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

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

Research output: Contribution to journalArticle

256 Citations (Scopus)

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 languageEnglish
Pages (from-to)97-102
Number of pages6
JournalNature
Volume478
Issue number7367
DOIs
Publication statusPublished - 6 Oct 2011
Externally publishedYes

Fingerprint

Gene Dosage
Thinness
Body Mass Index
Chromosomes
Failure to Thrive
Obesity
Intellectual Disability
Phenotype
Chromosomes, Human, Pair 16
Hyperphagia
Developmental Disabilities
Morbid Obesity
Chromosome Mapping
Anorexia Nervosa
Feeding Behavior
Psychiatry
MASS syndrome
Head
Weights and Measures
Mortality

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Jacquemont, S., Reymond, A., Zufferey, F., Harewood, L., Walters, R. G., Kutalik, Z., ... Froguel, P. (2011). Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature, 478(7367), 97-102. https://doi.org/10.1038/nature10406

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

In: Nature, Vol. 478, No. 7367, 06.10.2011, p. 97-102.

Research output: Contribution to journalArticle

Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, RG, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, ND, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, De Leeuw, N, De Vries, BBA, Esko, T, Fernandez, BA, Fernández-Aranda, F, Fernández-Real, JM, Gratacós, M, Guilmatre, A, Hoyer, J, Jarvelin, MR, Frank Kooy, R, Kurg, A, Le Caignec, C, Männik, K, Platt, OS, Sanlaville, D, Van Haelst, MM, Villatoro Gomez, S, Walha, F, Wu, BL, Yu, Y, Aboura, A, Addor, MC, Alembik, Y, Antonarakis, SE, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, HG, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, JM, Cuvellier, JC, David, A, De Freminville, B, Delobel, B, Delrue, MA, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, JS, Elliott, P, Faas, BHW, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, HJ, Guichet, A, Guillin, O, Hartikainen, AL, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez, S, Joly Helas, G, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, NVAM, Koolen, DA, Kroisel, PM, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, MacDermot, KD, Magnusson, P, Marshall, C, Mathieu-Dramard, M, McCarthy, MI, Meitinger, T, Antonietta Mencarelli, M, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Coumba Ndiaye, N, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Paolo Ramelli, G, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, JS, Rieubland, C, Roberts, W, Roetzer, KM, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, DJ, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, FJ, Touraine, R, Vallée, L, Van Binsbergen, E, Van Der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-Van Silfhout, AT, Waeber, G, Wallgren-Pettersson, C, Witwicki, RM, Zwolinksi, S, Andrieux, J, Estivill, XP, Gusella, JF, Gustafsson, O, Metspalu, A, Scherer, SW, Stefansson, K, Blakemore, AIF, Beckmann, JS & Froguel, P 2011, 'Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus', Nature, vol. 478, no. 7367, pp. 97-102. https://doi.org/10.1038/nature10406
Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG, Kutalik Z et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature. 2011 Oct 6;478(7367):97-102. https://doi.org/10.1038/nature10406
Jacquemont, Sébastien ; Reymond, Alexandre ; Zufferey, Flore ; Harewood, Louise ; Walters, Robin G. ; Kutalik, Zoltán ; Martinet, Danielle ; Shen, Yiping ; Valsesia, Armand ; Beckmann, Noam D. ; Thorleifsson, Gudmar ; Belfiore, Marco ; Bouquillon, Sonia ; Campion, Dominique ; De Leeuw, Nicole ; De Vries, Bert B A ; Esko, Tõnu ; Fernandez, Bridget A. ; Fernández-Aranda, Fernando ; Fernández-Real, José Manuel ; Gratacós, Mónica ; Guilmatre, Audrey ; Hoyer, Juliane ; Jarvelin, Marjo Riitta ; Frank Kooy, R. ; Kurg, Ants ; Le Caignec, Cédric ; Männik, Katrin ; Platt, Orah S. ; Sanlaville, Damien ; Van Haelst, Mieke M. ; Villatoro Gomez, Sergi ; Walha, Faida ; Wu, Bai Lin ; Yu, Yongguo ; Aboura, Azzedine ; Addor, Marie Claude ; Alembik, Yves ; Antonarakis, Stylianos E. ; Arveiler, Benoît ; Barth, Magalie ; Bednarek, Nathalie ; Béna, Frédérique ; Bergmann, Sven ; Beri, Myléne ; Bernardini, Laura ; Blaumeiser, Bettina ; Bonneau, Dominique ; Bottani, Armand ; Boute, Odile ; Brunner, Han G. ; Cailley, Dorothée ; Callier, Patrick ; Chiesa, Jean ; Chrast, Jacqueline ; Coin, Lachlan ; Coutton, Charles ; Cuisset, Jean Marie ; Cuvellier, Jean Christophe ; David, Albert ; De Freminville, Bénédicte ; Delobel, Bruno ; Delrue, Marie Ange ; Demeer, Bénédicte ; Descamps, Dominique ; Didelot, Gérard ; Dieterich, Klaus ; Disciglio, Vittoria ; Doco-Fenzy, Martine ; Drunat, Séverine ; Duban-Bedu, Bénédicte ; Dubourg, Christéle ; El-Sayed Moustafa, Julia S. ; Elliott, Paul ; Faas, Brigitte H W ; Faivre, Laurence ; Faudet, Anne ; Fellmann, Florence ; Ferrarini, Alessandra ; Fisher, Richard ; Flori, Elisabeth ; Forer, Lukas ; Gaillard, Dominique ; Gerard, Marion ; Gieger, Christian ; Gimelli, Stefania ; Gimelli, Giorgio ; Grabe, Hans J. ; Guichet, Agnés ; Guillin, Olivier ; Hartikainen, Anna Liisa ; Heron, Délphine ; Hippolyte, Loyse ; Holder, Muriel ; Homuth, Georg ; Isidor, Bertrand ; Jaillard, Sylvie ; Jaros, Zdenek ; Jiménez, Susana ; Joly Helas, Géraldine ; Jonveaux, Philippe ; Kaksonen, Satu ; Keren, Boris ; Kloss-Brandstätter, Anita ; Knoers, Nine V A M ; Koolen, David A. ; Kroisel, Peter M. ; Kronenberg, Florian ; Labalme, Audrey ; Landais, Emilie ; Lapi, Elisabetta ; Layet, Valérie ; Legallic, Solenn ; Leheup, Bruno ; Leube, Barbara ; Lewis, Suzanne ; Lucas, Josette ; MacDermot, Kay D. ; Magnusson, Pall ; Marshall, Christian ; Mathieu-Dramard, Michéle ; McCarthy, Mark I. ; Meitinger, Thomas ; Antonietta Mencarelli, Maria ; Merla, Giuseppe ; Moerman, Alexandre ; Mooser, Vincent ; Morice-Picard, Fanny ; Mucciolo, Mafalda ; Nauck, Matthias ; Coumba Ndiaye, Ndeye ; Nordgren, Ann ; Pasquier, Laurent ; Petit, Florence ; Pfundt, Rolph ; Plessis, Ghislaine ; Rajcan-Separovic, Evica ; Paolo Ramelli, Gian ; Rauch, Anita ; Ravazzolo, Roberto ; Reis, Andre ; Renieri, Alessandra ; Richart, Cristobal ; Ried, Janina S. ; Rieubland, Claudine ; Roberts, Wendy ; Roetzer, Katharina M. ; Rooryck, Caroline ; Rossi, Massimiliano ; Saemundsen, Evald ; Satre, Véronique ; Schurmann, Claudia ; Sigurdsson, Engilbert ; Stavropoulos, Dimitri J. ; Stefansson, Hreinn ; Tengström, Carola ; Thorsteinsdóttir, Unnur ; Tinahones, Francisco J. ; Touraine, Renaud ; Vallée, Louis ; Van Binsbergen, Ellen ; Van Der Aa, Nathalie ; Vincent-Delorme, Catherine ; Visvikis-Siest, Sophie ; Vollenweider, Peter ; Völzke, Henry ; Vulto-Van Silfhout, Anneke T. ; Waeber, Gérard ; Wallgren-Pettersson, Carina ; Witwicki, Robert M. ; Zwolinksi, Simon ; Andrieux, Joris ; Estivill, Xavier P. ; Gusella, James F. ; Gustafsson, Omar ; Metspalu, Andres ; Scherer, Stephen W. ; Stefansson, Kari ; Blakemore, Alexandra I F ; Beckmann, Jacques S. ; Froguel, Philippe. / Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. In: Nature. 2011 ; Vol. 478, No. 7367. pp. 97-102.
@article{15cdce9344424fa29abe82c70b4ce307,
title = "Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus",
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.",
author = "S{\'e}bastien Jacquemont and Alexandre Reymond and Flore Zufferey and Louise Harewood and Walters, {Robin G.} and Zolt{\'a}n Kutalik and Danielle Martinet and Yiping Shen and Armand Valsesia and Beckmann, {Noam D.} and Gudmar Thorleifsson and Marco Belfiore and Sonia Bouquillon and Dominique Campion and {De Leeuw}, Nicole and {De Vries}, {Bert B A} and T{\~o}nu Esko and Fernandez, {Bridget A.} and Fernando Fern{\'a}ndez-Aranda and Fern{\'a}ndez-Real, {Jos{\'e} Manuel} and M{\'o}nica Gratac{\'o}s and Audrey Guilmatre and Juliane Hoyer and Jarvelin, {Marjo Riitta} and {Frank Kooy}, R. and Ants Kurg and {Le Caignec}, C{\'e}dric and Katrin M{\"a}nnik and Platt, {Orah S.} and Damien Sanlaville and {Van Haelst}, {Mieke M.