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

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. and Beckmann, J. S. (2010) A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature, 463 7281: 671-675. doi:10.1038/nature08727

Author 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.
Title A new highly penetrant form of obesity due to deletions on chromosome 16p11.2
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
Publication date 2010-02-04
Year available 2010
Sub-type Article (original research)
DOI 10.1038/nature08727
Open Access Status Not yet assessed
Volume 463
Issue 7281
Start page 671
End page 675
Total pages 5
Place of publication London, United Kingdom
Publisher Nature
Language eng
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) τ40 kg m-2 or BMI standard deviation score ≥4; P = 6.4 × 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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID G0500539
201413 ENGAGE
5R01MH63706: 02
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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