Genetic risk scores demonstrate the cumulative association of single nucleotide polymorphisms in gut microbiome-related genes with obesity phenotypes in preschool age children

Background: Childhood obesity is a nutrition-related disease with multiple underlying aetiologies. While genetic factors contribute to obesity, the gut microbiome is also implicated through fermentation of nondigestible polysaccharides to short-chain fatty acids (SCFA), which provide some energy to the host and are postulated to act as signalling molecules to affect expression of gut hormones. Objective: To study the cumulative association of causal, regulatory, and tagged single nucleotide polymorphisms (SNPs) within genes involved in SCFA recognition and metabolism with obesity. Design: Study participants were non-Hispanic White (NHW, n = 270) and non-Hispanic Black (NHB, n = 113) children (2-5 years) from the Synergistic Theory and Research on Obesity and Nutrition Group (STRONG) Kids 1 Study. SNP variables were assigned values according to the additive, dominant, or recessive inheritance models. Weighted genetic risk scores (GRS) were constructed by multiplying the reassigned values by independently generated β-coefficients or by summing the β-coefficients. Ethnicity-specific SNPs were selected for inclusion in GRS by cohort. Results: GRS were directly associated with body mass index (BMI) z-score. The models explained 3.75%, 12.9%, and 26.7% of the variance for NHW/NHB, NHW, and NHB (β = 0.89 [CI: 0.43-1.35], P = 0.0002; β = 0.78 [CI: 0.54-1.03], P < 0.0001; β = 0.74 [CI: 0.51–0.97], P < 0.0001). Conclusion: This analysis supports the cumulative association of several candidate genetic variants selected for their role in SCFA signalling, transport, and metabolism with early-onset obesity. These data strengthen the concept that microbiome influences obesity development through host genes interacting with SCFA.