title: Large, rare chromosomal deletions associated with severe early-onset obesity.
abstract: Obesity is a highly heritable and genetically heterogeneous disorder. Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500 kilobases), rare (<1%) deletions were significantly enriched in patients compared to 7,366 controls (P < 0.001). We identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls. We identified five patients with overlapping deletions on chromosome 16p11.2 that were found in 2 out of 7,366 controls (P < 5 x 10(-5)). In three patients the deletion co-segregated with severe obesity. Two patients harboured a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism and mental retardation; both of these patients had mild developmental delay in addition to severe obesity. In an independent sample of 1,062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1, which is known to be involved in leptin and insulin signalling. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity.
authors: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors: Elena G
authors: EG
authors: Bochukova
authors: Ni
authors: N
authors: Huang
authors: Julia
authors: J
authors: Keogh
authors: Elana
authors: E
authors: Henning
authors: Carolin
authors: C
authors: Purmann
authors: Kasia
authors: K
authors: Blaszczyk
authors: Sadia
authors: S
authors: Saeed
authors: Julian
authors: J
authors: Hamilton-Shield
authors: Jill
authors: J
authors: Clayton-Smith
authors: Stephen
authors: S
authors: O'Rahilly
authors: Matthew E
authors: ME
authors: Hurles
authors: I Sadaf
authors: IS
authors: Farooqi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D017668:Age of Onset; D002648:Child; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D006963:Hyperphagia / Q000235:genetics; D040582:Inheritance Patterns / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009765:Obesity / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D006113:United Kingdom / Q000453:epidemiology; D044465:White People
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C518910:SH2B1 protein, human