A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation
Open accessAbstract
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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rs12150660, located 11.5 kb upstream of the major transcription start site of SHBG, represented the SNP with the strongest genotype-dependent difference in T.
“Rs12150660, located 11.5 kb upstream of the major transcription start site of SHBG, represented the SNP with the strongest genotype-dependent difference in T.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [67]
The Results identify rs12150660 at the SHBG locus as the SNP with the strongest association with circulating SHBG concentrations. They do not establish that it had the strongest genotype-dependent difference in T (testosterone), or place it 11.5 kb upstream of SHBG’s major transcription start site. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAnalysis of genome-wide association data of more than 8000 men identified that two SNPs within the SHBG locus are independently associated with serum T concentrations.
“Analysis of genome-wide association data of more than 8000 men identified that two SNPs within the SHBG locus are independently associated with serum T concentrations.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [67]
The Methods report a GWAS including 12,401 men, and the Results identify multiple statistically independent SNP signals at the SHBG locus. But the measured association was with circulating SHBG, not serum testosterone; the Results do not identify two SNPs independently associated with testosterone concentrations. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFor rs6258, a rare missense polymorphism in exon 4 of SHBG, lower concentrations of T were observed for the CT vs CC genotype.
“For the second SNP, rs6258, a rare missense polymorphism located in exon 4 of SHBG, lower concentrations of T were observed for the CT vs CC genotype.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [67]
The Discussion identifies rs6258 as a missense variant, and Results Table 2 shows that its T allele is uncommon and associated with lower SHBG concentrations. The paper does not report lower testosterone (T) concentrations for CT versus CC carriers or specify that rs6258 is in exon 4; the reported outcome is SHBG, not testosterone. (LLM, conf=0.88)
Experimental — accuracy not yet measuredrs12150660 and rs6258 are located within the SHBG locus and both show a relevant association with SHBG concentration.
“Additionally, as rs12150660 and rs6258 are located within the SHBG locus, a relevant association with SHBG concentration was demonstrated for both SNPs [65–67].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [67]
For rs12150660, mean serum T concentrations are highest in men with the TT genotype, lowest for the GG genotype, and intermediate for the GT genotype.
“Mean serum T concentrations are found to be highest in men with the TT genotype, lowest for the GG genotype and situated in between for the GT genotype of this SNP.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [67]
The Results (Table 1; page not available in our copy) identify rs12150660 and report its association with serum SHBG concentrations, not testosterone. Searches for serum testosterone by rs12150660 genotype found no passage comparing mean testosterone concentrations in men with TT, GT, and GG genotypes. (LLM, conf=0.77)
Experimental — accuracy not yet measured
Numerous estimating equations have been described, including bioavailable testosterone, free androgen index, and free testosterone index (Vermeulen method), with results suggesting high correlations with direct assays.
“Numerous estimating equations have been described in the literature including bioavailable T (non-SHBG bound T), free androgen index (FAI; 100T/SHBG), and free T index (Vermeulen method), among others, with results suggesting high correlations to direct assays.”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [104]
In the largest study evaluating predictive accuracy of free testosterone calculations, Sartorius and colleagues concluded that empirical methods (Ly, Sartorius) are most concordant, while other estimations (Vermeulen, Nanjee and Wheeler, Sodergard) overestimate the true value.
