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Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Jacquemont, Sébastien and Reymond, Alexandre and Zufferey, Flore and Harewood, Louise and Walters, Robin G. and Kutalik, Zoltán and Martinet, Danielle and Shen, Yiping and Valsesia, Armand and Beckmann, Noam D. and Thorleifsson, Gudmar and Belfiore, Marco and Bouquillon, Sonia and Campion, Dominique and de Leeuw, Nicole and de Vries, Bert B. A. and Esko, Tõnu and Fernandez, Bridget A. and Fernández-Aranda, Fernando and Fernández-Real, José Manuel and Gratacòs, Mònica and Guilmatre, Audrey and Hoyer, Juliane and Jarvelin, Marjo-Riitta and Kooy, R. Frank and Kurg, Ants and Le Caignec, Cédric and Männik, Katrin and Platt, Orah S. and Sanlaville, Damien and Van Haelst, Mieke M. and Villatoro Gomez, Sergi and Walha, Faida and Wu, Bai-Lin and Yu, Yongguo and Aboura, Azzedine and Addor, Marie-Claude and Alembik, Yves and Antonarakis, Stylianos E. and Arveiler, Benoît and Barth, Magalie and Bednarek, Nathalie and Béna, Frédérique and Bergmann, Sven and Beri, Mylène and Bernardini, Laura and Blaumeiser, Bettina and Bonneau, Dominique and Bottani, Armand and Boute, Odile and Brunner, Han G. and Cailley, Dorothée and Callier, Patrick and Chiesa, Jean and Chrast, Jacqueline and Coin, Lachlan and Coutton, Charles and Cuisset, Jean-Marie and Cuvellier, Jean-Christophe and David, Albert and de Freminville, Bénédicte and Delobel, Bruno and Delrue, Marie-Ange and Demeer, Bénédicte and Descamps, Dominique and Didelot, Gérard and Dieterich, Klaus and Disciglio, Vittoria and Doco-Fenzy, Martine and Drunat, Séverine and Duban-Bedu, Bénédicte and Dubourg, Christèle and El-Sayed Moustafa, Julia S. and Elliott, Paul and Faas, Brigitte H. W. and Faivre, Laurence and Faudet, Anne and Fellmann, Florence and Ferrarini, Alessandra and Fisher, Richard and Flori, Elisabeth and Forer, Lukas and Gaillard, Dominique and Gerard, Marion and Gieger, Christian and Gimelli, Stefania and Gimelli, Giorgio and Grabe, Hans J. and Guichet, Agnès and Guillin, Olivier and Hartikainen, Anna-Liisa and Heron, Délphine and Hippolyte, Loyse and Holder, Muriel and Homuth, Georg and Isidor, Bertrand and Jaillard, Sylvie and Jaros, Zdenek and Jiménez-Murcia, Susana and Helas, Géraldine Joly and Jonveaux, Philippe and Kaksonen, Satu and Keren, Boris and Kloss-Brandstätter, Anita and Knoers, Nine V. A. M. and Koolen, David A. and Kroisel, Peter M. and Kronenberg, Florian and Labalme, Audrey and Landais, Emilie and Lapi, Elisabetta and Layet, Valérie and Legallic, Solenn and Leheup, Bruno and Leube, Barbara and Lewis, Suzanne and Lucas, Josette and MacDermot, Kay D. and Magnusson, Pall and Marshall, Christian and Mathieu-Dramard, Michèle and McCarthy, Mark I. and Meitinger, Thomas and Mencarelli, Maria Antonietta and Merla, Giuseppe and Moerman, Alexandre and Mooser, Vincent and Morice-Picard, Fanny and Mucciolo, Mafalda and Nauck, Matthias and Ndiaye, Ndeye Coumba and Nordgren, Ann and Pasquier, Laurent and Petit, Florence and Pfundt, Rolph and Plessis, Ghislaine and Rajcan-Separovic, Evica and Ramelli, Gian Paolo and Rauch, Anita and Ravazzolo, Roberto and Reis, Andre and Renieri, Alessandra and Richart, Cristobal and Ried, Janina S. and Rieubland, Claudine and Roberts, Wendy and Roetzer, Katharina M. and Rooryck, Caroline and Rossi, Massimiliano and Saemundsen, Evald and Satre, Véronique and Schurmann, Claudia and Sigurdsson, Engilbert and Stavropoulos, Dimitri J. and Stefansson, Hreinn and Tengström, Carola and Thorsteinsdóttir, Unnur and Tinahones, Francisco J. and Touraine, Renaud and Vallée, Louis and van Binsbergen, Ellen and Van der Aa, Nathalie and Vincent-Delorme, Catherine and Visvikis-Siest, Sophie and Vollenweider, Peter and Völzke, Henry and Vulto-van Silfhout, Anneke T. and Waeber, Gérard and Wallgren-Pettersson, Carina and Witwicki, Robert M. and Zwolinksi, Simon and Andrieux, Joris and Estivill, Xavier and Gusella, James F. and Gustafsson, Omar and Metspalu, Andres and Scherer, Stephen W. and Stefansson, Kari and Blakemore, Alexandra I. F. and Beckmann, Jacques S. and Froguel, Philippe. (2011) Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature, Vol. 478, H. 7367. pp. 97-102.

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Official URL: http://edoc.unibas.ch/dok/A6004013

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Abstract

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ??18.5?kg?per?m(2) in adults and ??-2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ?600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB)
UniBasel Contributors:Ramelli, Gian Paolo
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Macmillan
ISSN:0028-0836
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:27 Feb 2014 15:45
Deposited On:27 Feb 2014 15:45

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