We aim to identify genetic and environmental factors that are causally associated with birth weight. Both lower and higher birth weights in the normal range are observationally associated with a higher risk of type 2 diabetes in later life, but the causes of these associations are poorly understood.
We propose to investigate three related research questions:
(1) Which common fetal genetic variants are robustly associated with offspring birth weight?
(2) Which common maternal genetic variants are robustly associated with offspring birth weight?
(3) Which maternal intra-uterine environmental exposures are causally associated with offspring birth weight? Improving the prevention, diagnosis and treatment of diabetes:
(1) Fetal genetic variants associated with an individual?s own birth weight will highlight biological pathways relevant to fetal growth and may indicate links with pathways relevant to diabetes, enabling a better understanding of what causes the disease.
(2) Maternal genetic variants known to influence diabetes- or obesity-related traits may be used to test the hypothesis that those traits are causally associated with the birth weight of her offspring. This will improve understanding of the factors responsible for increased fetal growth and associated risks in a diabetic or obese pregnancy. We will perform
(a) [hypothesis-free] genome-wide association studies examining
(i) associations between a participant’s genotype (fetal) and their own birth weight,
(ii) associations between a female participant’s genotype (maternal) and the birth weight of their first child, and
(b) [hypothesis-driven] analyses of associations between maternal genetic variants known to influence traits relevant to the maternal environment (fasting glucose, blood pressure etc) and offspring birth weight. Since genetic variants are unlikely to be confounded, the latter will be a Mendelian randomization analysis to investigate causality in associations between maternal environmental factors and offspring birth weight. We propose to use the full UK Biobank cohort for the fetal genome-wide association study, while for the maternal genome-wide association study and Mendelian randomization analyses, we plan to use the subset of women with data on birth weight of first child (n=221,522).