“In the largest study evaluating predictive accuracy of fT calculations, Sartorius and colleagues concluded that empirical methods (Ly, Sartorius) of calculated fT are most concordant, with other estimations (Vermeulen, Nanjee and Wheeler, Sodergard) resulting in overestimation of the true value.”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [104]
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Wang, L., Muromoto, N., Hayashi, H., et al. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7677 · Cited by 6 · see citing works
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- [62]Turgeon D Carrier JS Levesque E Hum DW Belanger A 2001 Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members. Endocrinology 142 778 787 11159850
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Ruth, K. S., Campbell, P. J., Chew, S., Lim, E. M., Hadlow, N., Stuckey, B. G., Brown, S. J., Feenstra, B., Joseph, J., Surdulescu, G. L., et al. (2016) · European Journal of Human Genetics · doi:10.1038/ejhg.2015.102 · Cited by 121 · see citing works
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Sofer, Y., Nevo, N., Vechoropoulos, M., Shefer, G., Osher, E., Landis, N., Tordjman, K., Hammond, G. L., & Stern, N. (2018) · Endocrine Connections · doi:10.1530/ec-17-0240 · Cited by 6 · see citing works
- Authors
- Coviello, A. D., Haring, R., Wellons, M., Vaidya, D., Lehtimäki, T., Keildson, S., Lunetta, K. L., He, C., Fornage, M., Lagou, V., Mangino, M., Onland-Moret, N. C., Chen, B., Eriksson, J., Garcia, M., Liu, Y. M., Koster, A., Lohman, K., Lyytikäinen, L.-P., Petersen, A.-K., Prescott, J., Stolk, L., Vandenput, L., Wood, A. R., Zhuang, W. V., Ruokonen, A., Hartikainen, A.-L., Pouta, A., Bandinelli, S., Biffar, R., Brabant, G., Cox, D. G., Chen, Y., Cummings, S., Ferrucci, L., Gunter, M. J., Hankinson, S. E., Martikainen, H., Hofman, A., Homuth, G., Illig, T., Jansson, J.-O., Johnson, A. D., Karasik, D., Karlsson, M., Kettunen, J., Kiel, D. P., Kraft, P., Liu, J., Ljunggren, Ö., Lorentzon, M., Maggio, M., Markus, M. R. P., Mellström, D., Miljkovic, I., Mirel, D., Nelson, S., Morin Papunen, L., Peeters, P. H. M., Prokopenko, I., Raffel, L., Reincke, M., Reiner, A. P., Rexrode, K., Rivadeneira, F., Schwartz, S. M., Siscovick, D., Soranzo, N., Stöckl, D., Tworoger, S., Uitterlinden, A. G., van Gils, C. H., Vasan, R. S., Wichmann, H.-E., Zhai, G., Bhasin, S., Bidlingmaier, M., Chanock, S. J., De Vivo, I., Harris, T. B., Hunter, D. J., Kähönen, M., Liu, S., Ouyang, P., Spector, T. D., van der Schouw, Y. T., Viikari, J., Wallaschofski, H., McCarthy, M. I., Frayling, T. M., Murray, A., Franks, S., Järvelin, M.-R., de Jong, F. H., Raitakari, O., Teumer, A., Ohlsson, C., Murabito, J. M., & Perry, J. R. B.
- Affiliations
- Boston University (US)
- Universität Greifswald (DE)
- University of Alabama at Birmingham (US)
- Johns Hopkins University (US)
- Tampere University Hospital (FI)
- Centre for Human Genetics (GB)
- Indiana University Indianapolis (US)
- The University of Texas Health Science Center at Houston (US)
- King's College London (GB)
- University of California, Los Angeles (US)
- University of Gothenburg (SE)
- Wake Forest University Health Sciences (US)
- National Institutes of Health (US)
- Helmholtz Munich (DE)
- Brigham and Women's Hospital (US)
- Erasmus MC (NL)
- University of Exeter (GB)
- University of Oulu (FI)
- Oulu University Hospital (FI)
- Azienda Sanitaria di Firenze (IT)
- University of Lübeck (DE)
- Inserm (FR)
- California Pacific Medical Center (US)
- National Institute on Aging (US)
- Imperial College London (GB)
- Framingham Heart Study (US)
- Harvard University (US)
- Lund University (SE)
- University of Helsinki (FI)
- Fred Hutch Cancer Center (US)
- Uppsala University (SE)
- University of Parma (IT)
- Universitätsmedizin Greifswald (DE)
- University of Pittsburgh (US)
- Broad Institute (US)
- University of Washington (US)
- University Medical Center Utrecht (NL)
- Cedars-Sinai Medical Center (US)
- Memorial University of Newfoundland (CA)
- Ludwig-Maximilians-Universität München (DE)
- University of Turku (FI)
- Corresponding author
- Murabito, Joanne M.
- Perry, John R. B.
- ORCID
- Coviello, Andrea D.
- Haring, Robin
- Vaidya, Dhananjay
- Lehtimäki, Terho
- Lunetta, Kathryn L.
- He, Chunyan
- Fornage, Myriam
- Lagou, Vasiliki
- Mangino, Massimo
- Chen, Brian
- Koster, Annemarie
- Lyytikäinen, Leo-Pekka
- Prescott, Jennifer
- Vandenput, Liesbeth
- Wood, Andrew R.
- Zhuang, Wei Vivian
- Bandinelli, Stefania
- Biffar, Reiner
- Brabant, Georg
- Cox, David G.
- Cummings, Steven
- Ferrucci, Luigi
- Gunter, Marc J.
- Hankinson, Susan E.
- Martikainen, Hannu
- Homuth, Georg
- Illig, Thomas
- Jansson, John-Olov
- Johnson, Andrew D.
