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

PLoS Genetics. 2012;8(7):e1002805 DOI 10.1371/journal.pgen.1002805

 

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Journal Title: PLoS Genetics

ISSN: 1553-7390 (Print); 1553-7404 (Online)

Publisher: Public Library of Science (PLoS)

LCC Subject Category: Science: Biology (General): Genetics

Country of publisher: United States

Language of fulltext: English

Full-text formats available: PDF, HTML, XML

 

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

EDITORIAL INFORMATION

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Instructions for authors

Time From Submission to Publication: 26 weeks

 

Abstract | Full Text

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.