Mendelian randomization analysis of factors related to ovulation and reproductive function and endometrial cancer risk

Shannon D'Urso; Pooja Arumugam; Therese Weider; Liang-Dar Hwang; Tom A Bond; John P Kemp; Nicole M Warrington; David M Evans; Tracy A O'Mara; Gunn-Helen Moen

doi:10.1186/s12916-022-02585-w

Mendelian randomization analysis of factors related to ovulation and reproductive function and endometrial cancer risk

BMC Med. 2022 Nov 1;20(1):419. doi: 10.1186/s12916-022-02585-w.

Authors

Shannon D'Urso¹, Pooja Arumugam², Therese Weider^{3

4}, Liang-Dar Hwang¹, Tom A Bond^{5

6

7

8}, John P Kemp^{1

5

6}, Nicole M Warrington^{1

5

6

9}, David M Evans^{1

5

6}, Tracy A O'Mara¹⁰, Gunn-Helen Moen^{11

12

13

14

15}

Affiliations

¹ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
² School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
³ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.
⁵ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
⁶ The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.
⁷ Bristol Medical School, Population Health Science, University of Bristol, Bristol, UK.
⁸ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁹ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁰ Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹¹ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. g.h.moen@medisin.uio.no.
¹² Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. g.h.moen@medisin.uio.no.
¹³ The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia. g.h.moen@medisin.uio.no.
¹⁴ Bristol Medical School, Population Health Science, University of Bristol, Bristol, UK. g.h.moen@medisin.uio.no.
¹⁵ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. g.h.moen@medisin.uio.no.

Abstract

Background: Observational epidemiological studies suggest a link between several factors related to ovulation and reproductive function and endometrial cancer (EC) risk; however, it is not clear whether these relationships are causal, and whether the risk factors act independently of each other. The aim of this study was to investigate putative causal relationships between the number of live births, age at last live birth, and years ovulating and EC risk. METHODS: We conducted a series of observational analyses to investigate various risk factors and EC risk in the UK Biobank (UKBB). Additionally, multivariate analysis was performed to elucidate the relationship between the number of live births, age at last live birth, and years ovulating and other related factors such as age at natural menopause, age at menarche, and body mass index (BMI). Secondly, we used Mendelian randomization (MR) to assess if these observed relationships were causal. Genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from previous studies of woman's number of live births, age at menopause and menarche, and BMI. We conducted a genome-wide association analysis using the UKBB to identify SNPs associated with years ovulating, years using the contraceptive pill, and age at last live birth.

Results: We found evidence for a causal effect of the number of live births (inverse variance weighted (IVW) odds ratio (OR): 0.537, p = 0.006), the number of years ovulating (IVW OR: 1.051, p = 0.014), in addition to the known risk factors BMI, age at menarche, and age at menopause on EC risk in the univariate MR analyses. Due to the close relationships between these factors, we followed up with multivariable MR (MVMR) analysis. Results from the MVMR analysis showed that number of live births had a causal effect on EC risk (OR: 0.783, p = 0.036) independent of BMI, age at menarche and age at menopause.

Conclusions: MVMR analysis showed that the number of live births causally reduced the risk of EC.

Keywords: Age at last live birth; Endometrial cancer; Fertility; GWAS; Mendelian randomization; Number of live births; UK biobank; Years ovulating.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Body Mass Index
Endometrial Neoplasms*
Female
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis*
Ovulation
Polymorphism, Single Nucleotide
Risk Factors

Abstract

Publication types

MeSH terms

Grants and funding