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dc.contributor.authorCoviello, AD
dc.contributor.authorHaring, R
dc.contributor.authorWellons, M
dc.contributor.authorVaidya, D
dc.contributor.authorLehtimäki, T
dc.contributor.authorKeildson, S
dc.contributor.authorLunetta, KL
dc.contributor.authorHe, C
dc.contributor.authorFornage, M
dc.contributor.authorLagou, V
dc.contributor.authorMangino, M
dc.contributor.authorOnland-Moret, NC
dc.contributor.authorChen, B
dc.contributor.authorEriksson, Joel
dc.contributor.authorGarcia, M
dc.contributor.authorLiu, YM
dc.contributor.authorKoster, A
dc.contributor.authorLohman, K
dc.contributor.authorLyytikäinen, LP
dc.contributor.authorPetersen, AK
dc.contributor.authorPrescott, J
dc.contributor.authorStolk, L
dc.contributor.authorVandenput, L
dc.contributor.authorWood, Andrew R.
dc.contributor.authorZhuang, WV
dc.contributor.authorRuokonen, A
dc.contributor.authorHartikainen, AL
dc.contributor.authorPouta, A
dc.contributor.authorBandinelli, S
dc.contributor.authorBiffar, R
dc.contributor.authorBrabant, G
dc.contributor.authorCox, David G.
dc.contributor.authorChen, Y
dc.contributor.authorCummings, S
dc.contributor.authorFerrucci, L
dc.contributor.authorGunter, MJ
dc.contributor.authorHankinson, SE
dc.contributor.authorMartikainen, H
dc.contributor.authorHofman, A
dc.contributor.authorHomuth, G
dc.contributor.authorIllig, T
dc.contributor.authorJansson, JO
dc.contributor.authorJohnson, AD
dc.contributor.authorKarasik, D
dc.contributor.authorKarlsson, M
dc.contributor.authorKettunen, J
dc.contributor.authorKiel, DP
dc.contributor.authorKraft, P
dc.contributor.authorLiu, J
dc.contributor.authorLjunggren, Ö
dc.contributor.authorLorentzon, M
dc.contributor.authorMaggio, M
dc.contributor.authorMarkus, MR
dc.contributor.authorMellström, D
dc.contributor.authorMiljkovic, I
dc.contributor.authorMirel, D
dc.contributor.authorNelson, S
dc.contributor.authorMorin Papunen, L
dc.contributor.authorPeeters, PH
dc.contributor.authorProkopenko, I
dc.contributor.authorRaffel, L
dc.contributor.authorReincke, M
dc.contributor.authorReiner, AP
dc.contributor.authorRexrode, K
dc.contributor.authorRivadeneira, F
dc.contributor.authorSchwartz, SM
dc.contributor.authorSiscovick, D
dc.contributor.authorSoranzo, N
dc.contributor.authorStöckl, D
dc.contributor.authorTworoger, S
dc.contributor.authorUitterlinden, AG
dc.contributor.authorvan Gils, CH
dc.contributor.authorVasan, RS
dc.contributor.authorWichmann, HE
dc.contributor.authorZhai, G
dc.contributor.authorBhasin, S
dc.contributor.authorBidlingmaier, M
dc.contributor.authorChanock, SJ
dc.contributor.authorDe Vivo, I
dc.contributor.authorHarris, Tamara
dc.contributor.authorHunter, DJ
dc.contributor.authorKähönen, M
dc.contributor.authorLiu, S
dc.contributor.authorOuyang, P
dc.contributor.authorSpector, TD
dc.contributor.authorvan der Schouw, YT
dc.contributor.authorViikari, J
dc.contributor.authorWallaschofski, H
dc.contributor.authorMcCarthy, MI
dc.contributor.authorFrayling, Timothy M.
dc.contributor.authorMurray, A
dc.contributor.authorFranks, S
dc.contributor.authorJärvelin, MR
dc.contributor.authorde Jong, FH
dc.contributor.authorRaitakari, O
dc.contributor.authorTeumer, A
dc.contributor.authorOhlsson, C
dc.contributor.authorMurabito, JM
dc.contributor.authorPerry, John R.B.
dc.date.accessioned2013-12-09T14:13:35Z
dc.date.issued2012
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(-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.en_GB
dc.identifier.citationVol. 8 (7), article e1002805en_GB
dc.identifier.doi10.1371/journal.pgen.1002805
dc.identifier.urihttp://hdl.handle.net/10871/14218
dc.language.isoenen_GB
dc.publisherPublic Library of Scienceen_GB
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/22829776en_GB
dc.relation.urlhttp://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002805en_GB
dc.subjectAllelesen_GB
dc.subjectFemaleen_GB
dc.subjectGenetic Heterogeneityen_GB
dc.subjectGenome-Wide Association Studyen_GB
dc.subjectGonadal Steroid Hormonesen_GB
dc.subjectHumansen_GB
dc.subjectMaleen_GB
dc.subjectMetabolic Networks and Pathwaysen_GB
dc.subjectPolymorphism, Single Nucleotideen_GB
dc.subjectSex Characteristicsen_GB
dc.subjectSex Hormone-Binding Globulinen_GB
dc.titleA genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulationen_GB
dc.typeArticleen_GB
dc.date.available2013-12-09T14:13:35Z
dc.identifier.issn1553-7390
exeter.place-of-publicationUnited States
dc.descriptionaddresses: Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts, United States of America.en_GB
dc.descriptionnotes: PMCID: PMC3400553en_GB
dc.descriptionThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_GB
dc.identifier.journalPLoS Geneticsen_GB


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