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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/4a9def3535b34414a48d70d8f4aa1e06
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id	oai:doaj.org-article:4a9def3535b34414a48d70d8f4aa1e06
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 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 A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.
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 × 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.
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author	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
author_facet	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
author_sort	Andrea D Coviello
title	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_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_sort	genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/4a9def3535b34414a48d70d8f4aa1e06
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spelling	oai:doaj.org-article:4a9def3535b34414a48d70d8f4aa1e062021-11-18T06:18:21ZA genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.1553-73901553-740410.1371/journal.pgen.1002805https://doaj.org/article/4a9def3535b34414a48d70d8f4aa1e062012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22829776/pdf/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Sex 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.Andrea D CovielloRobin HaringMelissa WellonsDhananjay VaidyaTerho LehtimäkiSarah KeildsonKathryn L LunettaChunyan HeMyriam FornageVasiliki LagouMassimo ManginoN Charlotte Onland-MoretBrian ChenJoel ErikssonMelissa GarciaYong Mei LiuAnnemarie KosterKurt LohmanLeo-Pekka LyytikäinenAnn-Kristin PetersenJennifer PrescottLisette StolkLiesbeth VandenputAndrew R WoodWei Vivian ZhuangAimo RuokonenAnna-Liisa HartikainenAnneli PoutaStefania BandinelliReiner BiffarGeorg BrabantDavid G CoxYuhui ChenSteven CummingsLuigi FerrucciMarc J GunterSusan E HankinsonHannu MartikainenAlbert HofmanGeorg HomuthThomas IlligJohn-Olov JanssonAndrew D JohnsonDavid KarasikMagnus KarlssonJohannes KettunenDouglas P KielPeter KraftJingmin LiuÖsten LjunggrenMattias LorentzonMarcello MaggioMarcello R P MarkusDan MellströmIva MiljkovicDaniel MirelSarah NelsonLaure Morin PapunenPetra H M PeetersInga ProkopenkoLeslie RaffelMartin ReinckeAlex P ReinerKathryn RexrodeFernando RivadeneiraStephen M SchwartzDavid SiscovickNicole SoranzoDoris StöcklShelley TworogerAndré G UitterlindenCarla H van GilsRamachandran S VasanH-Erich WichmannGuangju ZhaiShalender BhasinMartin BidlingmaierStephen J ChanockImmaculata De VivoTamara B HarrisDavid J HunterMika KähönenSimin LiuPamela OuyangTim D SpectorYvonne T van der SchouwJorma ViikariHenri WallaschofskiMark I McCarthyTimothy M FraylingAnna MurraySteve FranksMarjo-Riitta JärvelinFrank H de JongOlli RaitakariAlexander TeumerClaes OhlssonJoanne M MurabitoJohn R B PerryPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 8, Iss 7, p e1002805 (2012)

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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