Principal Investigator: Dr Rachel Freathy
Department: Medical School
Institution: University of Exeter
Institution:
University of Exeter, Medical School, St Luke’s Campus, Magdalen
Road, Exeter, Devon, EX1 2LU
Summary:
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)
New scope:
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 cardiometabolic diseases in later life, but the causes of these associations are poorly understood.
We propose to investigate four related research questions:
Original 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 intrauterine environmental exposures are causally associated with offspring birth weight?
Additional questions
(4) How can we use the genetics of birth weight to understand associations between early growth and later life diseases?
(5) Questions 1 and 2 above, but including not just common variants but also common and rare genetic variants.
The additional questions will require access to the full range of UK Biobank variables in Tim Frayling’s linked 9072 application, including accelerometry data (used to derive sleep and physical activity variables) and medical records (used to derive health outcomes). All will be analysed in relation to birth weight and genetics.
