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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Journal article
Authors R G Walters
S Jacquemont
A Valsesia
A J de Smith
D Martinet
J Andersson
M Falchi
F Chen
J Andrieux
S Lobbens
B Delobel
F Stutzmann
J S El-Sayed Moustafa
J-C Chèvre
C Lecoeur
V Vatin
S Bouquillon
J L Buxton
O Boute
M Holder-Espinasse
J-M Cuisset
M-P Lemaitre
A-E Ambresin
A Brioschi
M Gaillard
V Giusti
F Fellmann
A Ferrarini
N Hadjikhani
D Campion
A Guilmatre
A Goldenberg
N Calmels
J-L Mandel
C Le Caignec
A David
B Isidor
M-P Cordier
S Dupuis-Girod
A Labalme
D Sanlaville
M Béri-Dexheimer
P Jonveaux
B Leheup
K Ounap
E G Bochukova
E Henning
J Keogh
R J Ellis
K D Macdermot
M M van Haelst
C Vincent-Delorme
G Plessis
R Touraine
A Philippe
V Malan
M Mathieu-Dramard
J Chiesa
B Blaumeiser
R F Kooy
R Caiazzo
M Pigeyre
B Balkau
R Sladek
S Bergmann
V Mooser
D Waterworth
A Reymond
P Vollenweider
G Waeber
A Kurg
P Palta
T Esko
A Metspalu
M Nelis
P Elliott
A-L Hartikainen
M I McCarthy
L Peltonen
Lena M S Carlsson
Peter Jacobson
Lars Sjöström
N Huang
M E Hurles
S O'Rahilly
I S Farooqi
K Männik
M-R Jarvelin
F Pattou
D Meyre
A J Walley
L J M Coin
A I F Blakemore
P Froguel
J S Beckmann
Published in Nature
Volume 463
Issue 7281
Pages 671-5
ISSN 1476-4687
Publication year 2010
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 671-5
Language en
Keywords Adolescent, Adult, Age of Onset, Aging, Body Mass Index, Case-Control Studies, Child, Chromosome Deletion, Chromosomes, Human, Pair 16, genetics, Cognition Disorders, complications, genetics, Cohort Studies, Europe, Female, Genome-Wide Association Study, Heterozygote, Humans, Inheritance Patterns, genetics, Male, Mutation, genetics, Obesity, complications, genetics, physiopathology, Penetrance, Reproducibility of Results, Sex Characteristics, Young Adult
Subject categories Molecular medicine (genetics and pathology)


Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. 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. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. 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) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 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' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

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