Affiliation:
1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Phoenix Arizona USA
2. International Laboratory for Human Genome Research National Autonomous University of Mexico, Campus Juriquilla Queretaro Mexico
3. Regeneron Genetics Center Tarrytown New York USA
Abstract
AbstractObjectiveRare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole‐exome sequence data from 6803 longitudinally studied individuals.MethodsExome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI z score > 2 (N = 279) but not observed in a child with a maximum BMI z score ≤ 0 (n = 1542) or that occurred in adults in the top 5th percentile of BMI (n = 263) but not in adults below the median BMI (n = 2629). Variants were then functionally analyzed using luciferase assays.ResultsThe comparisons between cases of obesity and controls identified eight missense variants in six genes: DYRK1B, KSR2, MC4R, NTRK2, PCSK1, and SIM1. Among these, MC4R p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that KSR2 p.I402F and p.T193I and NTRK2 p.S249Y alter protein function.ConclusionsIn addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers.