¹⁵ Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
¹⁶ Department of Medicine, University of Washington, Seattle, WA 98195-6420, USA.
¹⁷ Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, 91375-345 Mashhad, Iran.
¹⁸ National Institute on Aging, NIH, Bethesda, MD 20892-9205, USA.
¹⁹ Department of Cardiology, Leiden University Medical Center, 2300 AC Leiden, the Netherlands.
²⁰ Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
²¹ University of Michigan Medical School, Ann Arbor, MI 48109, USA.
²² Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
²³ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
²⁴ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, 8010 Graz, Austria.
²⁵ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
²⁶ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
²⁷ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
²⁸ Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, 55131 Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany; Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
²⁹ Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G12 8QQ, UK.
³⁰ Robertson Center for Biostatistics, University of Glasgow, Glasgow G12 8QQ, UK.
³¹ Department of Medical Statistics and Bioinformatics, Section of Molecular Epidemiology, Leiden University Medical Center, 2300 AC Leiden, the Netherlands.
³² Quantitative Sciences Unit, School of Medicine, Stanford University, Stanford, CA 94304, USA.
³³ Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
³⁴ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
³⁵ Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
³⁶ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, 8010 Graz, Austria; Institute of Medical Informatics, Statistics and Documentation, Medical University Graz, 8010 Graz, Austria.
³⁷ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA.
³⁸ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³⁹ Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA.
⁴⁰ Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁴¹ Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴² Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
⁴³ Cardiovascular Medicine Division, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA.
⁴⁴ Icelandic Heart Association, 210 Kopavogur, Iceland.
⁴⁵ Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
⁴⁶ Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, 55131 Mainz, Germany.
⁴⁷ Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴⁸ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴⁹ Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, NIH, Bethesda, MD 20892-9205, USA.
⁵⁰ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
⁵¹ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2300 AC, the Netherlands.
⁵² Health Disparities Research Section, Clinical Research Branch, National Institute on Aging, NIH, Baltimore, MD 20892, USA.
⁵³ Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Pediatric Hematology/Oncology at DFCI, Harvard Stem Cell Institute, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA; Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
⁵⁴ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
⁵⁵ Biostatistics and Biomathematics, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁵⁶ Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul 03722, Korea.
⁵⁷ Johns Hopkins Bloomberg School of Public Health, George W. Comstock Center for Public Health Research and Prevention, Comstock Center & Cardiovascular Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, MD 21205, USA.
⁵⁸ School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
⁵⁹ Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD 21225, USA.
⁶⁰ Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA; Department of Biostatistics, Boston University of Public Health, Boston, MA 02118, USA.
⁶¹ Departments of Epidemiology, Health Services, and Medicine, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
⁶² Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2300 AC, the Netherlands; Department of BESC, Epidemiology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Department of Public Health and Primary Care, Leiden University Medical Center, 2300 AC Leiden, the Netherlands.
⁶³ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁶⁴ Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College, W2 1PG London, UK.
⁶⁵ Department of Biostatistics, University of Liverpool, Block F, Waterhouse Building, 1-5 Brownlow Street, Liverpool L69 3GL, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
⁶⁶ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
⁶⁷ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
⁶⁸ Division of Cardiovascular Medicine, Department of Internal Medicine, Department of Human Genetics, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: sganesh@umich.edu.

Abstract

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

Publication types

Meta-Analysis

MeSH terms

Africa / ethnology
Alleles
Animals
Asia, Eastern / ethnology
Bayes Theorem
Erythrocytes / metabolism*
Erythropoiesis / genetics*
Ethnicity / genetics
Europe / ethnology
Female
Genome-Wide Association Study
Humans
Linkage Disequilibrium
Male
RNA-Binding Proteins / genetics*
Racial Groups / genetics*
Zebrafish / genetics

Substances

RBPMS protein, human
RNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding