We conducted a developmental genetic investigation into the etiology of obesity in a prospective birth cohort study with 4 decades of follow-up. We measured polygenic risk for obesity using a multilocus GRS derived from GWASs of obesity-related phenotypes. Our analyses revealed that polygenic risk for obesity was partly mediated by rapid growth in the early childhood years after birth. This finding supported our hypothesis that developmental phenotypes were critical in linking a genetic predisposition to adult obesity. Furthermore, risk for obesity measured by the genetic risk score was independent of risk information available in parental BMI.
These findings have implications for clinical practice and for developmental and epidemiologic research. First, the results suggest promise for using genetic information in obesity risk assessments. Parental BMI has been proposed as a screening measure to target obesity prevention in children on the basis of effect-size correlations only slightly larger than those we report for our GRS.32
New developments in genome science, including next-generation sequencing, may uncover new variants that further improve the performance of SNP-based risk assessments.33–35
Moreover, the GRS contained information about children’s future obesity risk that could not be derived from measurements of parents, suggesting that positive family history may not always be an appropriate prerequisite for genetic testing. Second, our findings illustrate how polygenic influences on development can be investigated using the GRS. Prospective cohort studies containing repeated measures are necessary to elucidate developmental processes leading to complex diseases.36
However, to date, small single-locus effect sizes have made it challenging to incorporate genetic information into ongoing cohort studies. To address the challenge of small effects, we used a multilocus profile. The resulting GRS enables measurement of a larger, genome-wide effect size and reduces the number of hypothesis tests to 1, making follow-up of GWAS findings tractable in cohort studies that are needed to study development. Third, the longitudinal results illustrate that investigations of obesity as an outcome to developmental processes can inform public health initiatives and research priorities by identifying specific phases in development when genetic risk becomes manifest and thus might be amenable to intervention. Childhood growth in general—and, in particular, growth during the period between birth and the adiposity rebound—should be a focus for future research to understand genetic contributions to the development of obesity.
We acknowledge 3 limitations. First, we derived our GRS from GWASs of Europeans and conducted our study in individuals of European descent; these results may not generalize to other populations.37
Second, our family histories included only parents. More complete family histories might have greater overlap with the GRS. Third, we were unable to characterize growth trajectories during the earliest stages of life; regular follow-up of the cohort did not begin until 3 years of age. However, results from our analyses of birth weight and of weight gain from birth though 3 years of age were consistent with previous genetic investigations of this interval that did include repeated measurements.5,6,38,39
Moreover, we were able to capture growth from 3 years of age and onward with a high degree of resolution; our study included 12 measurements taken during the subsequent 35 years. In addition to repeated measures of height and weight, our study included more direct measures of adiposity, including childhood measurements of skinfold thicknesses and adult measurements of waist circumference and fat mass, all of which were associated with our GRS in parallel to BMI. Thus, the results present compelling evidence that SNPs identified in GWASs of adult BMI and other obesity-related phenotypes predispose to more rapid growth in childhood, leading to increased risk for obesity in adulthood, and provide information not forthcoming from a simple analysis of family history.