A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

Andrea D. Coviello(National Heart Lung and Blood Institute), Robin Haring(Universität Greifswald), Melissa Wellons(University of Alabama at Birmingham), Dhananjay Vaidya(Johns Hopkins University), Terho Lehtimäki(Tampere University Hospital), Sarah Keildson(University of Oxford), Kathryn L. Lunetta(Boston University), Chunyan He(Indiana University – Purdue University Indianapolis), Myriam Fornage(The University of Texas Health Science Center at Houston), Vasiliki Lagou(University of Oxford), Massimo Mangino(King's College London), N. Charlotte Onland‐Moret(University Medical Center Utrecht), Brian H. Chen(University of California, Los Angeles), Joel Eriksson(University of Gothenburg), Melissa García(National Institute on Aging), Yong Mei Liu(Wake Forest University), Annemarie Koster(National Institute on Aging), Kurt Lohman(Wake Forest University), Leo‐Pekka Lyytikäinen(Tampere University), Ann-Kristin Petersen(Helmholtz Zentrum München), Jennifer Prescott(Harvard University), Lisette Stolk(Erasmus MC), Liesbeth Vandenput(University of Gothenburg), Andrew R. Wood(University of Exeter), Wei Zhuang(Boston University), Aimo Ruokonen(University of Oulu), Anna‐Liisa Hartikainen(Oulu University Hospital), Anneli Pouta(University of Oulu), Stefania Bandinelli(Azienda Sanitaria di Firenze), Reiner Biffar(Universität Greifswald), Georg Brabant(University of Lübeck), David G. Cox(Centre de Recherche en Cancérologie de Lyon), Yuhui Chen(Centre for Human Genetics), Steven R. Cummings(California Pacific Medical Center), Luigi Ferrucci(National Institute on Aging), Marc J. Gunter(Imperial College London), Susan E. Hankinson(Harvard University), Hannu Martikainen(Oulu University Hospital), Albert Hofman(Erasmus University Rotterdam), Georg Homuth(Universität Greifswald), Thomas Illig(Helmholtz Zentrum München), John‐Olov Jansson(University of Gothenburg), Andrew D. Johnson(Framingham Heart Study), David Karasik(Hebrew SeniorLife), Magnus K. Karlsson(Lund University), Johannes Kettunen(Institute for Molecular Medicine Finland), Douglas P. Kiel(Hebrew SeniorLife), Peter Kraft(Harvard University), Jingmin Liu(Cancer Research Center), Östen Ljunggren(Uppsala University), Mattias Lorentzon(University of Gothenburg), Marcello Maggio(University of Parma), Marcello Ricardo Paulista Markus(Universitätsmedizin Greifswald), Dan Mellström(University of Gothenburg), Iva Miljkovic(University of Pittsburgh), Daniel B. Mirel(Broad Institute), Sarah C. Nelson(University of Washington), Laure Morin‐Papunen(Oulu University Hospital), Petra H. Peeters(University Medical Center Utrecht), Inga Prokopenko(University of Oxford), Leslie J. Raffel(Cedars-Sinai Medical Center), Martín Reincke(Ludwig-Maximilians-Universität München), Alex P. Reiner(Fred Hutch Cancer Center), Kathryn M. Rexrode(Harvard University), Fernando Rivadeneira(Erasmus MC), Stephen M. Schwartz(University of Washington), David S. Siscovick(University of Washington), Nicole Soranzo(King's College London), Doris Stöckl(Helmholtz Zentrum München), Shelley S. Tworoger(Brigham and Women's Hospital), André G. Uitterlinden(Netherlands Consortium for Healthy Ageing), Carla H. van Gils(University Medical Center Utrecht), Ramachandran S. Vasan(National Heart Lung and Blood Institute), Hans Wichmann(Zimmer Biomet (Germany)), Guangju Zhai(Memorial University of Newfoundland), Shalender Bhasin(Boston University), Martin Bidlingmaier(Ludwig-Maximilians-Universität München), Stephen J. Chanock(National Cancer Institute), Immaculata De Vivo(Brigham and Women's Hospital), Tamara B. Harris(National Institute on Aging), David J. Hunter(Brigham and Women's Hospital), Mika Kähönen(Tampere University), Simin Liu(University of California, Los Angeles), Pamela Ouyang(Johns Hopkins University), Tim D. Spector(King's College London), Yvonne T. van der Schouw(University Medical Center Utrecht), Jorma Viikari(Turku University Hospital), Henri Wallaschofski(Universität Greifswald), Mark I. McCarthy(Oxford Centre for Diabetes, Endocrinology and Metabolism), Timothy M. Frayling(Peninsula College of Medicine and Dentistry), Anna Murray(University of Exeter), Steve Franks(Imperial College London), Marjo‐Riitta Järvelin(University of Oulu), Frank H. de Jong(Erasmus University Rotterdam), Olli Raitakari(University of Turku), Alexander Teumer(Universität Greifswald), Claes Ohlsson(University of Gothenburg), Joanne M. Murabito(National Heart Lung and Blood Institute), John R. B. Perry(University of Exeter)
PLoS Genetics
July 19, 2012
10.1371/journal.pgen.1002805
Cited by 255Open Access
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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.

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