A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation

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

doi:10.1371/journal.pgen.1002805

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A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation

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A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation

Andrea D. Coviello, Robin Haring, Melissa Wellons, Dhananjay Vaidya, Terho Lehtimäki, Sarah Keildson, Kathryn L. Lunetta, Chunyan He, Myriam Fornage, Vasiliki Lagou, …

PLoS genetics, Vol.8(7), e1002805

07/2012

DOI: https://doi.org/10.1371/journal.pgen.1002805

PMCID: PMC3400553

PMID: 22829776

Abstract

Ecology, Evolution, Behavior and Systematics

Molecular Biology

Genetics

Genetics(clinical)

Cancer Research

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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Title: A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation
Creators: Andrea D. Coviello (Author) - Boston University;National Heart, Lung, and Blood Institute's The Framingham Heart Study
Robin Haring (Author) - University of Greifswald
Melissa Wellons (Author) - University of Alabama at Birmingham
Dhananjay Vaidya (Author) - Johns Hopkins University
Terho Lehtimäki (Author) - Tampere University
Sarah Keildson (Author) - University of Oxford
Kathryn L. Lunetta (Author) - Boston University
Chunyan He (Author) - Indiana University Bloomington
Myriam Fornage (Author) - University of Texas Health Science Center at Houston
Vasiliki Lagou (Author) - University of Oxford
Massimo Mangino (Author) - King's College London
N. Charlotte Onland-Moret (Author) - Utrecht University
Brian Chen (Author) - University of California at Los Angeles
Joel Eriksson (Author) - University of Gothenburg
Melissa Garcia (Author) - National Institutes of Health
Yong Mei Liu (Author) - Wake Forest University
Annemarie Koster (Author) - National Institutes of Health
Kurt Lohman (Author) - Wake Forest University
Leo Pekka Lyytikäinen (Author) - Tampere University
Ann Kristin Petersen (Author) - National Institutes of Health
Jennifer Prescott (Author) - Helmholtz Zentrum München - German Research Center for Environmental Health;Harvard University
Lisette Stolk (Author) - Harvard University;Netherlands Consortium of Healthy Aging
Liesbeth Vandenput (Author) - University of Gothenburg
Andrew R. Wood (Author) - Netherlands Consortium of Healthy Aging
Wei Vivian Zhuang (Author) - Public Health
Aimo Ruokonen (Author) - University of Exeter
Anna Liisa Hartikainen (Author) - University of Oulu
Anneli Pouta (Author) - University of Oulu
Stefania Bandinelli (Author) - University of Oulu
Reiner Biffar (Author) - Geriatric Unit
Georg Brabant (Author) - University of Greifswald
David G. Cox (Author) - University of Lübeck;Imperial College London
Yuhui Chen (Author) - University of Oxford
Steven Cummings (Author) - California Pacific Medical Center
Luigi Ferrucci (Author) - National Institutes of Health
Marc J. Gunter (Author) - UMR 5641 CNRS
Susan E. Hankinson (Author) - Harvard University;University of Massachusetts
Hannu Martikainen (Author) - University of Oulu
Albert Hofman (Author) - Erasmus University Rotterdam
Georg Homuth (Author) - University of Greifswald
Thomas Illig (Author) - Helmholtz Zentrum München - German Research Center for Environmental Health;Hannover Medical School
John Olov Jansson (Author) - University of Gothenburg
Andrew D. Johnson (Author) - National Heart, Lung, and Blood Institute's The Framingham Heart Study
David Karasik (Author) - Harvard University
Magnus Karlsson (Author) - Lund University
Johannes Kettunen (Author) - University of Helsinki;National Institute for Health and Welfare
Douglas P. Kiel (Author) - Hannover Medical School
