A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.
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 breas...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Public Library of Science
2012
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| _version_ | 1826297843055329280 |
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| author | Coviello, A Haring, R Wellons, M Vaidya, D Lehtimäki, T Keildson, S Lunetta, K He, C Fornage, M Lagou, V Mangino, M Onland-Moret, N Chen, B Eriksson, J Garcia, M Liu, Y Koster, A Lohman, K Lyytikäinen, L Petersen, A Prescott, J Stolk, L Vandenput, L Wood, A Zhuang, W Ruokonen, A Hartikainen, A Pouta, A Bandinelli, S Biffar, R Brabant, G Cox, D Chen, Y Cummings, S Ferrucci, L Gunter, M Hankinson, SE Martikainen, H Hofman, A Homuth, G Illig, T Jansson, J Johnson, A Karasik, D Karlsson, M Kettunen, J Kiel, D Kraft, P Liu, J Ljunggren, Ö Lorentzon, M Maggio, M Markus, MR Mellström, D Miljkovic, I Mirel, D Nelson, S Morin Papunen, L Peeters, P Prokopenko, I Raffel, L Reincke, M Reiner, A Rexrode, K Rivadeneira, F Schwartz, S Siscovick, D Soranzo, N Stöckl, D Tworoger, S Uitterlinden, A Gils, v Vasan, R Wichmann, H Zhai, G Bhasin, S Bidlingmaier, M Chanock, S De Vivo, I Harris, T Hunter, D Kähönen, M Liu, S Ouyang, P Spector, T van der Schouw, Y Viikari, J Wallaschofski, H McCarthy, M Frayling, T Murray, A Franks, S Järvelin, MR de Jong, F Raitakari, O Teumer, A Ohlsson, C Murabito, J Perry, JR |
| author_facet | Coviello, A Haring, R Wellons, M Vaidya, D Lehtimäki, T Keildson, S Lunetta, K He, C Fornage, M Lagou, V Mangino, M Onland-Moret, N Chen, B Eriksson, J Garcia, M Liu, Y Koster, A Lohman, K Lyytikäinen, L Petersen, A Prescott, J Stolk, L Vandenput, L Wood, A Zhuang, W Ruokonen, A Hartikainen, A Pouta, A Bandinelli, S Biffar, R Brabant, G Cox, D Chen, Y Cummings, S Ferrucci, L Gunter, M Hankinson, SE Martikainen, H Hofman, A Homuth, G Illig, T Jansson, J Johnson, A Karasik, D Karlsson, M Kettunen, J Kiel, D Kraft, P Liu, J Ljunggren, Ö Lorentzon, M Maggio, M Markus, MR Mellström, D Miljkovic, I Mirel, D Nelson, S Morin Papunen, L Peeters, P Prokopenko, I Raffel, L Reincke, M Reiner, A Rexrode, K Rivadeneira, F Schwartz, S Siscovick, D Soranzo, N Stöckl, D Tworoger, S Uitterlinden, A Gils, v Vasan, R Wichmann, H Zhai, G Bhasin, S Bidlingmaier, M Chanock, S De Vivo, I Harris, T Hunter, D Kähönen, M Liu, S Ouyang, P Spector, T van der Schouw, Y Viikari, J Wallaschofski, H McCarthy, M Frayling, T Murray, A Franks, S Järvelin, MR de Jong, F Raitakari, O Teumer, A Ohlsson, C Murabito, J Perry, JR |
| author_sort | Coviello, A |
| collection | OXFORD |
| description | 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 x 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 x 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 x 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 x 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 x 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 x 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 x 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 x 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 x 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 x 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 x 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 x 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 x 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 percent and ~8.4 percent 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. |
| first_indexed | 2024-03-07T04:37:59Z |
| format | Journal article |
| id | oxford-uuid:d08d6e26-45d2-40b7-b7bd-95af0bc4dbc1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:37:59Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:d08d6e26-45d2-40b7-b7bd-95af0bc4dbc12022-03-27T07:51:28ZA genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d08d6e26-45d2-40b7-b7bd-95af0bc4dbc1EnglishSymplectic Elements at OxfordPublic Library of Science2012Coviello, AHaring, RWellons, MVaidya, DLehtimäki, TKeildson, SLunetta, KHe, CFornage, MLagou, VMangino, MOnland-Moret, NChen, BEriksson, JGarcia, MLiu, YKoster, ALohman, KLyytikäinen, LPetersen, APrescott, JStolk, LVandenput, LWood, AZhuang, WRuokonen, AHartikainen, APouta, ABandinelli, SBiffar, RBrabant, GCox, DChen, YCummings, SFerrucci, LGunter, MHankinson, SEMartikainen, HHofman, AHomuth, GIllig, TJansson, JJohnson, AKarasik, DKarlsson, MKettunen, JKiel, DKraft, PLiu, JLjunggren, ÖLorentzon, MMaggio, MMarkus, MRMellström, DMiljkovic, IMirel, DNelson, SMorin Papunen, LPeeters, PProkopenko, IRaffel, LReincke, MReiner, ARexrode, KRivadeneira, FSchwartz, SSiscovick, DSoranzo, NStöckl, DTworoger, SUitterlinden, AGils, vVasan, RWichmann, HZhai, GBhasin, SBidlingmaier, MChanock, SDe Vivo, IHarris, THunter, DKähönen, MLiu, SOuyang, PSpector, Tvan der Schouw, YViikari, JWallaschofski, HMcCarthy, MFrayling, TMurray, AFranks, SJärvelin, MRde Jong, FRaitakari, OTeumer, AOhlsson, CMurabito, JPerry, JRSex 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 