CNV analysis and mutation screening indicate an important role for the NPY4R gene in human obesity

• Published in: Obesity (Silver Spring, Md.) Vol. 24; no. 4; pp. 970 - 976
• Main Authors: Aerts, Evi, Beckers, Sigri, Zegers, Doreen, Van Hoorenbeeck, Kim, Massa, Guy, Verrijken, An, Verhulst, Stijn L., Van Gaal, Luc F., Van Hul, Wim
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.04.2016
• Subjects: Adolescent; Adult; Body Weight - genetics; Child; DNA Copy Number Variations; DNA Mutational Analysis; Female; Genes; Humans; Male; Mutation; Obesity; Pediatric Obesity - genetics; Receptors, Neuropeptide Y - genetics; Teenagers
• DOI: 10.1002/oby.21435
• ISSN: 1930-7381

Objective Genome‐wide copy number variation (CNV) analyses have associated the 10q11.22 CNV with obesity. As the NPY4R gene is the most interesting candidate gene in this region, it was hypothesized that both genetic and structural variation in NPY4R might be implicated in the pathogenesis of obesity. Methods In the first part of this study, 326 children and adolescents with obesity and 298 healthy lean individuals were screened for CNV in the NPY4R‐containing chr.10q11.22 region. In the second part of this study, a mutation screen for variants in the NPY4R coding region was performed in 356 children and adolescents with obesity and 337 healthy lean adults. Results Our CNV analysis demonstrated a significantly higher frequency of NPY4R containing 10q11.22 CNV loss in the patient population (P = 0.0003), while CNV gain in this region was more prevalent in the control population (P = 0.031). Mutation analysis resulted in the identification of 15 rare non‐synonymous heterozygous variants. For two variants that could only be identified in the patient population, receptor dysfunction and thus a pathogenic effect were demonstrated. Conclusions In conclusion, these data support an essential role for genetic and structural variation within the NPY4R gene in the pathogenesis of obesity.