Journal
NATURE
Volume 463, Issue 7281, Pages 671-U104Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08727
Keywords
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Categories
Funding
- Wellcome Trust
- Medical Research Council (MRC) [G0500539]
- Swiss National Foundation [310000-112552, 33CSCO-122661]
- RCUK
- Swiss National Fund [320030_122674]
- Synapsis Foundation
- University of Lausanne
- Ludwig Institute for Cancer Research
- Swiss Institute of Bioinformatics
- le Conseil Regional Nord Pas de Calais/FEDER
- GlaxoSmithKline
- Faculty of Biology and Medicine of Lausanne
- Estonian Government [SF0180142s08]
- EU
- FP7 [201413 ENGAGE, 212111 BBMRI]
- ECOGENE [205419]
- Genome Canada
- Genome Quebec
- Swedish Research Council [K2008-65X-20753-01-4, K2007-55X-11285-13, 529-2002-6671]
- Swedish Foundation for Strategic Research
- Swedish Diabetes Foundation
- Ake Wiberg Foundation
- Foundations of the National Board of Health and Welfare
- Jeansson Foundations
- Magn Bergvall Foundation
- Tore Nilson Foundation
- Royal Physiographic Society
- INNOVA-VINNMER
- Swedish federal government
- INSERM
- CNAMTS
- Lilly
- Novartis Pharma
- Sanofi-Aventis
- Association Diabete Risque Vasculaire
- Federation Francaise de Cardiologie
- La Fondation de France
- ALFEDIAM
- ONIVINS
- Ardix Medical, Bayer Diagnostics
- Becton Dickinson
- Cardionics
- Merck Sante
- Novo Nordisk
- Pierre Fabre
- Roche and Topcon
- Academy of Finland [104781, 120315]
- University Hospital Oulu
- Biocenter, University of Oulu, Finland
- European Commission [QLG1-CT-2000-01643]
- NHLBI [5R01HL087679-02, 1RL1MH083268-01]
- NIH/NIMH [5R01MH63706: 02]
- ENGAGE [HEALTH-F4-2007-201413]
- [SF0180026s09]
- Medical Research Council [G0600331, G0900554] Funding Source: researchfish
- Swiss National Science Foundation (SNF) [320030_122674] Funding Source: Swiss National Science Foundation (SNF)
- MRC [G0600331, G0900554] Funding Source: UKRI
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Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution(1). Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component(1). Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge(2). Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >= 40 kg m(-2) or BMI standard deviation score >= 4; P = 6.43 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme'(4) in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
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