Polygenic risk score based on weight gain trajectories is a strong predictor of childhood obesity

Obesity is highly heritable, yet only a small fraction of its heritability has been attributed to specific genetic variants. These variants are traditionally ascertained from genome-wide association studies (GWAS), which utilize samples with tens or hundreds of thousands of individuals for whom a single summary measurement (e.g., BMI) is collected. An alternative approach is to focus on a smaller, more deeply characterized sample in conjunction with advanced statistical models that leverage detailed phenotypes. Here we use novel functional data analysis (FDA) techniques to capitalize on longitudinal growth information and construct a polygenic risk score (PRS) for obesity in children followed from birth to three years of age. This score, comprised of 24 single nucleotide polymorphisms (SNPs), is significantly higher in children with (vs. without) rapid infant weight gain--a predictor of obesity later in life. Using two independent cohorts, we show that genetic variants identified in early childhood are also informative in older children and in adults, consistent with early childhood obesity being predictive of obesity later in life. In contrast, PRSs based on SNPs identified by adult obesity GWAS are not predictive of weight gain in our cohort of children. Our research provides an example of a successful application of FDA to GWAS. We demonstrate that a deep, statistically sophisticated characterization of a longitudinal phenotype can provide increased statistical power to studies with relatively small sample sizes. This study shows how FDA approaches can be used as an alternative to the traditional GWAS. Author SummaryFinding genetic variants that confer an increased risk of developing a particular disease has long been a focus of modern genetics. Genome wide association studies (GWAS) have catalogued single nucleotide polymorphisms (SNPs) associated with a variety of complex diseases in humans, including obesity, but by and large have done so using increasingly large samples-- tens or even hundreds of thousands of individuals, whose phenotypes are thus often only superficially characterized. This, in turn, may hide the intricacies of the genetic influence on disease. GWAS findings are also usually study-population dependent. We found that genetic risk scores based on SNPs from large adult obesity studies are not predictive of the propensity to gain weight in very young children. However, using a small cohort of a few hundred children deeply characterized with growth trajectories between birth and two years, and leveraging such trajectories through novel functional data analysis (FDA) techniques, we were able to produce a strong childhood obesity genetic risk score.