Genetic studies of obesity in New Zealand: A Children of SCOPE study

Field: Biochemistry, Genetics and Molecular Biology (Life Sciences)

Childhood obesity is a global health problem and is associated with an increased risk of type 2 diabetes (T2D), cardiovascular disease and premature mortality. The prevalence of childhood and adolescent obesity is rising in New Zealand with the most recent health survey estimating 10% of all children (aged 2-14) are obese (2014/2015 New Zealand Health Survey). However, obesity varies with ethnicity, with the Māori (14.8%) and the Pacific Island (29.7%) children exhibiting higher rates of obesity when compared to the Asian (7.2%) and European/Other (7.7%) children. Although this obesity trend is underpinned by the presence of an ‘obesogenic’ environment, it is facilitated by the individual’s genetic susceptibility to excessive weight gain. This helps to explain some of the individual phenotypic variations in development. Further characterisation of these obesity related gene variants would assist with unravelling the molecular mechanism of an affliction that affects approximately 10% of New Zealand children, opening up new avenues in the management of a disease for which no effective treatment currently exists. The aim of this thesis was to characterise the relative contributions between 80 putative genetic variations and obesity traits (BMI z-scores and Percentage Body Fat) in the Auckland Children of SCOPE cohort; a follow-up cross sectional survey of six year old children whose mothers were participants of the landmark SCOPE study. In addition, we investigated the interplay between genetic and modifiable environmental influences (‘healthy’ dietary pattern, physical activity levels and average sleep duration) on the predisposition to childhood obesity. Recently, a genome wide study in the Samoan population has identified a protein-altering variant (p.Arg475Gln) in CREBRF as being associated with discordant risks of BMI and T2D. We have tested for the presence and association of CREBRF –rs373863828 using the “Genetics of Gout, Diabetes and Kidney Disease in Aotearoa” case-control study recruited by the University of Otago. This study has shown that genetic variants identified in adult studies, were also associated with obesity traits in six year old New Zealand European children. This would suggest that gene variants that influence weight gain in adults, may direct growth patterns and adiposity from childhood. We have also captured additional loci (not previously detected in our earlier genetic association analysis) from the gene-by-environmental interaction analyses. From this research, we propose that there is a role for these gene variants to control body weight through satiety, energy extraction from diet and dissipation of energy as heat, and therefore act as the underlying cause behind the increased weight gain in children. We have also confirmed the presence of the CREBRF –rs373863828 variant in the broader Polynesian population residing in Aotearoa New Zealand and replicated the association with increased BMI and reduced odds of T2D. This emphasises a need for obesity genetic research away from European dominant studies. This study offers a unique opportunity to advance our understanding of the complex relationship between genetic influences, and environmental factors, in relation to childhood obesity. The health importance for New Zealand is from identifying potentially modifiable risk factors for childhood obesity, which can then be evaluated in future intervention studies. Factors identified early in the life cycle may be more amenable to interventions compared with strategies which target children who are already overweight or obese.