x 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 x 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 x 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 x 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 x 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 x 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 x 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 x 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 x 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 x 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 x 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 x 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 x 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 percent and ~8.4 percent 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. |
| spellingShingle | Coviello, A Haring, R Wellons, M Vaidya, D Lehtimäki, T Keildson, S Lunetta, K He, C Fornage, M Lagou, V Mangino, M Onland-Moret, N Chen, B Eriksson, J Garcia, M Liu, Y Koster, A Lohman, K Lyytikäinen, L Petersen, A Prescott, J Stolk, L Vandenput, L Wood, A Zhuang, W Ruokonen, A Hartikainen, A Pouta, A Bandinelli, S Biffar, R Brabant, G Cox, D Chen, Y Cummings, S Ferrucci, L Gunter, M Hankinson, SE Martikainen, H Hofman, A Homuth, G Illig, T Jansson, J Johnson, A Karasik, D Karlsson, M Kettunen, J Kiel, D Kraft, P Liu, J Ljunggren, Ö Lorentzon, M Maggio, M Markus, MR Mellström, D Miljkovic, I Mirel, D Nelson, S Morin Papunen, L Peeters, P Prokopenko, I Raffel, L Reincke, M Reiner, A Rexrode, K Rivadeneira, F Schwartz, S Siscovick, D Soranzo, N Stöckl, D Tworoger, S Uitterlinden, A Gils, v Vasan, R Wichmann, H Zhai, G Bhasin, S Bidlingmaier, M Chanock, S De Vivo, I Harris, T Hunter, D Kähönen, M Liu, S Ouyang, P Spector, T van der Schouw, Y Viikari, J Wallaschofski, H McCarthy, M Frayling, T Murray, A Franks, S Järvelin, MR de Jong, F Raitakari, O Teumer, A Ohlsson, C Murabito, J Perry, JR A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. |
| title | A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. |
| title_full | A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. |
| title_fullStr | A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. |
| title_full_unstemmed | A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. |
| title_short | A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. |
| title_sort | genome wide association meta analysis of circulating sex hormone binding globulin reveals multiple loci implicated in sex steroid hormone regulation |
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genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT kield genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT kraftp genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT liuj genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT ljunggreno genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT lorentzonm genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT maggiom genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT markusmr 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siscovickd genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT soranzon genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT stockld genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT tworogers genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT uitterlindena genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT gilsv genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT vasanr genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT 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hunterd genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT kahonenm genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT lius genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT ouyangp genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT spectort genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT vanderschouwy genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT viikarij genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT wallaschofskih genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT mccarthym genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT fraylingt genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT murraya genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT frankss genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT jarvelinmr genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT dejongf genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT raitakario genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT teumera genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT ohlssonc genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT murabitoj genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation AT perryjr genomewideassociationmetaanalysisofcirculatingsexhormonebindingglobulinrevealsmultiplelociimplicatedinsexsteroidhormoneregulation |