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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A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation. / Coviello, Andrea D.; Haring, Robin; Wellons, Melissa; Vaidya, Dhananjay; Lehtimaki, Terho; Keildson, Sarah; Lunetta, Kathryn L.; He, Chunyan; Fornage, Myriam; Lagou, Vasiliki; Mangino, Massimo; Onland-Moret, N. Charlotte; Chen, Brian; Eriksson, Joel; Garcia, Melissa; Mei, Yong; Koster, Annemarie; Lohman, Kurt; Lyytikainen, Leo-Pekka; Petersen, Ann-Kristin; Prescott, Jennifer; Stolk, Lisette; Vandenput, Liesbeth; Wood, Andrew R.; Zhuang, Wei Vivian; Ruokonen, Aimo; Hartikainen, Anna-Liisa; Pouta, Anneli; Bandinelli, Stefania; Biffar, Reiner; Brabant, Georg; Cox, David G.; Chen, Yuhui; Cummings, Steven; Ferrucci, Luigi; Gunter, Marc J.; Hankinson, Susan E.; Martikainen, Hannu; Hofman, Albert; Homuth, Georg; Illig, Thomas; Jansson, John-Olov; Johnson, Andrew D.; Karasik, David; Karlsson, Magnus; Kettunen, Johannes; Kiel, Douglas P.; Kraft, Peter; Liu, Jingmin; Ljunggren, Osten; Lorentzon, Mattias; Maggio, Marcello; Markus, Marcello R. P.; Mellstrom, Dan; Miljkovic, Iva; Mirel, Daniel; Nelson, Sarah; Papunen, Laure Morin; Peeters, Petra H. M.; Prokopenko, Inga; Raffel, Leslie; Reincke, Martin; Reiner, Alex P.; Rexrode, Kathryn; Rivadeneira, Fernando; Schwartz, Stephen M.; Siscovick, David; Soranzo, Nicole; Stockl, Doris; Tworoger, Shelley; Uitterlinden, Andre G.; van Gils, Carla H.; Vasan, Ramachandran S.; Wichmann, H. -Erich; Zhai, Guangju; Bhasin, Shalender; Bidlingmaier, Martin; Chanock, Stephen J.; De Vivo, Immaculata; Harris, Tamara B.; Hunter, David J.; Kahonen, Mika; Liu, Simin; Ouyang, Pamela; Spector, Tim D.; van der Schouw, Yvonne T.; Viikari, Jorma; Wallaschofski, Henri; McCarthy, Mark I.; Frayling, Timothy M.; Murray, Anna; Franks, Steve; Jarvelin, Marjo-Riitta; de Jong, Frank H.; Raitakari, Olli; Teumer, Alexander; Ohlsson, Claes; Murabito, Joanne M.; Perry, John R. B.

In: PLoS Genetics, Vol. 8, No. 7, 2012.

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Harvard

Coviello, AD, Haring, R, Wellons, M, Vaidya, D, Lehtimaki, T, Keildson, S, Lunetta, KL, He, C, Fornage, M, Lagou, V, Mangino, M, Onland-Moret, NC, Chen, B, Eriksson, J, Garcia, M, Mei, Y, Koster, A, Lohman, K, Lyytikainen, L-P, Petersen, A-K, Prescott, J, Stolk, L, Vandenput, L, Wood, AR, Zhuang, WV, Ruokonen, A, Hartikainen, A-L, Pouta, A, Bandinelli, S, Biffar, R, Brabant, G, Cox, DG, Chen, Y, Cummings, S, Ferrucci, L, Gunter, MJ, Hankinson, SE, Martikainen, H, Hofman, A, Homuth, G, Illig, T, Jansson, J-O, Johnson, AD, Karasik, D, Karlsson, M, Kettunen, J, Kiel, DP, Kraft, P, Liu, J, Ljunggren, O, Lorentzon, M, Maggio, M, Markus, MRP, Mellstrom, D, Miljkovic, I, Mirel, D, Nelson, S, Papunen, LM, Peeters, PHM, Prokopenko, I, Raffel, L, Reincke, M, Reiner, AP, Rexrode, K, Rivadeneira, F, Schwartz, SM, Siscovick, D, Soranzo, N, Stockl, D, Tworoger, S, Uitterlinden, AG, van Gils, CH, Vasan, RS, Wichmann, H-E, Zhai, G, Bhasin, S, Bidlingmaier, M, Chanock, SJ, De Vivo, I, Harris, TB, Hunter, DJ, Kahonen, M, Liu, S, Ouyang, P, Spector, TD, van der Schouw, YT, Viikari, J, Wallaschofski, H, McCarthy, MI, Frayling, TM, Murray, A, Franks, S, Jarvelin, M-R, de Jong, FH, Raitakari, O, Teumer, A, Ohlsson, C, Murabito, JM & Perry, JRB 2012, 'A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation', PLoS Genetics, vol. 8, no. 7. https://doi.org/10.1371/journal.pgen.1002805

