Large copy-number variations are enriched in cases with moderate to extreme obesity.

Abstract

Obesity is an increasingly common disorder that predisposes to several medical conditions, including type 2 diabetes. We investigated whether large and rare copy-number variations (CNVs) differentiate moderate to extreme obesity from never-overweight control subjects. Using single nucleotide polymorphism (SNP) arrays, we performed a genome-wide CNV survey on 430 obese case subjects (BMI >35 kg/m(2)) and 379 never-overweight control subjects (BMI <25 kg/m(2)). All subjects were of European ancestry and were genotyped on the Illumina HumanHap550 arrays with ∼550,000 SNP markers. The CNV calls were generated by PennCNV software. CNVs >1 Mb were found to be overrepresented in case versus control subjects (odds ratio [OR] = 1.5 [95% CI 0.5-5]), and CNVs >2 Mb were present in 1.3% of the case subjects but were absent in control subjects (OR = infinity [95% CI 1.2-infinity]). When focusing on rare deletions that disrupt genes, even more pronounced effect sizes are observed (OR = 2.7 [95% CI 0.5-27.1] for CNVs >1 Mb). Interestingly, obese case subjects who carry these large CNVs have moderately high BMI and do not appear to be extreme cases. Several CNVs disrupt known candidate genes for obesity, such as a 3.3-Mb deletion disrupting NAP1L5 and a 2.1-Mb deletion disrupting UCP1 and IL15. Our results suggest that large CNVs, especially rare deletions, confer risk of obesity in patients with moderate obesity and that genes impacted by large CNVs represent intriguing candidates for obesity that warrant further study.