Peter Kraft (Author) - Helmholtz Zentrum München - German Research Center for Environmental Health
Jingmin Liu (Author) - National Institute for Health and Welfare
Östen Ljunggren (Author) - Harvard University
Mattias Lorentzon (Author) - University of Gothenburg
Marcello Maggio (Author) - Fred Hutchinson Cancer Research Center
Marcello R.P. Markus (Author) - Uppsala University
Dan Mellström (Author) - University of Gothenburg
Iva Miljkovic (Author) - University of Parma
Daniel Mirel (Author) - University of Greifswald
Sarah Nelson (Author) - University of Pittsburgh
Laure Morin Papunen (Author) - University of Oulu
Petra H.M. Peeters (Author) - Utrecht University
Inga Prokopenko (Author) - University of Oxford
Leslie Raffel (Author) - Broad Institute
Martin Reincke (Author) - Ludwig Maximilian University of Munich
Alex P. Reiner (Author) - Cedars-Sinai Medical Center
Kathryn Rexrode (Author) - Harvard University
Fernando Rivadeneira (Author) - Harvard University;Netherlands Consortium of Healthy Aging
Stephen M. Schwartz (Author) - University of Washington
David Siscovick (Author) - Fred Hutchinson Cancer Research Center
Nicole Soranzo (Author) - King's College London;Wellcome Sanger Institute
Doris Stöckl (Author) - Helmholtz Zentrum München - German Research Center for Environmental Health;Ludwig Maximilian University of Munich
Shelley Tworoger (Author) - Harvard University
André G. Uitterlinden (Author) - Harvard University;Netherlands Consortium of Healthy Aging;Erasmus University Rotterdam
Carla H. van Gils (Author) - Utrecht University
Ramachandran S. Vasan (Author) - Boston University;National Heart, Lung, and Blood Institute's The Framingham Heart Study
H. Erich Wichmann (Author) - Helmholtz Zentrum München - German Research Center for Environmental Health;Ludwig Maximilian University of Munich
Guangju Zhai (Author) - King's College London;Memorial University of Newfoundland
Shalender Bhasin (Author) - Boston University
Martin Bidlingmaier (Author) - University of Washington
Stephen J. Chanock (Author) - National Institutes of Health
Immaculata de Vivo (Author) - Helmholtz Zentrum München - German Research Center for Environmental Health;Harvard University
Tamara B. Harris (Author) - National Institutes of Health
David J. Hunter (Author) - Helmholtz Zentrum München - German Research Center for Environmental Health;Harvard University
Mika Kähönen (Author) - Tampere University
Simin Liu (Author) - University of California at Los Angeles
Pamela Ouyang (Author) - Johns Hopkins University
Tim D. Spector (Author) - King's College London
Yvonne T. van der Schouw (Author) - Utrecht University
Jorma Viikari (Author) - University of Turku
Henri Wallaschofski (Author) - University of Greifswald
Mark I. McCarthy (Author) - University of Oxford;Churchill Hospital
Timothy M. Frayling (Author) - Netherlands Consortium of Healthy Aging
Anna Murray (Author) - Netherlands Consortium of Healthy Aging
Steve Franks (Author) - Imperial College London
Marjo Riitta Järvelin (Author) - Imperial College London;University of Oulu
Frank H. de Jong (Author) - Harvard University
Olli Raitakari (Author) - University of Turku
Alexander Teumer (Author) - Erasmus University Rotterdam
Claes Ohlsson (Author) - University of Gothenburg
Joanne M. Murabito (Author) - National Heart, Lung, and Blood Institute's The Framingham Heart Study;Boston University
John R.B. Perry (Author) - University of Oxford;King's College London;University of Exeter
Additional links: Cohn, D.V.; Glorieux, F.H.; Martin, T.J.; Cohn, D.V.; Glorieux, F.H.; Martin, T.J.
Publication Details: PLoS genetics, Vol.8(7), e1002805
Series: 8
Identifiers: 991005930267702656
Academic Unit: Master Public Health
Language: English
Resource Type: Journal article