Establishing the relationships between adiposity and reproductive factors: a multivariable Mendelian randomization analysis

Abstract

Background: Few studies have investigated associations between adiposity and reproductive factors using causal methods, both of which have a number of consequences on women's health. Here we assess whether adiposity at different points in the lifecourse affects reproductive factors differently and independently, and the plausibility of the impact of reproductive factors on adiposity.

Methods: We used genetic data from UK Biobank (273,238 women) and other consortia (EGG, GIANT, ReproGen and SSGAC) for eight reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners, and two adiposity traits: childhood and adulthood body size. We applied multivariable Mendelian randomization to account for genetic correlation and to estimate the causal effects of childhood and adulthood adiposity, independently of each other, on reproductive factors. Additionally, we estimated the effects of reproductive factors, independently of other relevant reproductive factors, on adulthood adiposity.

Results: We found a higher childhood body size leads to an earlier age at menarche, and an earlier age at menarche leads to a higher adulthood body size. Furthermore, we find contrasting and independent effects of childhood and adulthood body size on age at first birth (beta 0.22 SD (95% confidence interval: 0.14, 0.31) vs - 2.49 (- 2.93, - 2.06) per 1 SD increase), age at last birth (0.13 (0.06,0.21) vs - 1.86 (- 2.23, - 1.48) per 1 SD increase), age at menopause (0.17 (0.09, 0.25) vs - 0.99 (- 1.39, - 0.59) per 1 SD increase), and likelihood of having children (Odds ratio 0.97 (0.95, 1.00) vs 1.20 (1.06, 1.37) per 1 SD increase).

Conclusions: Our findings demonstrate the importance of considering a lifecourse approach when investigating the inter-relationships between adiposity measures and reproductive events, as well as the use of 'age specific' genetic instruments when evaluating lifecourse hypotheses in a Mendelian randomization framework.

Keywords: Adiposity; Mendelian randomization; Reproductive factors; UK Biobank.

Fig. 1

Univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) findings: the effects of childhood body size (MVMR adjusted for adulthood body size) and adulthood body size (MVMR adjusted for childhood body size) on reproductive factors in the UK Biobank. GWAS regression coefficients were standardized prior to performing MR. CI Confidence interval

Fig. 2

Univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) findings: the effects of reproductive factors on adulthood body size in the UK Biobank. GWAS regression coefficients were standardized prior to performing MR. AAM Age at menarche, AFS Age first had sexual intercourse, AFB Age at first live birth, ALB Age at last live birth, NLB Number of live births, EPS Ever parous status, AMP Age at menopause, NSP Lifetime number of sexual partners, CI Confidence interval