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Genetic determinants of serum testosterone concentrations in men.

Journal article
Authors Claes Ohlsson
Henri Wallaschofski
Kathryn L Lunetta
Lisette Stolk
John R B Perry
Annemarie Koster
Ann-Kristin Petersen
Joel Eriksson
Terho Lehtimäki
Ilpo T Huhtaniemi
Geoffrey L Hammond
Marcello Maggio
Andrea D Coviello
Luigi Ferrucci
Margit Heier
Albert Hofman
Kate L Holliday
John-Olov Jansson
Mika Kähönen
David Karasik
Magnus K Karlsson
Douglas P Kiel
Yongmei Liu
Osten Ljunggren
Mattias Lorentzon
Leo-Pekka Lyytikäinen
Thomas Meitinger
Dan Mellström
David Melzer
Iva Miljkovic
Matthias Nauck
Maria Nilsson
Brenda Penninx
Stephen R Pye
Ramachandran S Vasan
Martin Reincke
Fernando Rivadeneira
Abdelouahid Tajar
Alexander Teumer
André G Uitterlinden
Jagadish Ulloor
Jorma Viikari
Uwe Völker
Henry Völzke
H Erich Wichmann
Tsung-Sheng Wu
Wei Vivian Zhuang
Elad Ziv
Frederick C W Wu
Olli Raitakari
Anna-Lena Eriksson
Martin Bidlingmaier
Tamara B Harris
Anna Murray
Frank H de Jong
Joanne M Murabito
Shalender Bhasin
Liesbeth Vandenput
Robin Haring
Published in PLoS genetics
Volume 7
Issue 10
Pages e1002313
ISSN 1553-7404
Publication year 2011
Published at Institute of Neuroscience and Physiology, Department of Physiology
Institute of Medicine, Department of Clinical Trials and Entrepreneurship
Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine
Pages e1002313
Language en
Links dx.doi.org/10.1371/journal.pgen.100...
Subject categories Endocrinology

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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