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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Coviello, Andrea D (author)

A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.

Article/chapterEnglish2012

Publisher, publication year, extent ...

2012-07-19
Public Library of Science (PLoS),2012

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LIBRIS-ID:oai:gup.ub.gu.se/161244
https://gup.ub.gu.se/publication/161244URI
https://doi.org/10.1371/journal.pgen.1002805DOI
https://lup.lub.lu.se/record/3073219URI
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-181141URI

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Language:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Ortopedi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Orthopaedics hsv//eng

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Haring, Robin (author)
Wellons, Melissa (author)
Vaidya, Dhananjay (author)
Lehtimäki, Terho (author)
Keildson, Sarah (author)
Lunetta, Kathryn L (author)
He, Chunyan (author)
Fornage, Myriam (author)
Lagou, Vasiliki (author)
Mangino, Massimo (author)
Onland-Moret, N Charlotte (author)
Chen, Brian (author)
Eriksson, JoelGothenburg University,Göteborgs universitet,Institutionen för medicin,Centre for Bone and Arthritis Research,Institute of Medicine(Swepub:gu)xerjoe (author)
Garcia, Melissa (author)
Liu, Yong Mei (author)
Koster, Annemarie (author)
Lohman, Kurt (author)
Lyytikäinen, Leo-Pekka (author)
Petersen, Ann-Kristin (author)
Prescott, Jennifer (author)
Stolk, Lisette (author)
Vandenput, Liesbeth,1974Gothenburg University,Göteborgs universitet,Institutionen för medicin,Centre for Bone and Arthritis Research,Institute of Medicine(Swepub:gu)xvanli (author)
Wood, Andrew R (author)
Zhuang, Wei Vivian (author)
Ruokonen, Aimo (author)
Hartikainen, Anna-Liisa (author)
Pouta, Anneli (author)
Bandinelli, Stefania (author)
Biffar, Reiner (author)
Brabant, Georg (author)
Cox, David G (author)
Chen, Yuhui (author)
Cummings, Steven (author)
Ferrucci, Luigi (author)
Gunter, Marc J (author)
Hankinson, Susan E (author)
Martikainen, Hannu (author)
Hofman, Albert (author)
Homuth, Georg (author)
Illig, Thomas (author)
Jansson, John-Olov,1954Gothenburg University,Göteborgs universitet,Institutionen för medicin,Centre for Bone and Arthritis Research,Institute of Medicine(Swepub:gu)xjanjo (author)
Johnson, Andrew D (author)
Karasik, David (author)
Karlsson, MagnusLund University,Lunds universitet,Ortopedi - klinisk och molekylär osteoporosforskning,Forskargrupper vid Lunds universitet,Orthopedics - Clinical and Molecular Osteoporosis Research,Lund University Research Groups(Swepub:lu)orto-mka (author)
Kettunen, Johannes (author)
Kiel, Douglas P (author)
Kraft, Peter (author)
Liu, Jingmin (author)
Ljunggren, ÖstenUppsala universitet,Metabola bensjukdomar(Swepub:uu)osteljun (author)
Lorentzon, Mattias,1970Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin,Institute of Medicine(Swepub:gu)xlomat (author)
Maggio, Marcello (author)
Markus, Marcello R P (author)
Mellström, Dan,1945Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin,Institute of Medicine(Swepub:gu)xmelda (author)
Miljkovic, Iva (author)
Mirel, Daniel (author)
Nelson, Sarah (author)
Morin Papunen, Laure (author)
Peeters, Petra H M (author)
Prokopenko, Inga (author)
Raffel, Leslie (author)
Reincke, Martin (author)
Reiner, Alex P (author)
Rexrode, Kathryn (author)
Rivadeneira, Fernando (author)
Schwartz, Stephen M (author)
Siscovick, David (author)
Soranzo, Nicole (author)
Stöckl, Doris (author)
Tworoger, Shelley (author)
Uitterlinden, André G (author)
van Gils, Carla H (author)
Vasan, Ramachandran S (author)
Wichmann, H-Erich (author)
Zhai, Guangju (author)
Bhasin, Shalender (author)
Bidlingmaier, Martin (author)
Chanock, Stephen J (author)
De Vivo, Immaculata (author)
Harris, Tamara B (author)
Hunter, David J (author)
Kähönen, Mika (author)
Liu, Simin (author)
Ouyang, Pamela (author)
Spector, Tim D (author)
van der Schouw, Yvonne T (author)
Viikari, Jorma (author)
Wallaschofski, Henri (author)
McCarthy, Mark I (author)
Frayling, Timothy M (author)
Murray, Anna (author)
Franks, Steve (author)
Järvelin, Marjo-Riitta (author)
de Jong, Frank H (author)
Raitakari, Olli (author)
Teumer, Alexander (author)
Ohlsson, Claes,1965Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin,Institute of Medicine(Swepub:gu)xohlcl (author)
Murabito, Joanne M (author)
Perry, John R B (author)
Göteborgs universitetInstitutionen för medicin (creator_code:org_t)

