Cited by 224Hormonal and reproductive studiesGenetic Associations and EpidemiologySperm and Testicular Function

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Genetic Determinants of Serum Testosterone Concentrations in Men

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Abstract

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10(-41) and rs6258, p = 2.3×10(-22)). Subjects with ≥ 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10(-16)). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.

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Crossref · 10.1371/journal.pgen.1002313

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Figure 1 Regional association plots for single-nucleotide polymorphisms rs12150660, rs6258, and rs5934505. Regional association plot of the two independent signals on chromosome 17 with either (A) rs12150660 or (B) rs6258 indicated by red diamond to evaluate linkage with other single-nucleotide polymorphisms in the region. In addition, the association plot of the (C) rs5934505 signal on chromosome X is given. The r2 is based on the CEU HapMap II samples. The blue line and right hand Y axis represent CEU HapMap II based recombination rates. (A) and (B) show the top SNPs of the inverse-variance weighted discovery stage meta-analysis of untransformed serum testosterone and (C) show the top SNP of the SHBG-adjusted serum testosterone using an imputation quality filter (observed/expected variance ratio) >0.4 at the individual cohort level during meta-analysis.
Figure 1 Regional association plots for single-nucleotide polymorphisms rs12150660, rs6258, and rs5934505. Regional association plot of the two independent signals on chromosome 17 with either (A) rs12150660 or (B) rs6258 indicated by red diamond to evaluate linkage with other single-nucleotide polymorphisms in the region. In addition, the association plot of the (C) rs5934505 signal on chromosome X is given. The r2 is based on the CEU HapMap II samples. The blue line and right hand Y axis represent CEU HapMap II based recombination rates. (A) and (B) show the top SNPs of the inverse-variance weighted discovery stage meta-analysis of untransformed serum testosterone and (C) show the top SNP of the SHBG-adjusted serum testosterone using an imputation quality filter (observed/expected variance ratio) >0.4 at the individual cohort level during meta-analysis.CC0 · PubMed Central
Figure 2 The genetic influence on low serum testosterone concentrations. (A) Odds ratio (OR) for risk of low serum testosterone concentrations (serum testosterone <300 ng/dl), per copy of minor allele. Summary estimates of the OR and their 95% confidence intervals (CI) are given. The size of the data markers is proportional to the weight (inverse of the variance) of each study. Combined discovery (n = 8,030, low serum testosterone 13%; KORA was not included as testosterone was analyzed in plasma rather than in serum, combined replication (n = 5,504, low serum testosterone 13%), and combined discovery and replication (n = 13,534, low serum testosterone 13%). (B) Percentage of men with low serum testosterone concentrations (serum testosterone <300 ng/dl), according to the number of combined risk alleles for rs12150660 (G) and rs6258 (T) in the three replication cohorts (MrOS Sweden, EMAS, and YFS). Only two individuals in the three replication cohorts had four risk alleles and therefore individuals with three and four risk alleles were pooled into one group with ≥3 risk alleles.
Figure 2 The genetic influence on low serum testosterone concentrations. (A) Odds ratio (OR) for risk of low serum testosterone concentrations (serum testosterone <300 ng/dl), per copy of minor allele. Summary estimates of the OR and their 95% confidence intervals (CI) are given. The size of the data markers is proportional to the weight (inverse of the variance) of each study. Combined discovery (n = 8,030, low serum testosterone 13%; KORA was not included as testosterone was analyzed in plasma rather than in serum, combined replication (n = 5,504, low serum testosterone 13%), and combined discovery and replication (n = 13,534, low serum testosterone 13%). (B) Percentage of men with low serum testosterone concentrations (serum testosterone <300 ng/dl), according to the number of combined risk alleles for rs12150660 (G) and rs6258 (T) in the three replication cohorts (MrOS Sweden, EMAS, and YFS). Only two individuals in the three replication cohorts had four risk alleles and therefore individuals with three and four risk alleles were pooled into one group with ≥3 risk alleles.CC0 · PubMed Central
Figure 3 SHBG affinity for testosterone. (A and B) Scatchard plots of SHBG binding affinity for testosterone in serum samples according to rs6258 genotype. (A) Representative Scatchard plots of serum SHBG binding to [3H]testosterone. Serum from individuals homozygous for the wild-type SHBG allele (CC dashed line) or the rs6258 SNP (TT, solid line), or heterozygous for these alleles (CT, solid line). (B) Dissociation constant (Kd) of serum SHBG according to rs6258 genotype (CC, n = 4 subjects; CT, n = 4 subjects; TT [rare variant] n = 1 and the variation for the TT subject is derived from three separate analyses). (*) p = 0.001. Values are means ± SEM. (C) Representative Scatchard plots of recombinant SHBG binding to [3H]testosterone. Recombinant wild type ( = WT, C genotype; dashed line) or rs6258 (T genotype; solid line) SHBG expressed by CHO cells was diluted 1∶10 and subjected to Scatchard analysis, as in panel A. (D) Free testosterone fraction in serum measured by an equilibrium dialysis method according to rs6258 genotype (CC, n = 87 subjects; CT, n = 32 subjects). Values are means ± SEM.
Figure 3 SHBG affinity for testosterone. (A and B) Scatchard plots of SHBG binding affinity for testosterone in serum samples according to rs6258 genotype. (A) Representative Scatchard plots of serum SHBG binding to [3H]testosterone. Serum from individuals homozygous for the wild-type SHBG allele (CC dashed line) or the rs6258 SNP (TT, solid line), or heterozygous for these alleles (CT, solid line). (B) Dissociation constant (Kd) of serum SHBG according to rs6258 genotype (CC, n = 4 subjects; CT, n = 4 subjects; TT [rare variant] n = 1 and the variation for the TT subject is derived from three separate analyses). (*) p = 0.001. Values are means ± SEM. (C) Representative Scatchard plots of recombinant SHBG binding to [3H]testosterone. Recombinant wild type ( = WT, C genotype; dashed line) or rs6258 (T genotype; solid line) SHBG expressed by CHO cells was diluted 1∶10 and subjected to Scatchard analysis, as in panel A. (D) Free testosterone fraction in serum measured by an equilibrium dialysis method according to rs6258 genotype (CC, n = 87 subjects; CT, n = 32 subjects). Values are means ± SEM.CC0 · PubMed Central

