Polygenic risk, rapid childhood growth, and the development of obesity: evidence from a 4-decade longitudinal study

Abstract

Objective: To test how genomic loci identified in genome-wide association studies influence the development of obesity.

Design: A 38-year prospective longitudinal study of a representative birth cohort.

Setting: The Dunedin Multidisciplinary Health and Development Study, Dunedin, New Zealand.

Participants: One thousand thirty-seven male and female study members.

Main exposures: We assessed genetic risk with a multilocus genetic risk score. The genetic risk score was composed of single-nucleotide polymorphisms identified in genome-wide association studies of obesity-related phenotypes. We assessed family history from parent body mass index data collected when study members were 11 years of age.

Main outcome measures: Body mass index growth curves, developmental phenotypes of obesity, and adult obesity outcomes were defined from anthropometric assessments at birth and at 12 subsequent in-person interviews through 38 years of age.

Results: Individuals with higher genetic risk scores were more likely to be chronically obese in adulthood. Genetic risk first manifested as rapid growth during early childhood. Genetic risk was unrelated to birth weight. After birth, children at higher genetic risk gained weight more rapidly and reached adiposity rebound earlier and at a higher body mass index. In turn, these developmental phenotypes predicted adult obesity, mediating about half the genetic effect on adult obesity risk. Genetic associations with growth and obesity risk were independent of family history, indicating that the genetic risk score could provide novel information to clinicians.

Conclusions: Genetic variation linked with obesity risk operates, in part, through accelerating growth in the early childhood years after birth. Etiological research and prevention strategies should target early childhood to address the obesity epidemic.

Figure 1

Developmental phenotypes of rapid early growth hypothesized to mediate polygenic risk for obesity. The genetic epidemiology of obesity indicates that a large number of common polymorphisms each contribute small, additive increments to risk for obesity.^, The combined influence of these polymorphisms can be summarized in a polygenic risk profile. The developmental epidemiology of obesity highlights the following 3 developmental phenotypes of rapid early growth that predispose children to become obese in later life: (1) growth during gestation, (2) postnatal growth, and (3) adiposity rebound.^, We tested the hypothesis that these developmental phenotypes would mediate polygenic risk for adult obesity. BMI indicates body mass index.

Figure 2

Life-course growth curves for children with high, low, and average genetic risk scores (GRSs). Individuals with higher-obesity GRSs were larger and grew more rapidly as children and adults. The solid line represents the population mean trajectory (average genetic risk). Dashed lines are for subgroups within 1 SD of the GRS (high and low genetic risk). Trajectories were derived from the life-course growth model (intercept fitted at 13 years of age; linear and quadratic slopes fitted during ages 3–13 years and 13–38 years), including intercept and linear slope effects for the GRS. Analyses included 856 individuals of European descent. Body mass index is calculated as weight in kilograms divided by height in meters squared.

Figure 3

Obesity prevalence among low and high genetic risk cohort members in their second, third, and fourth decades of life and chronically across ages 15 to 38 years. Individuals with higher genetic risk scores (GRSs) were more likely to be obese across 2 decades of adult follow-up. Error bars and numbers in parentheses reflect 95% CIs. The GRS was dichotomized at the sample mean to create low and high genetic risk categories. Relative risks (RRs) (95% CIs) are reported from Poisson regression models adjusted for sex that included the 856 individuals of European descent in the analysis sample.

Figure 4

Influence of genetic risk and family history on growth and obesity risk. The genetic risk score (GRS) contained information about children’s growth and their obesity risk that was not available in their family histories. Genetic risk and family history made independent and additive contributions to life-course growth predictions and to adult obesity risk in 856 individuals of European descent. A, Life-course growth curves show that genetic risk and family history made additive contributions to growth predictions. B, Bar graph shows that genetic risk and family history made additive contributions to children’s risk of becoming obese. Error bars reflect 95% CIs. Statistical analyses illustrating the independence of the GRS and family history in predicting growth and obesity risk are presented in eTable 2. Body mass index is calculated as weight in kilograms divided by height in meters squared.