Using human genetics to understand the disease impacts of testosterone in men and women.
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Authors
Ruth, Katherine S
Tyrrell, Jessica
Thompson, Deborah J
Wood, Andrew R
Mahajan, Anubha
Beaumont, Robin N
Wittemans, Laura
Hollis, Benjamin
Endometrial Cancer Association Consortium
McCarthy, Mark I
Murray, Anna
Frayling, Timothy M
Publication Date
2020-02Journal Title
Nat Med
ISSN
1078-8956
Publisher
Springer Science and Business Media LLC
Volume
26
Issue
2
Pages
252-258
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Ruth, K. S., Day, F., Tyrrell, J., Thompson, D. J., Wood, A. R., Mahajan, A., Beaumont, R. N., et al. (2020). Using human genetics to understand the disease impacts of testosterone in men and women.. Nat Med, 26 (2), 252-258. https://doi.org/10.1038/s41591-020-0751-5
Abstract
Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
Keywords
Endometrial Cancer Association Consortium, Humans, Polycystic Ovary Syndrome, Breast Neoplasms, Endometrial Neoplasms, Prostatic Neoplasms, Diabetes Mellitus, Type 2, Testosterone, Estradiol, Cluster Analysis, Odds Ratio, Sex Factors, Body Composition, Genotype, Haplotypes, Phenotype, Polymorphism, Single Nucleotide, Software, Biological Specimen Banks, Female, Male, Genome-Wide Association Study, Mendelian Randomization Analysis, Biomarkers, United Kingdom
Sponsorship
A.R.W. and T.M.F. are supported by the European Research Council grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. R.B. is funded by the Wellcome Trust and Royal Society grant 104150/Z/14/Z. J.T. is supported by the Academy of Medical Sciences Springboard award which is supported by the Wellcome Trust and GCRF [SBF004\1079]. This work was supported by the Medical Research Council [Unit Programme numbers MC_UU_12015/1 and MC_UU_12015/2].
Funder references
Medical Research Council (MC_UU_12015/2)
Medical Research Council (MC_UU_12015/1)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
MRC (MC_PC_13048)
Medical Research Council (MC_UU_00002/7)
MRC (MC_UU_00006/2)
Wellcome Trust (204623/Z/16/Z)
Identifiers
External DOI: https://doi.org/10.1038/s41591-020-0751-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299833
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