American Journal of Epidemiology Practice of Epidemiology Life-course Analysis of a Fat Mass and Obesity-associated (fto) Gene Variant and Body Mass Index in the Northern Finland Birth Cohort 1966 Using Structural Equation Modeling

which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The association between variation in the fat mass and obesity-associated (FTO) gene and adulthood body mass index (BMI; weight (kg)/height (m) 2) is well-replicated. More thorough analyses utilizing phenotypic data over the life course may deepen our understanding of the development of BMI and thus help in the prevention of obesity. The authors used a structural equation modeling approach to explore the network of variables associated with BMI from the prenatal period to age 31 years (1965–1997) in 4,435 subjects from the Northern Finland Birth Cohort 1966. The use of structural equation modeling permitted the easy inclusion of variables with missing values in the analyses without separate imputation steps, as well as differentiation between direct and indirect effects. There was an association between the FTO single nucleotide polymorphism rs9939609 and BMI at age 31 years that persisted after controlling for several relevant factors during the life course. The total effect of the FTO variant on adult BMI was mostly composed of the direct effect, but a notable part was also arising indirectly via its effects on earlier BMI development. In addition to well-established genetic determinants, many life-course factors such as physical activity, in spite of not showing mediation or interaction, had a strong independent effect on BMI. The prevalence of obesity is rapidly increasing in both developed and developing countries. Obesity predisposes people to many chronic diseases, such as the metabolic syndrome, type 2 diabetes, and cardiovascular disease (1). Recent progress in genome-wide association studies has led to the discovery of novel genetic variants associated with body mass index (BMI; weight (kg)/height (m) 2) and increased risk of obesity (2–5). The strongest signals discovered to date are located in the fat mass and obesity-associated (FTO) gene, which was originally found within a study on type 2 diabetes genes, but the association was mediated by BMI (6). Since then the association between FTO and BMI has been replicated in several studies (3, 4, 7, 8). The association between FTO and BMI growth throughout the life course is still somewhat unclear, but some studies suggest that the effect starts to show at least as early as approximately age 7 years (9–11). Genetic variants discovered so far explain only a small proportion of the variability in body weight. For instance, in the Northern Finland Birth …