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Genetic Determinants of Serum Testosterone Concentrations in Men

Ohlsson, Claes; Wallaschofski, Henri; Lunetta, Kathryn L.; Stolk, Lisette; Perry, John R. B.; Koster, Annemarie; Petersen, Ann-Kristin; Eriksson, Joel; Lehtimaki, Terho and Huhtaniemi, Ilpo T., et al. (2011) In PLoS Genetics 7(10).
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... (More)
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 = 1.2x10(-41) and rs6258, p = 2.3x10(-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 = 5.6610216). 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. (Less)
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PLoS Genetics
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issue
10
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Public Library of Science
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  • scopus:80155172604
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1553-7404
DOI
10.1371/journal.pgen.1002313
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English
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@article{f668e6fc-d262-44ef-95fb-419c01fbc8e8,
  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 = 1.2x10(-41) and rs6258, p = 2.3x10(-22)). Subjects with &gt;= 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 = 5.6610216). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p&lt;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.},
  author       = {Ohlsson, Claes and Wallaschofski, Henri and Lunetta, Kathryn L. and Stolk, Lisette and Perry, John R. B. and Koster, Annemarie and Petersen, Ann-Kristin and Eriksson, Joel and Lehtimaki, Terho and Huhtaniemi, Ilpo T. and Hammond, Geoffrey L. and Maggio, Marcello and Coviello, Andrea D. and Ferrucci, Luigi and Heier, Margit and Hofman, Albert and Holliday, Kate L. and Jansson, John-Olov and Kahonen, Mika and Karasik, David and Karlsson, Magnus and Kiel, Douglas P. and Liu, Yongmei and Ljunggren, Osten and Lorentzon, Mattias and Lyytikainen, Leo-Pekka and Meitinger, Thomas and Mellstrom, Dan and Melzer, David and Miljkovic, Iva and Nauck, Matthias and Nilsson, Maria and Penninx, Brenda and Pye, Stephen R. and Vasan, Ramachandran S. and Reincke, Martin and Rivadeneira, Fernando and Tajar, Abdelouahid and Teumer, Alexander and Uitterlinden, Andre G. and Ulloor, Jagadish and Viikari, Jorma and Voelker, Uwe and Voelzke, Henry and Wichmann, H. Erich and Wu, Tsung-Sheng and Zhuang, Wei Vivian and Ziv, Elad and Wu, Frederick C. W. and Raitakari, Olli and Eriksson, Anna and Bidlingmaier, Martin and Harris, Tamara B. and Murray, Anna and De Jong, Frank H. and Murabito, Joanne M. and Bhasin, Shalender and Vandenput, Liesbeth and Haring, Robin},
  issn         = {1553-7404},
  language     = {eng},
  number       = {10},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Genetic Determinants of Serum Testosterone Concentrations in Men},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1002313},
  volume       = {7},
  year         = {2011},
}