Abstract
Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≥18.5 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 ∼4600-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.
| Original language | English |
|---|---|
| Pages (from-to) | 97-102 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 478 |
| Issue number | 7367 |
| DOIs | |
| State | Published - 6 Oct 2011 |
| Externally published | Yes |
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In: Nature, Vol. 478, No. 7367, 06.10.2011, p. 97-102.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus
AU - Jacquemont, Sébastien
AU - Reymond, Alexandre
AU - Zufferey, Flore
AU - Harewood, Louise
AU - Walters, Robin G.
AU - Kutalik, Zoltán
AU - Martinet, Danielle
AU - Shen, Yiping
AU - Valsesia, Armand
AU - Beckmann, Noam D.
AU - Thorleifsson, Gudmar
AU - Belfiore, Marco
AU - Bouquillon, Sonia
AU - Campion, Dominique
AU - De Leeuw, Nicole
AU - De Vries, Bert B.A.
AU - Esko, Tõnu
AU - Fernandez, Bridget A.
AU - Fernández-Aranda, Fernando
AU - Fernández-Real, José Manuel
AU - Gratacós, Mónica
AU - Guilmatre, Audrey
AU - Hoyer, Juliane
AU - Jarvelin, Marjo Riitta
AU - Frank Kooy, R.
AU - Kurg, Ants
AU - Le Caignec, Cédric
AU - Männik, Katrin
AU - Platt, Orah S.
AU - Sanlaville, Damien
AU - Van Haelst, Mieke M.
AU - Villatoro Gomez, Sergi
AU - Walha, Faida
AU - Wu, Bai Lin
AU - Yu, Yongguo
AU - Aboura, Azzedine
AU - Addor, Marie Claude
AU - Alembik, Yves
AU - Antonarakis, Stylianos E.
AU - Arveiler, Benoît
AU - Barth, Magalie
AU - Bednarek, Nathalie
AU - Béna, Frédérique
AU - Bergmann, Sven
AU - Beri, Myléne
AU - Bernardini, Laura
AU - Blaumeiser, Bettina
AU - Bonneau, Dominique
AU - Bottani, Armand
AU - Boute, Odile
AU - Brunner, Han G.
AU - Cailley, Dorothée
AU - Callier, Patrick
AU - Chiesa, Jean
AU - Chrast, Jacqueline
AU - Coin, Lachlan
AU - Coutton, Charles
AU - Cuisset, Jean Marie
AU - Cuvellier, Jean Christophe
AU - David, Albert
AU - De Freminville, Bénédicte
AU - Delobel, Bruno
AU - Delrue, Marie Ange
AU - Demeer, Bénédicte
AU - Descamps, Dominique
AU - Didelot, Gérard
AU - Dieterich, Klaus
AU - Disciglio, Vittoria
AU - Doco-Fenzy, Martine
AU - Drunat, Séverine
AU - Duban-Bedu, Bénédicte
AU - Dubourg, Christéle
AU - El-Sayed Moustafa, Julia S.
AU - Elliott, Paul
AU - Faas, Brigitte H.W.
AU - Faivre, Laurence
AU - Faudet, Anne
AU - Fellmann, Florence
AU - Ferrarini, Alessandra
AU - Fisher, Richard
AU - Flori, Elisabeth
AU - Forer, Lukas
AU - Gaillard, Dominique
AU - Gerard, Marion
AU - Gieger, Christian
AU - Gimelli, Stefania
AU - Gimelli, Giorgio
AU - Grabe, Hans J.
AU - Guichet, Agnés
AU - Guillin, Olivier
AU - Hartikainen, Anna Liisa
AU - Heron, Délphine
AU - Hippolyte, Loyse
AU - Holder, Muriel
AU - Homuth, Georg
AU - Isidor, Bertrand
AU - Jaillard, Sylvie
AU - Jaros, Zdenek
AU - Jiménez, Susana
AU - Joly Helas, Géraldine
AU - Jonveaux, Philippe
AU - Kaksonen, Satu
AU - Keren, Boris
AU - Kloss-Brandstätter, Anita
AU - Knoers, Nine V.A.M.
AU - Koolen, David A.
AU - Kroisel, Peter M.
AU - Kronenberg, Florian
AU - Labalme, Audrey
AU - Landais, Emilie
AU - Lapi, Elisabetta
AU - Layet, Valérie
AU - Legallic, Solenn
AU - Leheup, Bruno
AU - Leube, Barbara
AU - Lewis, Suzanne
AU - Lucas, Josette
AU - MacDermot, Kay D.
AU - Magnusson, Pall
AU - Marshall, Christian
AU - Mathieu-Dramard, Michéle
AU - McCarthy, Mark I.
AU - Meitinger, Thomas
AU - Antonietta Mencarelli, Maria
AU - Merla, Giuseppe
AU - Moerman, Alexandre
AU - Mooser, Vincent
AU - Morice-Picard, Fanny
AU - Mucciolo, Mafalda
AU - Nauck, Matthias
AU - Coumba Ndiaye, Ndeye
AU - Nordgren, Ann
AU - Pasquier, Laurent
AU - Petit, Florence
AU - Pfundt, Rolph
AU - Plessis, Ghislaine
AU - Rajcan-Separovic, Evica
AU - Paolo Ramelli, Gian
AU - Rauch, Anita
AU - Ravazzolo, Roberto
AU - Reis, Andre
AU - Renieri, Alessandra
AU - Richart, Cristobal
AU - Ried, Janina S.
