Genetically Predicted Sex Hormone Levels and Health Outcomes: Phenome-Wide Mendelian Randomization Investigation

Abstract

Background Sex hormone-binding globulin (SHBG), testosterone and oestradiol have been associated with many diseases in observational studies; however, the causality of associations remains unestablished. Methods A phenome-wide Mendelian randomization (MR) association study was performed to explore disease outcomes associated with genetically proxied circulating SHBG, testosterone and oestradiol levels by using updated genetic instruments in 339 197 unrelated White British individuals (54% female) in the UK Biobank. Two-sample MR analyses with data from large genetic studies were conducted to replicate identified associations in phenome-wide MR analyses. Multivariable MR analyses were performed to investigate mediation effects of hormone-related biomarkers in observed associations with diseases. Results Phenome-wide MR analyses examined associations of genetically predicted SHBG, testosterone and oestradiol levels with 1211 disease outcomes, and identified 28 and 13 distinct phenotypes associated with genetically predicted SHBG and testosterone, respectively; 22 out of 28 associations for SHBG and 10 out of 13 associations for testosterone were replicated in two-sample MR analyses. Higher genetically predicted SHBG levels were associated with a reduced risk of hypertension, type 2 diabetes, diabetic complications, coronary atherosclerotic outcomes, gout and benign and malignant neoplasm of uterus, but an increased risk of varicose veins and fracture (mainly in females). Higher genetically predicted testosterone levels were associated with a lower risk of type 2 diabetes, coronary atherosclerotic outcomes, gout and coeliac disease mainly in males, but an increased risk of cholelithiasis in females. Conclusions These findings suggest that sex hormones may causally affect risk of several health outcomes.

Contribution highlights

• Background Sex hormone-binding globulin (SHBG), testosterone and oestradiol have been associated with many diseases in observational studies; however, the causality of associations remains unestablished.
• Methods A phenome-wide Mendelian randomization (MR) association study was performed to explore disease outcomes associated with genetically proxied circulating SHBG, testosterone and oestradiol levels by using updated genetic instruments in 339 197 unrelated White British individuals (54% female) in the UK Biobank.

Extracted from the public abstract; no claims have been added.

Code and data

Publication metadata

DOI

10.1093/ije/dyac036

PMID

35218343

PMCID

PMC9749729

Volume

51

Issue

6

Pages / article

1931-1942

Version relationship

No separate preprint-to-publication relationship is currently recorded.

BibTeX

@article{Yuan2022Geneticallypredicted,
  title = {Genetically Predicted Sex Hormone Levels and Health Outcomes: Phenome-Wide Mendelian Randomization Investigation},
  author = {Shuai Yuan and Lijuan Wang and Jing Sun and Lili Yu and Xuan Zhou and Jie Yang and Yimin Zhu and Dipender Gill and Stephen Burgess and Joshua C Denny},
  journal = {International Journal of Epidemiology},
  year = {2022},
  url = {https://academic.oup.com/ije/article/51/6/1931/6590882},
  doi = {10.1093/ije/dyac036},
  pmid = {35218343},
  volume = {51},
  number = {6},
  pages = {1931--1942}
}