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By the author/editor: Coviello, Andrea ...; Haring, Robin; Wellons, Melissa; Vaidya, Dhananja ...; Lehtimäki, Terho; Keildson, Sarah; show more...; Lunetta, Kathryn ...; He, Chunyan; Fornage, Myriam; Lagou, Vasiliki; Mangino, Massimo; Onland-Moret, N ...; Chen, Brian; Eriksson, Joel; Garcia, Melissa; Liu, Yong Mei; Koster, Annemari ...; Lohman, Kurt; Lyytikäinen, Leo ...; Petersen, Ann-Kr ...; Prescott, Jennif ...; Stolk, Lisette; Vandenput, Liesb ...; Wood, Andrew R; Zhuang, Wei Vivi ...; Ruokonen, Aimo; Hartikainen, Ann ...; Pouta, Anneli; Bandinelli, Stef ...; Biffar, Reiner; Brabant, Georg; Cox, David G; Chen, Yuhui; Cummings, Steven; Ferrucci, Luigi; Gunter, Marc J; Hankinson, Susan ...; Martikainen, Han ...; Hofman, Albert; Homuth, Georg; Illig, Thomas; Jansson, John-Ol ...; Johnson, Andrew ...; Karasik, David; Karlsson, Magnus; Kettunen, Johann ...; Kiel, Douglas P; Kraft, Peter; Liu, Jingmin; Ljunggren, Östen; Lorentzon, Matti ...; Maggio, Marcello; Markus, Marcello ...; Mellström, Dan, ...; Miljkovic, Iva; Mirel, Daniel; Nelson, Sarah; Morin Papunen, L ...; Peeters, Petra H ...; Prokopenko, Inga; Raffel, Leslie; Reincke, Martin; Reiner, Alex P; Rexrode, Kathryn; Rivadeneira, Fer ...; Schwartz, Stephe ...; Siscovick, David; Soranzo, Nicole; Stöckl, Doris; Tworoger, Shelle ...; Uitterlinden, An ...; van Gils, Carla ...; Vasan, Ramachand ...; Wichmann, H-Eric ...; Zhai, Guangju; Bhasin, Shalende ...; Bidlingmaier, Ma ...; Chanock, Stephen ...; De Vivo, Immacul ...; Harris, Tamara B; Hunter, David J; Kähönen, Mika; Liu, Simin; Ouyang, Pamela; Spector, Tim D; van der Schouw, ...; Viikari, Jorma; Wallaschofski, H ...; McCarthy, Mark I; Frayling, Timoth ...; Murray, Anna; Franks, Steve; Järvelin, Marjo- ...; de Jong, Frank H; Raitakari, Olli; Teumer, Alexande ...; Ohlsson, Claes, ...; Murabito, Joanne ...; Perry, John R B; show less...

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