APA

CBE

Coviello AD, Haring R, Wellons M, Vaidya D, Lehtimaki T, Keildson S, Lunetta KL, He C, Fornage M, Lagou V, Mangino M, Onland-Moret NC, Chen B, Eriksson J, Garcia M, Mei Y, Koster A, Lohman K, Lyytikainen L-P, Petersen A-K, Prescott J, Stolk L, Vandenput L, Wood AR, Zhuang WV, Ruokonen A, Hartikainen A-L, Pouta A, Bandinelli S, Biffar R, Brabant G, Cox DG, Chen Y, Cummings S, Ferrucci L, Gunter MJ, Hankinson SE, Martikainen H, Hofman A, Homuth G, Illig T, Jansson J-O, Johnson AD, Karasik D, Karlsson M, Kettunen J, Kiel DP, Kraft P, Liu J, Ljunggren O, Lorentzon M, Maggio M, Markus MRP, Mellstrom D, Miljkovic I, Mirel D, Nelson S, Papunen LM, Peeters PHM, Prokopenko I, Raffel L, Reincke M, Reiner AP, Rexrode K, Rivadeneira F, Schwartz SM, Siscovick D, Soranzo N, Stockl D, Tworoger S, Uitterlinden AG, van Gils CH, Vasan RS, Wichmann H-E, Zhai G, Bhasin S, Bidlingmaier M, Chanock SJ, De Vivo I, Harris TB, Hunter DJ, Kahonen M, Liu S, Ouyang P, Spector TD, van der Schouw YT, Viikari J, Wallaschofski H, McCarthy MI, Frayling TM, Murray A, Franks S, Jarvelin M-R, de Jong FH, Raitakari O, Teumer A, Ohlsson C, Murabito JM, Perry JRB. 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). https://doi.org/10.1371/journal.pgen.1002805

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Coviello, Andrea D. ; Haring, Robin ; Wellons, Melissa ; Vaidya, Dhananjay ; Lehtimaki, Terho ; Keildson, Sarah ; Lunetta, Kathryn L. ; He, Chunyan ; Fornage, Myriam ; Lagou, Vasiliki ; Mangino, Massimo ; Onland-Moret, N. Charlotte ; Chen, Brian ; Eriksson, Joel ; Garcia, Melissa ; Mei, Yong ; Koster, Annemarie ; Lohman, Kurt ; Lyytikainen, Leo-Pekka ; Petersen, Ann-Kristin ; Prescott, Jennifer ; Stolk, Lisette ; Vandenput, Liesbeth ; Wood, Andrew R. ; Zhuang, Wei Vivian ; Ruokonen, Aimo ; Hartikainen, Anna-Liisa ; Pouta, Anneli ; Bandinelli, Stefania ; Biffar, Reiner ; Brabant, Georg ; Cox, David G. ; Chen, Yuhui ; Cummings, Steven ; Ferrucci, Luigi ; Gunter, Marc J. ; Hankinson, Susan E. ; Martikainen, Hannu ; Hofman, Albert ; Homuth, Georg ; Illig, Thomas ; Jansson, John-Olov ; Johnson, Andrew D. ; Karasik, David ; Karlsson, Magnus ; Kettunen, Johannes ; Kiel, Douglas P. ; Kraft, Peter ; Liu, Jingmin ; Ljunggren, Osten ; Lorentzon, Mattias ; Maggio, Marcello ; Markus, Marcello R. P. ; Mellstrom, Dan ; Miljkovic, Iva ; Mirel, Daniel ; Nelson, Sarah ; Papunen, Laure Morin ; Peeters, Petra H. M. ; Prokopenko, Inga ; Raffel, Leslie ; Reincke, Martin ; Reiner, Alex P. ; Rexrode, Kathryn ; Rivadeneira, Fernando ; Schwartz, Stephen M. ; Siscovick, David ; Soranzo, Nicole ; Stockl, Doris ; Tworoger, Shelley ; Uitterlinden, Andre G. ; van Gils, Carla H. ; Vasan, Ramachandran S. ; Wichmann, H. -Erich ; Zhai, Guangju ; Bhasin, Shalender ; Bidlingmaier, Martin ; Chanock, Stephen J. ; De Vivo, Immaculata ; Harris, Tamara B. ; Hunter, David J. ; Kahonen, Mika ; Liu, Simin ; Ouyang, Pamela ; Spector, Tim D. ; van der Schouw, Yvonne T. ; Viikari, Jorma ; Wallaschofski, Henri ; McCarthy, Mark I. ; Frayling, Timothy M. ; Murray, Anna ; Franks, Steve ; Jarvelin, Marjo-Riitta ; de Jong, Frank H. ; Raitakari, Olli ; Teumer, Alexander ; Ohlsson, Claes ; Murabito, Joanne M. ; Perry, John R. B. / A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation. In: PLoS Genetics. 2012 ; Vol. 8, No. 7.

