A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation
Year: 2012
Type: review
Study design: Observational Study
Abstract: Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Source: PLoS Genetics
Authors: Andrea D. Coviello, Robin Haring, Melissa Wellons, Dhananjay Vaidya, Terho Lehtimäki, Sarah Keildson, Kathryn L. Lunetta, Chunyan He, Myriam Fornage, Vasiliki Lagou, Massimo Mangino, N. Charlotte Onland-Moret, Brian Chen, Joel Eriksson, Melissa Garcia, Yong Mei Liu, Annemarie Koster, Kurt Lohman, Leo-Pekka Lyytikäinen, Ann-Kristin Petersen, Jennifer Prescott, Lisette Stolk, Liesbeth Vandenput, Andrew R. Wood, Wei Vivian Zhuang, Aimo Ruokonen, Anna-Liisa Hartikainen, Anneli Pouta, Stefania Bandinelli, Reiner Biffar, Georg Brabant, David G. Cox, Yuhui Chen, Steven Cummings, Luigi Ferrucci, Marc J. Gunter, Susan E. Hankinson, Hannu Martikainen, Albert Hofman, Georg Homuth, Thomas Illig, John-Olov Jansson, Andrew D. Johnson, David Karasik, Magnus Karlsson, Johannes Kettunen, Douglas P. Kiel, Peter Kraft, Jingmin Liu, Östen Ljunggren, Mattias Lorentzon, Marcello Maggio, Marcello R. P. Markus, Dan Mellström, Iva Miljkovic, Daniel Mirel, Sarah Nelson, Laure Morin Papunen, Petra H. M. Peeters, Inga Prokopenko, Leslie Raffel, Martin Reincke, Alex P. Reiner, Kathryn Rexrode, Fernando Rivadeneira, Stephen M. Schwartz, David Siscovick, Nicole Soranzo, Doris Stöckl, Shelley Tworoger, André G. Uitterlinden, Carla H. van Gils, Ramachandran S. Vasan, H.-Erich Wichmann, Guangju Zhai, Shalender Bhasin, Martin Bidlingmaier, Stephen J. Chanock, Immaculata De Vivo, Tamara B. Harris, David J. Hunter, Mika Kähönen, Simin Liu, Pamela Ouyang, Tim D. Spector, Yvonne T. van der Schouw, Jorma Viikari, Henri Wallaschofski, Mark I. McCarthy, Timothy M. Frayling, Anna Murray, Steve Franks, Marjo-Riitta Järvelin, Frank H. de Jong, Olli Raitakari, Alexander Teumer, Claes Ohlsson, Joanne M. Murabito, John R. B. Perry
Institutions: Boston University, Framingham Heart Study, Universität Greifswald, University of Alabama at Birmingham, UAB Medicine, Johns Hopkins University, Tampere University Hospital, Fimlab (Finland), University of Tampere, Centre for Human Genetics, University of Oxford, Indiana University Indianapolis, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, The University of Texas Health Science Center at Houston, Oxford Centre for Diabetes, Endocrinology and Metabolism, King's College London, University Medical Center Utrecht, University of California, Los Angeles, University of Gothenburg, National Institutes of Health, National Institute on Aging, Wake Forest University Health Sciences, Wake Forest University, Helmholtz Munich, Brigham and Women's Hospital, Harvard University, Erasmus MC, Netherlands Consortium for Healthy Ageing, University of Exeter, University of Oulu, Oulu University Hospital, Azienda Sanitaria di Firenze, University of Lübeck, Inserm, Centre de Recherche en Cancérologie de Lyon, Imperial College London, California Pacific Medical Center, University of Massachusetts Amherst, Medizinische Hochschule Hannover, Hebrew SeniorLife, Lund University, University of Helsinki, Finnish Institute for Health and Welfare, Institute for Molecular Medicine Finland, Fred Hutch Cancer Center, Women's Health Initiative, Uppsala University, University of Parma, Universitätsmedizin Greifswald, University of Pittsburgh, Broad Institute, Massachusetts Institute of Technology, University of Washington, Cedars-Sinai Medical Center, Ludwig-Maximilians-Universität München, Wellcome Sanger Institute, München Klinik, Memorial University of Newfoundland, Division of Cancer Epidemiology and Genetics, Johns Hopkins Bayview Medical Center, University of Turku, Turku University Hospital, Churchill Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: National Science Foundation, Pfizer, Wake Forest University, School of Medicine, Boston University, Helsingin Yliopisto, Wellcome Trust, Broad Institute, National Institute for Health and Care Research, King's College London, European Commission, Stiftelsen för Strategisk Forskning, ZonMw, Kela, Academy of Finland, Bundesministerium für Bildung und Forschung, Erasmus Medisch Centrum, Suomen Kulttuurirahasto, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Juho Vainion Säätiö, Novo Nordisk, Vetenskapsrådet, Emil Aaltosen Säätiö, Siemens, Göteborgs Universitet, Oulun Yliopisto, Tampereen Tuberkuloosisäätiö, Paavo Nurmen Säätiö, Turun Yliopistollinen Keskussairaala, Universität Greifswald, Ministry of Cultural Affairs, National Institutes of Health, Directorate for Biological Sciences, U.S. Public Health Service, Medical Research Council, Biotechnology and Biological Sciences Research Council, Biocenter, University of Oulu, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Human Genome Research Institute, National Eye Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities
