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dc.contributor.authorCoviello, Andrea D.
dc.contributor.authorHaring, Robin
dc.contributor.authorWellons, Melissa
dc.contributor.authorVaidya, Dhananjay
dc.contributor.authorLehtimäki, Terho
dc.contributor.authorKeildson, Sarah
dc.contributor.authorLunetta, Kathryn L.
dc.contributor.authorHe, Chunyan
dc.contributor.authorFornage, Myriam
dc.contributor.authorLagou, Vasiliki
dc.contributor.authorMangino, Massimo
dc.contributor.authorOnland-Moret, N. Charlotte
dc.contributor.authorEriksson, Joel
dc.contributor.authorGarcia, Melissa
dc.contributor.authorLiu, Yong Mei
dc.contributor.authorKoster, Annemarie
dc.contributor.authorLohman, Kurt
dc.contributor.authorLyytikäinen, Leo-Pekka
dc.contributor.authorPetersen, Ann-Kristin
dc.contributor.authorStolk, Lisette
dc.contributor.authorVandenput, Liesbeth
dc.contributor.authorWood, Andrew R.
dc.contributor.authorZhuang, Wei Vivian
dc.contributor.authorRuokonen, Aimo
dc.contributor.authorHartikainen, Anna-Liisa
dc.contributor.authorPouta, Anneli
dc.contributor.authorBandinelli, Stefania
dc.contributor.authorBiffar, Reiner
dc.contributor.authorBrabant, Georg
dc.contributor.authorChen, Yuhui
dc.contributor.authorCummings, Steven
dc.contributor.authorFerrucci, Luigi
dc.contributor.authorGunter, Marc J.
dc.contributor.authorMartikainen, Hannu
dc.contributor.authorHomuth, Georg
dc.contributor.authorIllig, Thomas
dc.contributor.authorJansson, John-Olov
dc.contributor.authorKarlsson, Magnus
dc.contributor.authorKettunen, Johannes
dc.contributor.authorLiu, Jingmin
dc.contributor.authorLjunggren, Östen
dc.contributor.authorLorentzon, Mattias
dc.contributor.authorMaggio, Marcello
dc.contributor.authorMarkus, Marcello R. P.
dc.contributor.authorMellström, Dan
dc.contributor.authorMiljkovic, Iva
dc.contributor.authorMirel, Daniel
dc.contributor.authorMorin Papunen, Laure
dc.contributor.authorPeeters, Petra H. M.
dc.contributor.authorProkopenko, Inga
dc.contributor.authorRaffel, Leslie
dc.contributor.authorReincke, Martin
dc.contributor.authorReiner, Alex P.
dc.contributor.authorRivadeneira, Fernando
dc.contributor.authorSchwartz, Stephen M.
dc.contributor.authorSiscovick, David
dc.contributor.authorSoranzo, Nicole
dc.contributor.authorStöckl, Doris
dc.contributor.authorUitterlinden, André G.
dc.contributor.authorvan Gils, Carla H.
dc.contributor.authorVasan, Ramachandran S.
dc.contributor.authorWichmann, H.-Erich
dc.contributor.authorZhai, Guangju
dc.contributor.authorBhasin, Shalender
dc.contributor.authorBidlingmaier, Martin
dc.contributor.authorChanock, Stephen J.
dc.contributor.authorHarris, Tamara B.
dc.contributor.authorKähönen, Mika
dc.contributor.authorLiu, Simin
dc.contributor.authorOuyang, Pamela
dc.contributor.authorSpector, Tim D.
dc.contributor.authorvan der Schouw, Yvonne T.
dc.contributor.authorViikari, Jorma
dc.contributor.authorWallaschofski, Henri
dc.contributor.authorMcCarthy, Mark I.
dc.contributor.authorFrayling, Timothy M.
dc.contributor.authorMurray, Anna
dc.contributor.authorFranks, Steve
dc.contributor.authorJärvelin, Marjo-Riitta
dc.contributor.authorde Jong, Frank H.
dc.contributor.authorRaitakari, Olli
dc.contributor.authorTeumer, Alexander
dc.contributor.authorOhlsson, Claes
dc.contributor.authorMurabito, Joanne M.
dc.contributor.authorPerry, John R. B.
dc.contributor.authorChen, Brian
dc.contributor.authorPrescott, Jennifer
dc.contributor.authorCox, David G.
dc.contributor.authorHankinson, Susan Elizabeth
dc.contributor.authorHofman, Albert
dc.contributor.authorJohnson, Andrew D.
dc.contributor.authorKarasik, David
dc.contributor.authorKiel, Douglas P.
dc.contributor.authorNelson, Sarah
dc.contributor.authorRexrode, Kathryn Marian
dc.contributor.authorTworoger, Shelley Slate
dc.contributor.authorDe Vivo, Immaculata
dc.contributor.authorHunter, David J.
dc.contributor.authorKraft, Peter
dc.date.accessioned2013-03-26T19:26:28Z
dc.date.issued2012
dc.identifier.citationCoviello, Andrea D., Robin Haring, Melissa Wellons, Dhananjay Vaidya, Terho Lehtimäki, Sarah Keildson, Kathryn L. Lunetta, et al. 2012. A genome-wide association meta-analysis of circulating sex hormone–binding globulin reveals multiple loci implicated in sex steroid hormone regulation. PLoS Genetics 8(7): e1002805.en_US
dc.identifier.issn1553-7390en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10465991
dc.description.abstractSex 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×\(10^{−9}\)), 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.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pgen.1002805en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400553/pdf/en_US
dash.licenseLAA
dc.subjectMedicineen_US
dc.subjectEndocrinologyen_US
dc.subjectEndocrine Physiologyen_US
dc.subjectReproductive Endocrinologyen_US
dc.subjectEpidemiologyen_US
dc.subjectGenetic Epidemiologyen_US
dc.titleA Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulationen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Geneticsen_US
dash.depositing.authorKarasik, David
dc.date.available2013-03-26T19:26:28Z
dc.identifier.doi10.1371/journal.pgen.1002805*
dash.authorsorderedfalse
dash.contributor.affiliatedKarasik, David
dash.contributor.affiliatedDe Vivo, Immaculata
dash.contributor.affiliatedRexrode, Kathryn
dash.contributor.affiliatedPrescott, Jennifer
dash.contributor.affiliatedHankinson, Susan
dash.contributor.affiliatedKiel, Douglas
dash.contributor.affiliatedTworoger, Shelley
dash.contributor.affiliatedHofman, Albert
dash.contributor.affiliatedHunter, David
dc.identifier.orcid0000-0002-6986-7046
dc.identifier.orcid0000-0002-9865-121X


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