There is a robust and well-documented relationship between lower birthweight (BW) and higher risk of cardiometabolic disease in later life, including Type 2 Diabetes (T2D) and cardiovascular disease. Two major hypotheses have been put forward to explain this association. The first is the Developmental Origins of Health and Disease hypothesis (DOHaD), which posits that adverse intrauterine environments result in fetal growth restriction and increased future risk of cardiometabolic disease through developmental compensation. In contrast, the Fetal Insulin Hypothesis postulates that the same genetic factors that alter intrauterine growth also affect future risk of disease. Broadly speaking, T2D risk alleles in the mother result in higher levels of circulating glucose tending to increase offspring BW. However, many of the same loci in the fetus decrease sensitivity to insulin (an important growth factor for the baby), decreasing offspring BW, and predisposing the child to T2D in later life.
Few large-scale studies in the world have data on both mother and offspring and far fewer have genome-wide genetic data on both generations. The HUNT (Helseundersøkelsen i Nord-Trøndelag) has large numbers of mother offspring pairs where the offspring are old enough to start showing symptoms of cardiometabolic disease. Participants of the HUNT2 and HUNT3 have complete information on a variety of cardiometabolic outcomes, including self-reported T2D. By applying innovative statistical techniques developed by our collaborators in the Evans’ group (University of Queensland) to the unique parent-offspring GWAS data from the Norwegian HUNT cohort, we will in this project be able to investigate the relationship between BW and cardiometabolic disease in a way that has not been possible previously.