AU - Rieubland, Claudine
AU - Roberts, Wendy
AU - Roetzer, Katharina M.
AU - Rooryck, Caroline
AU - Rossi, Massimiliano
AU - Saemundsen, Evald
AU - Satre, Véronique
AU - Schurmann, Claudia
AU - Sigurdsson, Engilbert
AU - Stavropoulos, Dimitri J.
AU - Stefansson, Hreinn
AU - Tengström, Carola
AU - Thorsteinsdóttir, Unnur
AU - Tinahones, Francisco J.
AU - Touraine, Renaud
AU - Vallée, Louis
AU - Van Binsbergen, Ellen
AU - Van Der Aa, Nathalie
AU - Vincent-Delorme, Catherine
AU - Visvikis-Siest, Sophie
AU - Vollenweider, Peter
AU - Völzke, Henry
AU - Vulto-Van Silfhout, Anneke T.
AU - Waeber, Gérard
AU - Wallgren-Pettersson, Carina
AU - Witwicki, Robert M.
AU - Zwolinksi, Simon
AU - Andrieux, Joris
AU - Estivill, Xavier
AU - Gusella, James F.
AU - Gustafsson, Omar
AU - Metspalu, Andres
AU - Scherer, Stephen W.
AU - Stefansson, Kari
AU - Blakemore, Alexandra I.F.
AU - Beckmann, Jacques S.
AU - Froguel, Philippe
N1 - Funding Information: Acknowledgements We thank the Vital-IT high-performance computing centre of the Swiss Instituteof Bioinformatics.S.J. isrecipientof a boursede relève académiquedela Faculté de Biologie et Médecine de l’Université de Lausanne. This work was supported by the Leenaards Foundation Prize (S.J., D.M. and A.Reymond), the Jérôme Lejeune Foundation (A.Reymond), the Telethon Action Suisse Foundation (A.Reymond), the Swiss National Science Foundation (A.Reymond, J.S.B., S.B. and S.E.A.), a Swiss National Science Foundation Sinergia grant (S.J., D.M., S.B., J.S.B. and A.Reymond), the European Commission anEUploidy Integrated Project grant 037627 (A.Reymond, S.B., X.E., H.G.B. and S.E.A.), the Ludwig Institute for Cancer Research (A.V.), the Swiss Institute of Bioinformatics (S.B. and Z.K.), an Imperial College Department of Medicine PhD studentship (J.S.E.-S.M), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (P.E.), the Wellcome Trust and the Medical Research Council (A.I.F.B. and P.F.), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) (A.Reis), European Union-FEDER (PI081714, PS09/01778) (F.F.A., M.G. and X.E.), SAF2008-02278 (C.R.), the Belgian National Fund for Scientific Research, Flanders (N.V.A. and R.F.K.), the Dutch Organisation for Health Research and Development (ZON-MW grant 917-86-319) and Hersenstichting Nederland (B.B.A.d.V.), grant 81000346 from the Chinese National Natural Science Foundation (Y.G.Y.), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (J.F.G.), and Oesterreichische Nationalbank (OENB) grant 13059 (A.K.-B.). Y.S. holds a Young Investigator Award from the Children’s Tumor Foundation and a Catalyst Award from Harvard Medical School. B.L.W. holds a Fudan Scholar Research Award from Fudan University, a grant from Chinese National ‘973’ project on Population and Health (2010CB529601) and a grant from the Science and Technology Council of Shanghai (09JC1402400). E.R.S. and S.L., recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. The Estonian Genome Center of the University of Tartu (EGCUT) received support from the EU Centre of Excellence in Genomics and FP7 grants 201413 and 245536, and from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (A.M., K.M. and A.K.). D.S. thanks the Direction Générale de l’Organisation des Soins from the French Ministry of Health for their support in the development of several array-CGH platforms, and the Centres Labellisés Anomalies duDevelopment in France. TheHelmholtzZentrum Munichandthe State of Bavaria financed the KORA study, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). S.W.S. holds the GlaxoSmithKline-Canadian Institutes of Health Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children, and is supported by Genome Canada and the McLaughlin Centre. Funding for deCODE came in part from NIH grant MH071425 (K.S.), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds. NFBC1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/ NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the Medical Research Council, UK (G0500539, G0600705, PrevMetSyn/SALVE). The DNA extractions, sample quality controls, biobank up-keeping and aliquotting was performed in the National Public Health Institute, Biomedicum Helsinki, Finland and supported financially by the Academy of Finland and Biocentrum Helsinki. We thank M. Hass, Z. Jaros, M. Jussila, M. Koiranen, P. Rantakallio, M. C. Rudolf, V. Soo, O. Tornwall, S. Vaara, T. Ylitalo and the French DHOS national CGH network for their help, as well as all participating patients and clinicians. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2011/10/6
Y1 - 2011/10/6
N2 - Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≥18.5 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 ∼4600-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.
AB - Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≥18.5 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 ∼4600-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.
UR - https://www.scopus.com/pages/publications/80053920983
U2 - 10.1038/nature10406
DO - 10.1038/nature10406
M3 - Article
C2 - 21881559
AN - SCOPUS:80053920983
SN - 0028-0836
VL - 478
SP - 97
EP - 102
JO - Nature
JF - Nature
IS - 7367
ER -