Awards: G100949702, CARDIA, G1077033501, G1083180012, A PROSPECTIVE STUDY OF DIET AND CANCER IN WOMEN, G119964413, G1241292848, G1261793039, MESA, Genetic Determinants of Visceral Adiposity, G1276754516, G1344639305, G1409423729, G141457348, DYNAMICS OF HEALTH,AGING, AND BODY COMPOSITION, Population-Based Reference Ranges for Testosterone, G1495020029, G151562090, G1518085888, CARDIA, G1567724564, G1639455850, G1640378483, CARDIA, G1686417863, G178033515, G1891033315, G191650467, CAREER: Statistical and Computational Tools for the Analysis of High Dimensional Genetic Data, G2026946236, G2070131968, G2109279595, G2135880156, G2144938473, CARDIA-ECHOCARDIOGRAPHY READING, G2178492673, DYNAMICS OF HEALTH, AGING, AND BODY COMPOSITION, G2230772921, G22458031, G2262782284, Verbundprojekt: Spitzenforschung und Innovation in den Neuen Ländern - GANI_MED - Greifswald Approach to Individualized Medicine, MESA, G2439840495, G2473961061, Clinical and Translational Science Award, CARDIA, G250621538, G2540691155, Biochemical Markers in the nurses' Health Study Cohort, G259853090, G261675466, G262043649, G2786045897, G2815873878, MESA, G2837638605, G2861369480, G2868073770, G2873282741, G290884426, G2918387404, G291913881, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, G2973790809, LONGITUDINAL STUDIES OF CORONARY HEART DISEASE RISK FACTORS IN YOUNG ADULTS, G3107571658, G3117239229, HEALTH ABC--COORDINATING UNIT, CORONARY ARTERY DISEASE RISK DEVELOPMENT IN YOUNG ADULTS, G3164675021, G3205625555, G3207356259, G3226848658, UCLA Clinical and Translational Science Institute, G3294462333, Genetic Influences on ADHD in a Finnish Birth Cohort, G3316531930, G3367174484, G3396487927, G3444966432, G3514318409, G3520205971, G3647016462, G3655053135, G3687594596, G36937976, G3721894273, G37846424, G3814398992, MESA, G3839646794, G3860090032, G3868930229, G393177772, Dietary and Hormonal Determinants of Cancer in Women, G399481048, G4104599821, G4139205196, G4139317420, G4165892905, Coronary Artery Risk Development in Young Adults (CARDIA) Study - Field Center, COORDINATING CENTER FOR WOMEN'S HEALTH INITIATIVE, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), G4321089066, G443405440, G4484576498, G4512137732, G4515475997, G451789889, Genome Wide Association Coordinating Center, G459566519, European Network for Genetic and Genomic Epidemiology, G4735382418, Anwendung von DNA-Array-Technologien in Molekularer Medizin und Mikrobiologie, G4793881792, GENETIC FACTORS FOR OSTEOPOROSIS, G4847987001, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, G4870157667, MESA, G4975632709, Serum Sex Hormone Levels and Subclinical Atherosclerosis, Verbesserung der Leistungsfähigkeit der klinischen Forschung besonders in den Schwerpunkten Community Medicine und Molekulare Medizin, Phase II, G5026349245, CARDIA, G50822097, G5087288417, Genetics of cardiovascular risk factors in large founder population birth control, G510023084, GWAS of longitudinal blood pressure profiles from young adulthood to middle-age, A Center for GEI Association Studies, G5164707915, Statistical Methods for Gene Mapping, G5209003178, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, G5232982263, G5233356934, G5249440708, Clinical Correlates of High and Low Testosterone in Women: Framingham Heart Study, G537455924, G5452216648, G5457026379, G5702163051, G5770909501, G5787256936, G5810988395, G581554933, G582705428, G5881391427, G5909482378, CHARGE consortium: omics discovery for CVD and aging phenotypes, G6029994567, G6091493096, G6095866717, G616491540, Serum Sex Hormonoe Levels & Subclinical Atherosclerosis, Whole Genome Assoc. Analysis Strategies for Multi. Phenotypes, Increased Cardiovacular Risk and Early Natural Menopause in a Biracial Cohort, Genetics of Reproductive Life Period and Health Outcomes, G6355767702, G6359107525, G6401035755, G6413504379, MESA, An NCRR Center for High Throughput SNP Genotyping and Analysis, G6514094751, G6518651994, G6519421474, G6520056932, G6562605244, G6604908402, G66341962, G670738241, G6802942620, THE FRAMINGHAM HEART STUDY-N01HC25195-268025195-268025195, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., GWAS of Hormone Treatment and CVD and Metabolic Outcomes in the WHI, G715477388, G7154858182, G7219708928, G7333372387, MESA, Characterizing Genetic Susceptibility to Breast and Prostate Cancer; the BPC3, G7453583093, G7613770001, Biochemical Markers in the Nurses? Health Study Cohort, G7764220001, G78770644, G792437752, G7981393333, G80149192, Population-Based Reference Ranges for Estradiol and Estrone in Men, G816910144, G8178424689, G820615960, Genome Wide Association Study: Variants Influencing Steroid Hormone Levels, G8267674335, G8345909828, G8399797517, G8487463859, G8506930532, G861947890, G8629017599, Genes of the CYP450-Derived Eicosanoids Pathway in Subclinical Atherosclerosis, Verbesserung der Struktur- und Leistungsfähigkeit der klinischen Forschung besonders in den Schwerpunkten Community Medicine und Molekulare Medizin, G870807107, HISPANIC SECONDARY STROKE PREVENTION INITIATIVE, G8750984004, REGULATION OF MUCIN GENE EXPRESSION BY ELASTASE, G8894861209, G890705022, G9000072420, G9000124674, Novel Molecular Biomarkers of Bone Microarchitecture, Diabetes Research Center (DRC), G915808470, G93682057, G945304896, G991334795
OpenAlex ID: W2134471459