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

Details

Serval ID
serval:BIB_779A2B29ACBA
Type
Article: article from journal or magazin.
Collection
Publications
Title
A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.
Journal
Nature
Author(s)
Walters R.G., Jacquemont S., Valsesia A., de Smith A.J., Martinet D., Andersson J., Falchi M., Chen F., Andrieux J., Lobbens S., Delobel B., Stutzmann F., El-Sayed Moustafa J.S., Chèvre J.C., Lecoeur C., Vatin V., Bouquillon S., Buxton J.L., Boute O., Holder-Espinasse M., Cuisset J.M., Lemaitre M.P., Ambresin A.E., Brioschi A., Gaillard M., Giusti V., Fellmann F., Ferrarini A., Hadjikhani N., Campion D., Guilmatre A., Goldenberg A., Calmels N., Mandel J.L., Le Caignec C., David A., Isidor B., Cordier M.P., Dupuis-Girod S., Labalme A., Sanlaville D., Béri-Dexheimer M., Jonveaux P., Leheup B., Ounap K., Bochukova E.G., Henning E., Keogh J., Ellis R.J., Macdermot K.D., van Haelst M.M., Vincent-Delorme C., Plessis G., Touraine R., Philippe A., Malan V., Mathieu-Dramard M., Chiesa J., Blaumeiser B., Kooy R.F., Caiazzo R., Pigeyre M., Balkau B., Sladek R., Bergmann S., Mooser V., Waterworth D., Reymond A., Vollenweider P., Waeber G., Kurg A., Palta P., Esko T., Metspalu A., Nelis M., Elliott P., Hartikainen A.L., McCarthy M.I., Peltonen L., Carlsson L., Jacobson P., Sjöström L., Huang N., Hurles M.E., O'Rahilly S., Farooqi I.S., Männik K., Jarvelin M.R., Pattou F., Meyre D., Walley A.J., Coin L.J., Blakemore A.I., Froguel P., Beckmann J.S.
ISSN
1476-4687[electronic], 0028-0836[linking]
Publication state
Published
Issued date
2010
Peer-reviewed
Oui
Volume
463
Number
7281
Pages
671-675
Language
english
Abstract
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.
Keywords
Adolescent, Adult, Age of Onset, Aging, Body Mass Index, Case-Control Studies, Child, Chromosome Deletion, Chromosomes, Human, Pair 16/genetics, Cognition Disorders/complications, Cognition Disorders/genetics, Cohort Studies, Type="Geographic">Europe, Female, Genome-Wide Association Study, Heterozygote, Humans, Inheritance Patterns/genetics, Male, Mutation/genetics, Obesity/complications, Obesity/genetics, Penetrance, Reproducibility of Results, Sex Characteristics, Young Adult , Colaus Study
Pubmed
Web of science
Create date
09/02/2010 14:05
Last modification date
20/08/2019 15:34
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