} and {Villatoro Gomez}, Sergi and Faida Walha and Wu, {Bai Lin} and Yongguo Yu and Azzedine Aboura and Addor, {Marie Claude} and Yves Alembik and Antonarakis, {Stylianos E.} and Beno{\^i}t Arveiler and Magalie Barth and Nathalie Bednarek and Fr{\'e}d{\'e}rique B{\'e}na and Sven Bergmann and Myl{\'e}ne Beri and Laura Bernardini and Bettina Blaumeiser and Dominique Bonneau and Armand Bottani and Odile Boute and Brunner, {Han G.} and Doroth{\'e}e Cailley and Patrick Callier and Jean Chiesa and Jacqueline Chrast and Lachlan Coin and Charles Coutton and Cuisset, {Jean Marie} and Cuvellier, {Jean Christophe} and Albert David and {De Freminville}, B{\'e}n{\'e}dicte and Bruno Delobel and Delrue, {Marie Ange} and B{\'e}n{\'e}dicte Demeer and Dominique Descamps and G{\'e}rard Didelot and Klaus Dieterich and Vittoria Disciglio and Martine Doco-Fenzy and S{\'e}verine Drunat and B{\'e}n{\'e}dicte Duban-Bedu and Christ{\'e}le Dubourg and {El-Sayed Moustafa}, {Julia S.} and Paul Elliott and Faas, {Brigitte H W} and Laurence Faivre and Anne Faudet and Florence Fellmann and Alessandra Ferrarini and Richard Fisher and Elisabeth Flori and Lukas Forer and Dominique Gaillard and Marion Gerard and Christian Gieger and Stefania Gimelli and Giorgio Gimelli and Grabe, {Hans J.} and Agn{\'e}s Guichet and Olivier Guillin and Hartikainen, {Anna Liisa} and D{\'e}lphine Heron and Loyse Hippolyte and Muriel Holder and Georg Homuth and Bertrand Isidor and Sylvie Jaillard and Zdenek Jaros and Susana Jim{\'e}nez and {Joly Helas}, G{\'e}raldine and Philippe Jonveaux and Satu Kaksonen and Boris Keren and Anita Kloss-Brandst{\"a}tter and Knoers, {Nine V A M} and Koolen, {David A.} and Kroisel, {Peter M.} and Florian Kronenberg and Audrey Labalme and Emilie Landais and Elisabetta Lapi and Val{\'e}rie Layet and Solenn Legallic and Bruno Leheup and Barbara Leube and Suzanne Lewis and Josette Lucas and MacDermot, {Kay D.} and Pall Magnusson and Christian Marshall and Mich{\'e}le Mathieu-Dramard and McCarthy, {Mark I.} and Thomas Meitinger and {Antonietta Mencarelli}, Maria and Giuseppe Merla and Alexandre Moerman and Vincent Mooser and Fanny Morice-Picard and Mafalda Mucciolo and Matthias Nauck and {Coumba Ndiaye}, Ndeye and Ann Nordgren and Laurent Pasquier and Florence Petit and Rolph Pfundt and Ghislaine Plessis and Evica Rajcan-Separovic and {Paolo Ramelli}, Gian and Anita Rauch and Roberto Ravazzolo and Andre Reis and Alessandra Renieri and Cristobal Richart and Ried, {Janina S.} and Claudine Rieubland and Wendy Roberts and Roetzer, {Katharina M.} and Caroline Rooryck and Massimiliano Rossi and Evald Saemundsen and V{\'e}ronique Satre and Claudia Schurmann and Engilbert Sigurdsson and Stavropoulos, {Dimitri J.} and Hreinn Stefansson and Carola Tengstr{\"o}m and Unnur Thorsteinsd{\'o}ttir and Tinahones, {Francisco J.} and Renaud Touraine and Louis Vall{\'e}e and {Van Binsbergen}, Ellen and {Van Der Aa}, Nathalie and Catherine Vincent-Delorme and Sophie Visvikis-Siest and Peter Vollenweider and Henry V{\"o}lzke and {Vulto-Van Silfhout}, {Anneke T.} and G{\'e}rard Waeber and Carina Wallgren-Pettersson and Witwicki, {Robert M.} and Simon Zwolinksi and Joris Andrieux and Estivill, {Xavier P.} and Gusella, {James F.} and Omar Gustafsson and Andres Metspalu and Scherer, {Stephen W.} and Kari Stefansson and Blakemore, {Alexandra I F} and Beckmann, {Jacques S.} and Philippe Froguel",
year = "2011",
month = "10",
day = "6",
doi = "10.1038/nature10406",
language = "English",
volume = "478",
pages = "97--102",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7367",

}

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 P.

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

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 - http://www.scopus.com/inward/record.url?scp=80053920983&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053920983&partnerID=8YFLogxK

U2 - 10.1038/nature10406

DO - 10.1038/nature10406

M3 - Article

C2 - 21881559

AN - SCOPUS:80053920983

VL - 478

SP - 97

EP - 102

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7367

ER -