Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity

Nat Genet. 2013 May;45(5):513-7. doi: 10.1038/ng.2607. Epub 2013 Apr 7.


Common and rare variants associated with body mass index (BMI) and obesity account for <5% of the variance in BMI. We performed SNP and copy number variation (CNV) association analyses in 1,509 children with obesity at the extreme tail (>3 s.d. from the mean) of the BMI distribution and 5,380 controls. Evaluation of 29 SNPs (P < 1 × 10(-5)) in an additional 971 severely obese children and 1,990 controls identified 4 new loci associated with severe obesity (LEPR, PRKCH, PACS1 and RMST). A previously reported 43-kb deletion at the NEGR1 locus was significantly associated with severe obesity (P = 6.6 × 10(-7)). However, this signal was entirely driven by a flanking 8-kb deletion; absence of this deletion increased risk for obesity (P = 6.1 × 10(-11)). We found a significant burden of rare, single CNVs in severely obese cases (P < 0.0001). Integrative gene network pathway analysis of rare deletions indicated enrichment of genes affecting G protein-coupled receptors (GPCRs) involved in the neuronal regulation of energy homeostasis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Mass Index
  • Case-Control Studies
  • Child
  • DNA Copy Number Variations / genetics*
  • Genetic Predisposition to Disease*
  • Genome, Human*
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Obesity / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Quantitative Trait Loci*