- Karasik, David
- Karlsson, Magnus
- Kettunen, Johannes
- Kiel, Douglas P.
- Kraft, Peter
- Lorentzon, Mattias
- Maggio, Marcello
- Markus, Marcello R. P.
- Mellström, Dan
- Miljkovic, Iva
- Nelson, Sarah
- Peeters, Petra H. M.
- Prokopenko, Inga
- Reiner, Alex P.
- Rexrode, Kathryn
- Rivadeneira, Fernando
- Schwartz, Stephen M.
- Siscovick, David
- Soranzo, Nicole
- Tworoger, Shelley
- Uitterlinden, André G.
- Vasan, Ramachandran S.
- Wichmann, H.-Erich
- Zhai, Guangju
- Bhasin, Shalender
- Bidlingmaier, Martin
- Chanock, Stephen J.
- Harris, Tamara B.
- Kähönen, Mika
- Liu, Simin
- Ouyang, Pamela
- Spector, Tim D.
- Viikari, Jorma
- McCarthy, Mark I.
- Frayling, Timothy M.
- Murray, Anna
- Järvelin, Marjo-Riitta
- Raitakari, Olli
- Teumer, Alexander
- Ohlsson, Claes
- Murabito, Joanne M.
- Perry, John R. B.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-07-19
- Volume
- 8
- Issue
- 7
- Pages
- e1002805
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3400553
- OpenAlex
- W2134471459
- Cited by
- 250
- References
- 76
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 13 · 2023: 11 · 2022: 17 · 2021: 16 · 2020: 18 · 2019: 19 · 2018: 17 · 2017: 20 · 2016: 18 · 2015: 30 · 2014: 33 · 2013: 18 · 2012: 1
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Tampere University Institutional Repository (Tampere University) (publishedVersion)
- Memorial University Research Repository (Memorial University) (acceptedVersion)
- D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, public-domain)
- Tampere University Institutional Repository (Tampere University) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, public-domain)
- Figshare (submittedVersion, cc-by)
- Figshare (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Memorial University Research Repository (Memorial University) (submittedVersion)
- Site cant be reached (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- WOS
- Funders
- National Science Foundation (0239427, N01-HC-25195, FP7/2007-2013)
- Pfizer
- Wake Forest University
- School of Medicine, Boston University (N01-HC25195)
- Helsingin Yliopisto
- Wellcome Trust (FP7/2007–2013, GR069224, G0600705, 090532)
- Broad Institute
- National Institute for Health and Care Research (FP7/2007–2013)
- King's College London
- European Commission (QLG2-CT-2002-01254, 2007–2013, G0500539, 01ZZ0103, FP7 2007-2013, 201413, 201865, FP7/2007, 01ZZ0403, 01254, 03ZIK012, QLG1‐CT‐2000‐01643, 5R01MH63706:02, 01ZZ9603)
- Stiftelsen för Strategisk Forskning
- ZonMw (050-060-810)
- Kela
- Academy of Finland (124,282, 134309, 121584, QLG1-CT-2000-01643, 129378, 126925, 121584, 124282, 129378, 5R01MH63706:02, 129269, 1114194, 126,925, 41071, 117787, 120315, project grants 104781, 120315, 129269, 1114194, 104781)
- Bundesministerium für Bildung und Forschung (01ZZ9603, 01ZZ0103, and 01ZZ0403, 03IS2061A, 03ZIK012, 01ZZ0403, and 01ZZ0403, 01ZZ0103, 01ZZ9603)
- Erasmus Medisch Centrum (014-93-015)
- Suomen Kulttuurirahasto
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (050.060.810, FP7 2007-2013, 911-03-012, 175.010.2005.011)
- Juho Vainion Säätiö
- Novo Nordisk
- Vetenskapsrådet (FP7/2007-2013, 2006‐3832)
- Emil Aaltosen Säätiö
- Siemens
- Göteborgs Universitet
- Oulun Yliopisto (75617, 129269, NFBC1966, FP7/2007-2013)
- Tampereen Tuberkuloosisäätiö
- Paavo Nurmen Säätiö
- Turun Yliopistollinen Keskussairaala (9N035, 9M048)
- Universität Greifswald
- Ministry of Cultural Affairs
