Genetic determinants of serum testosterone concentrations in men

Ohlsson, C and Wallaschofski, H and Lunetta, KL and Stolk, L and Perry, JRB and Koster, A and Petersen, AK and Eriksson, J and Lehtimäki, T and Huhtaniemi, IT and Hammond, GL and Maggio, M and Coviello, AD and Emas Study Group, and Ferrucci, L and Heier, M and Hofman, A and Holliday, KL and Jansson, JO and Kähönen, M and Karasik, D and Karlsson, MK and Kiel, DP and Liu, Y and Ljunggren, O and Lorentzon, M and Lyytikäinen, LP and Meitinger, T and Mellström, D and Melzer, D and Miljkovic, I and Nauck, M and Nilsson, M and Penninx, B and Pye, SR and Vasan, RS and Reincke, M and Rivadeneira, F and Tajar, A and Teumer, A and Uitterlinden, AG and Ulloor, J and Viikari, J and Völker, U and Völzke, H and Wichmann, HE and Wu, TS and Zhuang, WV and Ziv, E and Wu, FCW and Raitakari, O and Eriksson, A and Bidlingmaier, M and Harris, TB and Murray, A and de Jong, FH and Murabito, JM and Bhasin, S and Vandenput, L and Haring, R (2011) Genetic determinants of serum testosterone concentrations in men. PLoS Genetics, 7 (10). ISSN 1553-7390

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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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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Ohlsson, C Wallaschofski, H Lunetta, KL Stolk, L Perry, JRB Koster, A Petersen, AK Eriksson, J Lehtimäki, T Huhtaniemi, IT Hammond, GL Maggio, M Coviello, AD Emas Study Group, Ferrucci, L Heier, M Hofman, A Holliday, KL Jansson, JO Kähönen, M Karasik, D Karlsson, MK Kiel, DP Liu, Y Ljunggren, O Lorentzon, M Lyytikäinen, LP Meitinger, T Mellström, D Melzer, D Miljkovic, I MiljkovicI@edc.pitt.edu IVM1 Nauck, M Nilsson, M Penninx, B Pye, SR Vasan, RS Reincke, M Rivadeneira, F Tajar, A Teumer, A Uitterlinden, AG Ulloor, J Viikari, J Völker, U Völzke, H Wichmann, HE Wu, TS Zhuang, WV Ziv, E Wu, FCW Raitakari, O Eriksson, A Bidlingmaier, M Harris, TB Murray, A de Jong, FH Murabito, JM Bhasin, S Vandenput, L Haring, R
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Abecasis, Goncalo R UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	1 October 2011
Date Type:	Publication
Journal or Publication Title:	PLoS Genetics
Volume:	7
Number:	10
DOI or Unique Handle:	10.1371/journal.pgen.1002313
Schools and Programs:	School of Public Health > Epidemiology
Refereed:	Yes
ISSN:	1553-7390
MeSH Headings:	Adult; Aged, 80 and over; Alleles; Body Mass Index; Chromosomes, Human, X--genetics; Genome-Wide Association Study; Humans; Male; Middle Aged; Nuclear Proteins--genetics; Polymorphism, Single Nucleotide; Sex Hormone-Binding Globulin--genetics; Testosterone--blood
Other ID:	NLM PMC3188559
PubMed Central ID:	PMC3188559
PubMed ID:	21998597
Date Deposited:	10 Sep 2012 14:30
Last Modified:	22 Jun 2021 16:55
URI:	http://d-scholarship.pitt.edu/id/eprint/13979

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