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

 

Journal Homepage

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

Peer review

Editorial Board

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.