title: Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity.
abstract: 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.
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Wheeler
authors.forename: Ni
authors.initials: N
authors.lastname: Huang
authors.forename: Elena G
authors.initials: EG
authors.lastname: Bochukova
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Sarah
authors.initials: S
authors.lastname: Lindsay
authors.forename: Sumedha
authors.initials: S
authors.lastname: Garg
authors.forename: Elana
authors.initials: E
authors.lastname: Henning
authors.forename: Hannah
authors.initials: H
authors.lastname: Blackburn
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
mesh_terms: D015992:Body Mass Index; D016022:Case-Control Studies; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci
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