RIS

TY - JOUR

T1 - A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

AU - Coviello, Andrea D.

AU - Haring, Robin

AU - Wellons, Melissa

AU - Vaidya, Dhananjay

AU - Lehtimaki, Terho

AU - Keildson, Sarah

AU - Lunetta, Kathryn L.

AU - He, Chunyan

AU - Fornage, Myriam

AU - Lagou, Vasiliki

AU - Mangino, Massimo

AU - Onland-Moret, N. Charlotte

AU - Chen, Brian

AU - Eriksson, Joel

AU - Garcia, Melissa

AU - Mei, Yong

AU - Koster, Annemarie

AU - Lohman, Kurt

AU - Lyytikainen, Leo-Pekka

AU - Petersen, Ann-Kristin

AU - Prescott, Jennifer

AU - Stolk, Lisette

AU - Vandenput, Liesbeth

AU - Wood, Andrew R.

AU - Zhuang, Wei Vivian

AU - Ruokonen, Aimo

AU - Hartikainen, Anna-Liisa

AU - Pouta, Anneli

AU - Bandinelli, Stefania

AU - Biffar, Reiner

AU - Brabant, Georg

AU - Cox, David G.

AU - Chen, Yuhui

AU - Cummings, Steven

AU - Ferrucci, Luigi

AU - Gunter, Marc J.

AU - Hankinson, Susan E.

AU - Martikainen, Hannu

AU - Hofman, Albert

AU - Homuth, Georg

AU - Illig, Thomas

AU - Jansson, John-Olov

AU - Johnson, Andrew D.

AU - Karasik, David

AU - Karlsson, Magnus

AU - Kettunen, Johannes

AU - Kiel, Douglas P.

AU - Kraft, Peter

AU - Liu, Jingmin

AU - Ljunggren, Osten

AU - Lorentzon, Mattias

AU - Maggio, Marcello

AU - Markus, Marcello R. P.

AU - Mellstrom, Dan

AU - Miljkovic, Iva

AU - Mirel, Daniel

AU - Nelson, Sarah

AU - Papunen, Laure Morin

AU - Peeters, Petra H. M.

AU - Prokopenko, Inga

AU - Raffel, Leslie

AU - Reincke, Martin

AU - Reiner, Alex P.

AU - Rexrode, Kathryn

AU - Rivadeneira, Fernando

AU - Schwartz, Stephen M.

AU - Siscovick, David

AU - Soranzo, Nicole

AU - Stockl, Doris

AU - Tworoger, Shelley

AU - Uitterlinden, Andre G.

AU - van Gils, Carla H.

AU - Vasan, Ramachandran S.

AU - Wichmann, H. -Erich

AU - Zhai, Guangju

AU - Bhasin, Shalender

AU - Bidlingmaier, Martin

AU - Chanock, Stephen J.

AU - De Vivo, Immaculata

AU - Harris, Tamara B.

AU - Hunter, David J.

AU - Kahonen, Mika

AU - Liu, Simin

AU - Ouyang, Pamela

AU - Spector, Tim D.

AU - van der Schouw, Yvonne T.

AU - Viikari, Jorma

AU - Wallaschofski, Henri

AU - McCarthy, Mark I.

AU - Frayling, Timothy M.

AU - Murray, Anna

AU - Franks, Steve

AU - Jarvelin, Marjo-Riitta

AU - de Jong, Frank H.

AU - Raitakari, Olli

AU - Teumer, Alexander

AU - Ohlsson, Claes

AU - Murabito, Joanne M.

AU - Perry, John R. B.

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1002805

DO - 10.1371/journal.pgen.1002805

M3 - Article

VL - 8

JO - PLoS Genetics

T2 - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7404

IS - 7

ER -