Using human genetics to understand the disease impacts of testosterone in men and women

Ruth, Katherine S.; Day, Felix R.; Tyrrell, Jess; Thompson, Deborah J.; Wood, Andrew R.; Mahajan, Anubha; Beaumont, Robin N; Wittemans, Laura B. L.; Martin, Susan; Busch, Alexander; Erzurumluoglu, A. Mesut; Hollis, Benjamin; O’Mara, Tracy A.; McCarthy, Mark; Langenberg, Claudia; Easton, Douglas F.; Wareham, Nicholas J.; Burgess, Stephen; Murray, Anna; Ong, Ken K.; Frayling, Timothy M.; Perry, John R. B.

doi:10.1038/s41591-020-0751-5

Cited by 475 publications

(664 citation statements)

References 52 publications

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“…Our observational and MR analyses provide strong evidence that men with higher circulating IGF-I have an elevated risk of prostate cancer; further, our observational analyses suggest a higher risk of prostate cancer mortality in these men, suggesting that IGF-I is associated with risk for more severe forms of prostate cancer and/or may increase the risk of prostate cancer progression. Higher serum free testosterone was associated with a higher risk of prostate cancer diagnosis, which is supported by a recent MR analysis 9 . We also found that men with higher SHBG had a lower risk.…”

Section: Discussionsupporting

confidence: 55%

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Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Watts

Fensom

Smith-Byrne

et al. 2020

Preprint

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Background: Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using newly available data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we aimed to investigate the associations of circulating concentrations of IGF-I, sex hormone-binding globulin (SHBG), total and calculated free testosterone with prostate cancer risk. Patients and methods: For prospective analyses of prostate cancer incidence and mortality, we studied 199,698 male UK Biobank participants using Cox proportional hazards models. Multivariable-adjusted hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample of up to 7,776 men. A 2-sample Mendelian randomization (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from 79,148 cases and 61,106 controls from the PRACTICAL consortium. We used cis- and all (cis and trans) SNP MR approaches. Results: After a mean follow-up of 6.9 years, 5,402 men were diagnosed with and 295 died from prostate cancer. Higher circulating IGF-I was associated with an elevated risk (HR per 5 nmol/L increment=1.09, 95% CI 1.05-1.12) and prostate cancer mortality (HR per 5 nmol/L increment=1.15,1.02-1.29) in observational analyses. Cis- and all SNPs MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment=1.34,1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment=1.10,1.05-1.15), and higher SHBG was associated with a lower risk of prostate cancer (HR per 10 nmol/L increment=0.95,0.94-0.97), but neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. Conclusion(s): These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.

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Section: Discussionsupporting

confidence: 55%

“…Epidemiological studies have also reported an inverse association between prostate cancer risk and circulating SHBG 8 , although results from MR analyses are inconclusive 9 .…”

Section: Introductionmentioning

confidence: 99%

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Watts

Fensom

Smith-Byrne

et al. 2020

Preprint

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“…Sex hormone supplementation has commonly effects on metabolic traits, sexual function and bone health [23]. Epidemiological study has indicated strong correlations between sex hormone supplements and health conditions [15].…”

Section: Discussionmentioning

confidence: 99%

Evaluating the genetic effects of sex hormone traits on the development of mental traits: a polygenic score analysis and genome-wide genetic interaction analysis in UK Biobank cohort

