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

Abstract

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.

Figure 1.

Relation between the fat mass and obesity-associated (FTO) rs9939609 genotype and A) maternal body mass index (BMI; weight (kg)/height (m)²); B) the subject's own BMI at birth; C) BMI at age 14 years; and D) BMI at age 31 years in the Northern Finland Birth Cohort 1966, 1965–1997. Data are presented as geometric mean values (circles) with back-transformed 95% confidence intervals (bars). Results were adjusted for sex and gestational age (for birth BMI) or sex only (for BMI at ages 14 and 31 years).

Figure 2.

Structural equation model of relations between the fat mass and obesity-associated (FTO) rs9939609 genotype and body mass index (BMI; weight (kg)/height (m)²) fitted to data from the Northern Finland Birth Cohort 1966, 1965–1997. Four simultaneous equations were fitted using maternal BMI, BMI at birth, BMI at age 14 years, and BMI at age 31 years as the outcome variables. SES, socioeconomic status.