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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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 = 1.8x10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4x10(-11)), GCKR (rs780093, 2p23.3, p=2.2x10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4x10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1x10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9x10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3x10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5x10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1x10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3x10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7x10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5x10(-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 = 2.5x10(-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 similar to 15.6% and similar to 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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Authors
  • Andrea D. Coviello
  • Robin Haring
  • Melissa Wellons
  • Dhananjay Vaidya
  • Terho Lehtimaki
  • 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
  • Annemarie Koster
  • Kurt Lohman
  • Leo-Pekka Lyytikainen
  • 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
  • Johannes Kettunen
  • Douglas P. Kiel
  • Peter Kraft
  • Jingmin Liu
  • Osten Ljunggren
  • Mattias Lorentzon
  • Marcello Maggio
  • Marcello R. P. Markus
  • Dan Mellstrom
  • 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 Stockl
  • Shelley Tworoger
  • Andre 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 Kahonen
  • 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 Jarvelin
  • Frank H. de Jong
  • Olli Raitakari
  • Alexander Teumer
  • Claes Ohlsson
  • Joanne M. Murabito
  • John R. B. Perry
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Subject classification (UKÄ) – MANDATORY

  • Orthopedics
Original languageEnglish
JournalPLoS Genetics
Volume8
Issue number7
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes

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