The Challenge of Stratifying Obesity: Attempts in the Quebec Family Study

Background and aims: Obesity is a major health problem worldwide. Given the heterogeneous obesity phenotype, an optimal obesity stratification would improve clinical management. Since obesity has a strong genetic component, we aimed to develop a polygenic risk score (PRS) to stratify obesity according to the genetic background of the individuals. Methods: A total of 231 single nucleotide polymorphisms (SNP) significantly associated to body mass index (BMI) from 21 genome-wide association studies were genotyped or imputed in 881 subjects from the Quebec Family Study (QFS). The population was randomly split into discovery (80%; n = 704) and validation (20%; n = 177) samples with similar obesity (BMI ≥ 30) prevalence (27.8% and 28.2%, respectively). Family-based associations with obesity were tested for every SNP in the discovery sample and a weighed and continuous PRS₂₃₁ was constructed. Generalized linear mixed effects models were used to test the association of PRS₂₃₁ with obesity in the QFS discovery sample and validated in the QFS replication sample. Furthermore, the Fatty Acid Sensor (FAS) Study (n = 141; 27.7% obesity prevalence) was used as an independent sample to replicate the results. Results: The linear trend test demonstrated a significant association of PRS₂₃₁ with obesity in the QFS discovery sample (OR_trend = 1.19 [95% CI, 1.14-1.24]; P = 2.0x10^-16). We also found that the obesity prevalence was significantly greater in the higher PRS₂₃₁ quintiles compared to the lowest quintile. Significant and consistent results were obtained in the QFS validation sample for both the linear trend test (OR_trend = 1.16 [95% CI, 1.07-1.26]; P = 6.7x10^-4), and obesity prevalence across quintiles. These results were partially replicated in the FAS sample (OR_trend = 1.12 [95% CI, 1.02-1.24]; P = 2.2x10^-2). PRS₂₃₁ explained 7.5%, 3.2%, and 1.2% of BMI variance in QFS discovery, QFS validation, and FAS samples, respectively. Conclusions: These results revealed that genetic background in the form of a 231 BMI-associated PRS has a significant impact on obesity, but a limited potential to accurately stratify it. Further studies are encouraged on larger populations.