High-frequency variants in PKA signaling-related genes within a large pediatric cohort with obesity or metabolic abnormalities

INTRODUCTION: Pediatric obesity has steadily increased in recent decades. Large-scale genome-wide association studies (GWAS) conducted primarily in Eurocentric adult populations have identified approximately 100 loci that predispose to obesity and type II diabetes. GWAS in children and individuals of non-European descent, both disproportionately affected by obesity, are fewer. Rare syndromic and monogenic obesities account for only a small portion of childhood obesity, so understanding the role of other genetic variants and their combinations in heritable obesities is key to developing targeted and personalized therapies. Tight and responsive regulation of the cAMP-dependent protein kinase (PKA) signaling pathway is crucial to maintaining healthy energy metabolism, and mutations in PKA-linked genes represent the most common cause of monogenic obesity. METHODS: For this study, we performed targeted exome sequencing of 53 PKA signaling-related genes to identify variants in genomic DNA from a large, ethnically diverse cohort of obese or metabolically challenged youth. RESULTS: We confirmed 49 high-frequency variants, including a novel variant in the PDE11A gene (c.152C>T). Several other variants were associated with metabolic characteristics within ethnic groups. DISCUSSION: We conclude that a PKA pathway-specific variant search led to the identification of several new genetic associations with obesity in an ethnically diverse population.