Why does low birth weight increase the risk of diabetes and other cardiometabolic diseases? A study of genetic factors in HUNT

There is a robust relationship between lower birthweight and higher risk of cardiometabolic disease in later life, including type 2 diabetes and cardiovascular disease. Two major hypotheses have been put forward to explain this association. The first is the Developmental Origins of Health and Disease (DOHaD) hypothesis, 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, type 2 diabetes risk alleles in the mother result in higher levels of circulating glucose tending to increase offspring birthweight. This happens because the same risk alleles in the child leads to decreased sensitivity to insulin (an important growth factor for the baby), decreasing offspring birthweight, and predisposing the child to type 2 diabetes in later life. In the Norwegian HUNT study we have explored if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother-offspring pairs (and 19,792 father-offspring pairs). We show in our paper published in Nature Communications (Moen et al 2020) that there are little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. In an abstract submitted to the DOHAD conference we further explore the relationship between birthweight and cardiometabolic traits by simultaneously partitioning the genetic covariation into maternally mediated and offspring mediated contributions. We subsequently model the covariance between birthweight and later life outcomes, such as blood pressure, non-fasting glucose, blood lipids and body mass index in the Norwegian HUNT cohort. The Norwegian HUNT cohort has a large number of mother-offspring pairs with genetic and phenotypic data, and has offspring who are now at an age where adverse values on cardiometabolic risk factors are becoming prevalent. Additionally data from the HUNT study are contributing to the next birthweight genome-wide association meta-analysis, which is currently being undertaken within the Early Growth Genetics (EGG) consortium.

In our first aim we wanted to identify novel genetic loci associated with birthweight. Our analysis in the HUNT cohort are finished and are currently being meta-analysed with data from the EGG Consortium, and will represent the worlds largest genetic study of birthweight. In our second aim we have partitioned the correlation between birthweight and several later life traits like blood pressure and non-fasting glucose into maternal and fetal genetic components. Results from this study will help our understanding of the mechanism behind developmental origin of health and disease hypothesis. Lastly our third project - using Mendelian randomization to investigate whether in utero growth restriction is causally increase risk of offspring later life disease - was published in 2020 in Nature communication. For this project we also produced a podcast with scipod (https://www.scipod.global/do-maternal-influences-on-birthweight-influence-future-cardiometabolic-risk-dr-gunn-helen-moen/).

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 (CVD). 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 (FIH) postulates that the same genetic factors that alter intrauterine growth also affect future risk of disease. Broadly speaking, diabetes risk alleles in the mother result in higher levels of circulating glucose tending to increase offspring BW. However, the same loci present in the fetus decrease sensitivity to insulin thereby decreasing offspring BW, and predisposing the child to T2D in later life. A recent publication in Nature showed that the negative phenotypic correlation between BW and cardiometabolic disease was primarily mediated by genetic factors. The significance of the findings and their relevance to perinatal epidemiology depends on the correct partitioning of genetic effects into maternal and fetal components. Studying this is something that has not been previously possible because of the small number of mother-offspring cohorts across the world. However, the Norwegian HUNT cohort is ideal for studying the maternal and fetal effect as it has a large number of mother-offspring pairs with genetic and phenotypic data. Furthermore, the HUNT offspring now are at an age where cardiometabolic risk factors are becoming clinically apparent, and as such we have a unique opportunity to study the effects of birthweight and later risk of CVD and T2D in a population where maternal and fetal effects can be disentangled.