Unravelling the Genetic Trajectories of Childhood Growth – From Trio-GWAS to Mechanisms.

The development of obesity early in life is a strong risk factor for having to fight a lifelong battle against obesity and the problems it entails, such as diabetes and heart problems. In this project, we base our research on children from the Norwegian Mother, Father and Child Survey (MoBa) where pregnant mothers have been recruited and followed them and their children through pregnancy and up to the child is 8 years old. We are looking for gene variants that are associated with BMI development in these children. Once we have identified these gene variants in MoBa, we will then study in more detail how they affect weight development in children, among other things through studies in a diet intervention study from Sweden (OTIS study) where children are followed from they are 6 months and up to 18 months old, and in children with early overweight problems from Bergen. We will also perform laboratory experiments in cell models to better understand how these gene variants affect the processes inside our cells. The results will give us increased understanding of the factors that affect children’s growth and can in the future form the basis for improved interventions among children who are at risk of developing severe obesity. Some of the most important findings so far in the project concern the genetic variants that we identified as affecting how the very smallest children gain weight in the first year of life (published in Nature Metabolism). Here we find strong evidence that many of these gene variants are involved in controlling the child’s appetite and energy consumption. We have now started laboratory studies on some of these gene variants to understand the biological mechanisms behind these findings and how these play a role in the risk of becoming overweight later in life. In another study that we recently published in Nature Genetics, we performed genetic analyses in mothers, fathers and children from MoBa and other international studies and linked these gene analyses to the development of the placenta during pregnancy. Our findings, which were the first major genetic study on placental growth, showed that the child’s genes have a greater impact than the mother’s when it comes to the size/weight of the placenta at birth. Overall, the project has provided a lot of new knowledge about how genetic differences in both mother and child affect the child’s growth from the early beginning of life and up to the teenage years. Our continued studies will further strengthen this knowledge with the aim of being able to prevent the development of overweight and obesity in children and adolescents in the future.

Obesity is one of the main health concerns for the21th century. Children becoming overweight early in life are at high risk of developing obesity and later complications such as type 2 diabetes that follow in it´s footpath. Early interventions with life-style and dietary changes can potentially change the progressing weight problems, We propose a thorough omics, molecular, and phenotypic investigation of the biological effects of genetic variants involved in early growth. To achieve this goal, we will utilize GWAS-data from 240,000 MoBa participants, publicly available data, patient-derived cell-lines and three unique and deeply phenotyped cohorts: (1) A complementary feeding study of 250 Swedish children followed from 6-18 months of age (OTIS), (2) The Bergen Childhood Obesity Clinical Cohort following over 300 severely obese children in active treatment over 10 years (PFO) and (3) a puberty study of 1100 children from 6-14 years of age (BGS2). We will perform GWAS analyses in more than 90 000 children and their parents in MoBa, to deliver a comprehensive map of genetic influences on child weight development. Using a novel method based on effect-trajectory modelling, we will group these genes into distinct groups that better reflect the underlying biological mechanisms and facilitate much more predictive genetic risk scores (so called PRS). These results will be taken forward to the three deeply phenotyped cohorts to study their impact on weight development, food preference, blood lipids and transcript levels from 6 to 24 months of age and on childhood obesity. Molecular and cellular studies will be performed in patient derived cell-lines in order to better understand the biological mechanisms As a proof of concept, we have already identified common novel genetic variants in the leptin signaling cascade that have a strong effect on BMI in infancy. This study has unique potential to identify biological markers and molecular mechanisms that reduce risk for obesity.