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Authors
Ohlsson, C., Wallaschofski, H., Lunetta, K. L., Stolk, L., Perry, J. R. B., Koster, A., Petersen, A.-K., Eriksson, J., Lehtimäki, T., Huhtaniemi, I. T., Hammond, G. L., Maggio, M., Coviello, A. D., EMAS Study Group, Ferrucci, L., Heier, M., Hofman, A., Holliday, K. L., Jansson, J.-O., Kähönen, M., Karasik, D., Karlsson, M. K., Kiel, D. P., Liu, Y., Ljunggren, Ö., Lorentzon, M., Lyytikäinen, L.-P., Meitinger, T., Mellström, D., Melzer, D., Miljkovic, I., Nauck, M., Nilsson, M., Penninx, B., Pye, S. R., Vasan, R. S., Reincke, M., Rivadeneira, F., Tajar, A., Teumer, A., Uitterlinden, A. G., Ulloor, J., Viikari, J., Völker, U., Völzke, H., Wichmann, H. E., Wu, T.-S., Zhuang, W. V., Ziv, E., Wu, F. C. W., Raitakari, O., Eriksson, A., Bidlingmaier, M., Harris, T. B., Murray, A., de Jong, F. H., Murabito, J. M., Bhasin, S., Vandenput, L., & Haring, R.
Affiliations
  • University of Gothenburg (SE)
  • Universitätsmedizin Greifswald (DE)
  • Boston University (US)
  • Erasmus MC (NL)
  • Centre for Human Genetics (GB)
  • National Institutes of Health (US)
  • Helmholtz Munich (DE)
  • Tampere University Hospital (FI)
  • Imperial College London (GB)
  • University of British Columbia (CA)
  • University of Parma (IT)
  • Manchester Academic Health Science Centre (GB)
  • Harvard University (US)
  • Uppsala University (SE)
  • University of Exeter (GB)
  • University of Pittsburgh (US)
  • Amsterdam Public Health (NL)
  • University of Turku (FI)
  • University of California, San Francisco (US)
  • Ludwig-Maximilians-Universität München (DE)
Corresponding author
Ohlsson, Claes
Venue
PLoS Genetics
Published
2011-10-06
Volume
7
Issue
10
Pages
e1002313
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
OpenAlex
W2108434880
Cited by
224
References
36
Citations by year
2026: 5 · 2025: 14 · 2024: 11 · 2023: 7 · 2022: 17 · 2021: 14 · 2020: 12 · 2019: 18 · 2018: 19 · 2017: 19 · 2016: 12 · 2015: 16 · 2014: 24 · 2013: 16 · 2012: 18
FWCI
2.59
Type
journal article
Language
en
Open access
Locations
  • PLoS Genetics (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
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  • Tampere University Institutional Repository (Tampere University) (publishedVersion)
  • D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, public-domain)
  • Figshare (submittedVersion, cc-by)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
  • VU Research Portal (submittedVersion, other-oa)
  • Tampere University Institutional Repository (Tampere University) (submittedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
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  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, other-oa)
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  • Figshare (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion, other-oa)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • Site cant be reached (submittedVersion)
