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

Abstract

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. To study the cumulative association of causal, regulatory, and tagged single nucleotide polymorphisms (SNPs) within genes involved in SCFA recognition and metabolism with obesity. Study participants were non-Hispanic White (NHW, n=270) and non-Hispanic Black (NHB, n=113) children (2-5years) 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. 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). 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.