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

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Title: A new highly penetrant form of obesity due to deletions on chromosome 16p11.2
Authors: Walters, RG
Jacquemont, S
Valsesia, A
De Smith, AJ
Martinet, D
Andersson, J
Falchi, M
Chen, F
Andrieux, J
Lobbens, S
Delobel, B
Stutzmann, F
El-Sayed Moustafa, JS
Chevre, JC
Lecoeur, C
Vatin, V
Bouquillon, S
Buxton, JL
Boute, O
Holder-Espinasse, M
Cuisset, JM
Lemaitre, MP
Ambresin, AE
Brioschi, A
Gaillard, M
Giusti, V
Fellmann, F
Ferrarini, A
Hadjikhani, N
Campion, D
Guilmatre, A
Goldenberg, A
Calmels, N
Mandel, JL
Le Caignec, C
David, A
Isidor, B
Cordier, MP
Dupuis-Girod, S
Labalme, A
Sanlaville, D
Beri-Dexheimer, M
Jonveaux, P
Leheup, B
Ounap, K
Bochukova, EG
Henning, E
Keogh, J
Ellis, RJ
Macdermot, KD
Van Haelst, MM
Vincent-Delorme, C
Plessis, G
Touraine, R
Philippe, A
Malan, V
Mathieu-Dramard, M
Chiesa, J
Blaumeiser, B
Kooy, RF
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, AL
McCarthy, MI
Peltonen, L
Carlsson, L
Jacobson, P
Sjostrom, L
Huang, N
Hurles, ME
O'Rahilly, S
Farooqi, IS
Mannik, K
Jarvelin, MR
Pattou, F
Meyre, D
Walley, AJ
Coin, LJ
Blakemore, AI
Froguel, P
Beckmann, JS
Item Type: Journal Article
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.
Issue Date: 4-Feb-2010
Date of Acceptance: 1-Dec-2009
URI: http://hdl.handle.net/10044/1/85527
DOI: 10.1038/nature08727
ISSN: 1476-4687
Publisher: Springer
Start Page: 671
End Page: 675
Journal / Book Title: Nature
Volume: 463
Copyright Statement: ©2010 Macmillan Publishers Limited. All rights reserved. The final publication is available at Springer via https://doi.org/10.1038/nature08727
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: G0600331
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
GENOME-WIDE ASSOCIATION
CIRCULAR BINARY SEGMENTATION
COPY NUMBER VARIATION
FRAMESHIFT MUTATION
RISK LOCI
MICRODELETION
AUTISM
SAMPLE
BIRTH
MC4R
Adolescent
Adult
Age of Onset
Aging
Body Mass Index
Case-Control Studies
Child
Chromosome Deletion
Chromosomes, Human, Pair 16
Cognition Disorders
Cohort Studies
Europe
Female
Genome-Wide Association Study
Heterozygote
Humans
Inheritance Patterns
Male
Mutation
Obesity
Penetrance
Reproducibility of Results
Sex Characteristics
Young Adult
Chromosomes, Human, Pair 16
Humans
Obesity
Chromosome Deletion
Body Mass Index
Case-Control Studies
Cohort Studies
Reproducibility of Results
Cognition Disorders
Age of Onset
Aging
Sex Characteristics
Heterozygote
Inheritance Patterns
Penetrance
Mutation
Adolescent
Adult
Child
Europe
Female
Male
Genome-Wide Association Study
Young Adult
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
General Science & Technology
Notes: 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 Chevre, 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 Beri-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 Sjostrom, L Huang, N Hurles, M E O'Rahilly, S Farooqi, I S Mannik, K Jarvelin, M-R Pattou, F Meyre, D Walley, A J Coin, L J M Blakemore, A I F Froguel, P Beckmann, J S 077014/Wellcome Trust/United Kingdom 079534/Wellcome Trust/United Kingdom 082390/Wellcome Trust/United Kingdom 089061/Wellcome Trust/United Kingdom 1RL1MH083268-01/MH/NIMH NIH HHS/United States 5R01HL087679-02/HL/NHLBI NIH HHS/United States 5R01MH63706:02/MH/NIMH NIH HHS/United States G0500539/Medical Research Council/United Kingdom G0600331(77796)/Medical Research Council/United Kingdom Wellcome Trust/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nature Nature. 2010 Feb 4;463(7281):671-5. 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.
Online Publication Date: 2010-02-04
Appears in Collections:Department of Immunology and Inflammation
Department of Metabolism, Digestion and Reproduction
Department of Infectious Diseases
Faculty of Medicine
School of Public Health