Neil Murphy

Ph.D

International Agency for Research on Cancer

Scientist

PLCO (Learn more about this study)

PLCO-1170

Mar 8, 2023

Genome-Wide Association Study of Circulating Estradiol in Postmenopausal Women

Estradiol regulates physiological processes such as sexual development, reproductive cycle, and stress regulation. Exposure to unopposed estrogens has been related to breast, ovarian, and endometrial cancer risk. However, genome-wide association studies (GWAS) conducted to date have identified few loci associated with circulating levels of estradiol (1-3). These previous GWAS have been hampered by relatively small sample sizes (ranging from ~1600 to 2800 women).

Study design
IARC will perform a GWAS of estradiol levels in postmenopausal women from the PLCO.

Analysis plan
For the proposed GWAS IARC will use measured estradiol concentrations available at the PLCO and combine with genetic data available via dbGaP (phs001286.v2.p2):
IARC will include women with at least 12 months after their last menstrual period, and non-users of hormone therapy only.
The association of genetic variants with estradiol concentrations (natural log transformed and inverse normalized transformed) will be estimated using additive linear regression models adjusted for age at blood sample collection, genetic principal components and (with or without) body mass index. IARC will include all variants with imputation accuracy R2>0.4.

Pertinent variables
- Available plasma or serum estradiol measure.
o Laboratory batch for estradiol measure.
o Estradiol laboratory measurement information.
o Status of participant in the estradiol measurement study (e.g. case/non-case).
- Available GWAS data.
o Genotyping platform.
o GWAS imputation reference panel.
- Plasma/serum sex hormone binding globulin (SHBG) measure (if available).
- Plasma/serum estrone measure (if available).
- Ancestry.
- Age at blood collection.
- BMI.
- Waist circumference.
- Hip circumference.
- Previous HT use.
- Previous oral contraceptive use.
- Diabetes status.
- Diabetes medication use.
- Glucocorticoid use.
- Osteoporosis medication use.

References
1. Prescott J, Thompson DJ, Kraft P, Chanock SJ, Audley T, Brown J, et al. Genome-Wide Association Study of Circulating Estradiol, Testosterone, and Sex Hormone-Binding Globulin in Postmenopausal Women. PLOS ONE. 2012;7(6):e37815.
2. Ruth KS, Campbell PJ, Chew S, Lim EM, Hadlow N, Stuckey BGA, et al. Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. Eur J Hum Genet. 2016;24(2):284-90.
3. Pott J, Bae YJ, Horn K, Teren A, Kühnapfel A, Kirsten H, et al. Genetic Association Study of Eight Steroid Hormones and Implications for Sexual Dimorphism of Coronary Artery Disease. The Journal of Clinical Endocrinology & Metabolism. 2019;104(11):5008-23.

Our objective is to further expand our knowledge on genetic determinants of estradiol concentrations by:

1) conducting a GWAS of postmenopausal estradiol levels in women of European ancestry from the PLCO, and

2) perform a GWAS meta-analysis with other eligible studies IARC have currently approved proposals (Women’s Health Initiative, Twins UK, Melbourne Collaborative Cohort Study, European Prospective Investigation into Cancer and Nutrition, Nurses’ Health Study, and the Leipzig Research Centre for Civilization Diseases (LIFE) studies including ~10,000 women).