Background: Few studies have investigated associations between adiposity and reproductive factors using causal methods, both of which have a number of consequences on disease. 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 and other consortia 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 body size and adulthood body mass index (BMI). We applied multivariable mendelian randomization to account for genetic correlation and estimate 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. Findings: We found a higher childhood body size leads to an earlier age at menarche, which in turn leads to higher adulthood BMI. Furthermore, we find contrasting and independent effects of childhood body size and adulthood BMI 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: We highlight the importance of untangling the effects of exposures at different timepoints across the lifecourse, as demonstrated with adiposity, where accounting for measures at one point in the lifecourse can alter the direction and magnitude of effects at another time point and should therefore be considered in further studies.

The authors have declared no competing interest.

All authors work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MRC) (MC_UU_00011/1, MC_UU_00011/5, MC_UU_00011/6). All authors are members of the Menarche, Menstruation, Menopause and Mental Health (4M) consortium, which is supported by the GW4 Alliance. C.P. is supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (108902/B/15/Z). G.C.S. is supported by the UK MRC (New Investigator Research Grant, MR/S009310/1) and the European Joint Programming Initiative 'A Healthy Diet for a Healthy Life' (JPI HDHL, NutriPROGRAM project, UK MRC MR/S036520/1). L.D.H. is supported by Career Development Awards from the UK MRC (MR/M020894/1). R.C.R. is supported by the CRUK-funded Integrative Cancer Epidemiology Programme (C18281/A19169).

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UK Biobank received ethical approval from the North West Multi-Centre Research Ethics Committee (REC reference: 16/NW/0274) and was conducted in accordance with the principles of the Declaration of Helsinki.

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