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  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Research Explorer (The University of Manchester) (submittedVersion)
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Funders
  • Wake Forest University
  • School of Medicine, Boston University (N01-HC25195)
  • Johns Hopkins University (HHSN268200782096C)
  • European Commission (01ZZ0103, 201865, 01ZZ0403, 03ZIK012, 01ZZ9603, 014-93-015)
  • Stiftelsen för Strategisk Forskning
  • ZonMw (050-060-810)
  • Erasmus Universiteit Rotterdam
  • Bundesministerium für Bildung und Forschung (01ZZ9603, 01ZZ0103, and 01ZZ0403, 03IS2061A, 01GS0823, NGFN-2, 03ZIK012, 01ZZ0403, and 01ZZ0403, 01ZZ0103, 01ZZ9603)
  • Erasmus Medisch Centrum (050-060-810, 014-93-015)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (050.060.810, 014-93-015, 911-03-012, 01ZZ9603, 01ZZ0403, 175.010.2005.011, 01ZZ0103)
  • Novo Nordisk
  • Vetenskapsrådet (2006‐3832)
  • Siemens
  • Göteborgs Universitet
  • Bayerische Akademie der Wissenschaften
  • Novo Nordisk Fonden
  • Universität Greifswald
  • Ministry of Cultural Affairs
  • National Institutes of Health (N01-AG-6-2103, 5r01ag032098-05, R01 AR/AG 41398, 35627, N01‐AG‐6‐2106, N01-AG-6-2101, n01hc025195-11-0-0, HHSN268200782096C, N01-HC 25195, 5P30AG031679, 5p30ag031679-15)
  • Canadian Institutes of Health Research (N01-HC-25195, MOP 15261)
  • Leibniz-Gemeinschaft
  • Münchner Zentrum für Gesundheitswissenschaften
  • Leibniz-Rechenzentrum
  • National Institute on Aging (N01‐AG‐6–2101, N.1‐AG‐1‐2111, N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106, R01AG031206, R01AG032098, N.1-AG-1-1, 5 P30 AG031679, R01AR/AG 41398, AR/AG 41398, N02-HL-6-4278, N01-HC-25195, AG-6-2106, AG-6-2103, and N01-AG, P30-AG031679, 1R01-AG-31206, AG-6-2101, R21AG032598, and N01-AG-6–2106, N01AG62106, 1R01AG032098, AG41398, 1R01AG032098‐01A1, N01-AG-62103, N01 AG-5-0002)
  • National Heart, Lung, and Blood Institute (HC25195, N01‐HC25195, N01-HC, N02- HL-64278, N01AG62101, N01-HC-025195, N01AG62106, HHSN268200782096C, N01AG62103)
  • National Human Genome Research Institute (HHSN268200782096C)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041398)
  • National Institute on Minority Health and Health Disparities (263MD9164, 263MD 821336, R01MD009164)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
Keywords
serum testosterone, androgen deficiency, sex hormone-binding globulin, X chromosome, free testosterone, genetic factors, heritability
MeSH terms
Adult, Aged, 80 and over, Alleles, Humans, Male, Middle Aged, Nuclear Proteins, Sex Hormone-Binding Globulin, Testosterone, Body Mass Index, Polymorphism, Single Nucleotide, Chromosomes, Human, X, Genome-Wide Association Study

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