Liang

Cheng

et al. 2020

Preprint

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Objective: To evaluate the genetic effects of sex hormone traits on the development of mental traits in middle-aged adults.Methods: The SNPs associated with sex hormone traits were derived from a two-stage genome-wide association study (GWAS). Four sex hormone traits were selected in the current study, including sex hormone-binding globulin (SHBG), testosterone, bioavailable testosterone and estradiol. The polygenic risk score (PRS) of sex hormone traits were calculated from individual-level genotype data of the United Kingdom (UK) Biobank cohort. We then used logistic and linear regression models to assess the associations between individual PRS of sex hormone traits and the frequency of alcohol consumption, anxiety, intelligence and so on. Finally, genome-wide genetic interaction study (GWGIS) was performed to detect novel candidate genes interacting with the sex hormone traits on the development of fluid intelligence and the frequency of smoking and alcohol consumption by PLINK2.0.Results: We observed positive association between SHBG and the frequency of alcohol consumption (b=0.0101, p=3.84×10–11) in middle-aged males and females. In addition, estradiol was positively associated with the frequency of alcohol consumption (b=0.0128, p=1,96×10–8), fluid intelligence (b=0.0084, p=1.90×10–2) and the frequency of smoking (b=0.0054, p=1.77×10–2) in middle-aged males. Moreover, SHBG was associated with the frequency of alcohol consumption (b=0.0067, p=2.60×10–3), fluid intelligence (b=0.0067, p=4.25×10–2) and anxiety (b=-0.0071, p=3.79×10–2) in middle-aged females. Finally, GWGIS identified one significant loci, Tenascin R (TNR) (rs34633780, p=3.45×10–8) interacting with total testosterone for fluid intelligence.Conclusion: Our study results support the genetic effects of sex hormone traits on the development of intelligence and the frequency of alcohol consumption in middle-aged adults in UK.

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“…The sex hormone associated SNPs was driven from a published GWAS [23]. Brie y, the study analyzed four sex hormone traits, including sex hormone-binding globulin (SHBG), testosterone, bioavailable testosterone and estradiol.…”

Section: Gwas Data Of Sex Hormone Related Traitsmentioning

confidence: 99%

“…Additionally, Belsky et al [22] observed that individuals at higher PRS were more likely to persist longer in smoking heavily and develop nicotine dependence more frequently. Recently, Katherine et al [23] conducted a two-stage GWAS in 425,097 United Kingdom (UK) Biobank study participants and identi ed 2,571 genetic variant-sex hormone associations. Using the PRS of sex hormone as instrumental variables, we can calculate the PRS of sex hormone and explore the correlations between PRS of sex hormone and mental traits.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the genetic effects of sex hormone on the development of mental traits: a polygenic score analysis and genome-wide genetic interaction analysis in the UK Biobank cohort

Liang¹,

Cheng²,

Ye³

et al. 2020

Preprint

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Objective: To evaluate the genetic effects of sex hormone on the development of mental traits.Methods: The SNPs significantly associated with sex hormone traits were driven from a two-stage genome-wide association study (GWAS). Four sex hormone were selected in this study, including sex hormone-binding globulin (SHBG), testosterone, bioavailable testosterone and estradiol. The polygenic risk scores (PRS) of sex hormone traits were calculated from individual-level genotype data of the UK Biobank cohort. We then used logistic and linear regression models to assess the associations between individual PRS of sex hormone traits and the frequency of alcohol consumption, anxiety, intelligence and so on. Finally, genome-wide genetic interaction study (GWGIS) was performed to detect novel candidate genes interacting with the sex hormone on the development of fluid intelligence and the frequency of smoking and alcohol consumption by PLINK2.0.Results: We observed positive associations between SHBG and the frequency of alcohol consumption (b=0.01, p=3.84×10–11) in males and females. In addition, estradiol was positively associated with the frequency of alcohol consumption (b=0.01, p=1,96×10–8), fluid intelligence (b=0.01, p=1.90×10–2) and the frequency of smoking (b=0.01, p=1.77×10–2) in males. Moreover, SHBG was associated with the frequency of alcohol consumption (b=0.01, p=2.60×10–3), fluid intelligence (b=0.01, p=4.25×10–2) and anxiety (b=-0.01, p=3.79×10–2) in females. Finally, GWGIS identified one significant loci, Tenascin R (TNR) (rs34633780, p=3.45×10–8) interacting with total testosterone for fluid intelligence.Conclusion: Our study results support the genetic effects of sex hormone on the development of intelligence and the frequency of alcohol consumption.

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Using human genetics to understand the disease impacts of testosterone in men and women

Cited by 475 publications

References 52 publications

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Evaluating the genetic effects of sex hormone traits on the development of mental traits: a polygenic score analysis and genome-wide genetic interaction analysis in UK Biobank cohort

Evaluating the genetic effects of sex hormone on the development of mental traits: a polygenic score analysis and genome-wide genetic interaction analysis in the UK Biobank cohort

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