- National Institutes of Health (n01hc95095-66-0-1, N01-AG-6-2103, n01hc95164-17-0-1, 5r01ag032098-05, R01 AR/AG 41398, n01ag062101-007, n01hc48050-59-0-1, n01hc48048-58-0-1, 35627, n01hc045134-008, n01ag062103-006, n01hc95165-34-0-1, n01hc48047-55-0-1, 5r01ca049449-18, N01‐AG‐6‐2106, n01hc95161-24-0-1, n01hc095169-003, FP7/2007-2013, n01hc45205-9-0-0, n01ag062106-007, n01hc005187-000, UL1TR000124, n01hc95166-21-0-1, n01hc48049-61-0-1, n01wh22110-38-0-0, n01hc95162-31-0-1, n01hc95168-27-0-1, n01hc95160-18-0-1, n01hc45204-11-0-1, 6r01hl087679-03, n01hc095167-000, N01-AG-6-2101, 5rl1mh083268-05, n01hc95163-22-0-1, 6u54rr020278-06, n01hc025195-11-0-0, n01hc95159-40-0-1, 5r01hl084099-04, N01 WH022110, N01-HC 25195)
- Directorate for Biological Sciences
- U.S. Public Health Service (NFBC1966, 44221, 32122, 24152, 42107-26, 42129-32, 32118-32119, 32100-2, 32105-6, 41071, 32108-9, 32111-13, 32115)
- Medical Research Council (G0500539, G0600705, G0500539, G0600705, PrevMetSyn/SALVE)
- Biotechnology and Biological Sciences Research Council (G20234)
- Biocenter, University of Oulu
- National Institute on Aging (N01‐AG‐6–2101, R01AG031206, R01AG032098, R01AG31206, N.1-AG-1-1, N02-HL-6-4278, 1-AG-1-2111, N01-HC-25195, N01 AG062106, R21AG032598, N01AG62106, 1R01AG032098‐01A1, N01-AG-62103, N01 AG062103, N01 AG-5-0002, N01 AG062101)
- National Heart, Lung, and Blood Institute (N01HC48050, N01 HC-95159, N01-HC-95160, N01-HC095169, HL-087679, N01-HC045134, N01 HC-95168, N01-HC-095165, 5R01 HL087679-02, N01 HC 95095, N01 HC95167, (N01-HC-95163, N01 HC095163, N01‐HC25195, R01-HL-084099, N01 HC045205, N01 HC-95161, N01 HC95165, N01HC95164, N01 HC048048, N01-HC05187, N01-HC-048049, N01 HC045204, 5R01HL087679, N01-HC-095159, N01 HC095168, N02- HL-64278, N01AG62101, N01-HC-095162, N01-HC- 45204, N01 HC095095, 5-K23-HL087114, N01-HC-095161, R01HL074338, N01 HC048050, R01 HL087679, N01-HC48048, N01-HC-025195, N01-HC-45205, R01HL094755, N01AG62106, N01 HC005187, N01 HC095167, N01-HC-48-049, R01HL105756, N01-HC-095160, R01HL074406, K23HL087114, N01 HC095166, N01AG62103, N01 HC095164, 1RL1MH083268-01, N01 HC048047, N01‐HC‐95166, N01-HC-480-47, HL074338, HL074406, N01 HC-95162, R01HL065611, N01 HC95169)
- National Institute of Mental Health (HEALTH-F4-2007-201413, R01MH063706, RL1-MH083268, 1RL1MH083268-01, 5R01 MH63706:02, 5R01MH63706, MH083268)
- National Human Genome Research Institute (N01-HC-25195, N02-HL-6-4278, U01HG004446, U01HG004729, U01HG004424, U01HG005152, HHSN268200782096C)
- National Eye Institute
- National Cancer Institute (R01CA040356, CA-49449, CA-87969, CA-40356, P01CA087969, R01‐CA049449, CA128034, U01 CA 98233, U01CA098233, U01CA049449, R03CA128034)
- National Institute of General Medical Sciences (R01GM053275, GM053275-14)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK092938, P30DK063491)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-41398, R01AR041398)
- National Center for Research Resources (U54-RR020278, UL1RR024156, RR024156)
- National Center for Advancing Translational Sciences
- National Institute on Minority Health and Health Disparities (263MD9164, 263MD 821336, R01MD009164)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- sex hormone-binding globulin, genetic loci, single nucleotide polymorphisms, type 2 diabetes, breast cancer, prostate cancer, testosterone, estradiol, PRMT6, GCKR, LHCGR, JMJD1C, ZBTB10, SLCO1B1
- MeSH terms
- Alleles, Female, Humans, Male, Sex Characteristics, Sex Hormone-Binding Globulin, Gonadal Steroid Hormones, Genetic Heterogeneity, Polymorphism, Single Nucleotide, Metabolic Networks and Pathways, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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