The relationship of genetic variation in biological pathways to longitudinal changes in body mass index among children and adolescents
Excess adiposity is a primary health concern for individuals in developed nations and may appear as early as childhood. Many common genetic variants have been identified for obesity and body mass index (BMI), but they cumulatively explain very little of the variation in these phenotypes. To better understand the biological mechanisms involved in weight changes, this study aimed to characterize the metabolic pathways affecting BMI during childhood and adolescence. Longitudinal BMI profiles and DNA samples were collected from two biracial cohort studies, the Bogalusa Heart Study (BHS) and Project HeartBeat! (PHB). Up to 128,141 single nucleotide polymorphisms (SNPs) were analyzed for each race based on candidate gene genotyping using two microarrays. Multilevel models of individual SNP effects and SNP-by-age interactions were constructed for white and black participants aged 8-18 years. Effect estimates from each cohort were combined between each race using meta-analysis and analyzed at the gene and pathway levels. After sensitivity analysis of the identified pathways, four KEGG pathways were significantly associated with longitudinal BMI changes: calcium signaling, neuroactive ligand-receptor interaction, toxoplasmosis, and glutathione metabolism. Integration of the pathway results with previous findings revealed a complex interactive network connecting pathway functions regulating BMI of children and adolescents. These findings support a complex signaling dynamic between ghrelin, neuropeptide Y, epinephrine, norepinephrine, acetylcholine, and pituitary adenylcyclase involving calcium signaling, cAMP formation, and the insulin-glucagon control of glucose levels. FTO and leptin were found to be linked to these pathways through functional implications with the identified genes. SNPs and genes significant for BMI changes in their respective analyses are also reported.
Richard, Melissa, "The relationship of genetic variation in biological pathways to longitudinal changes in body mass index among children and adolescents" (2014). Texas Medical Center Dissertations (via ProQuest). AAI3665233.