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

Sébastien Jacquemont 1 Alexandre Reymond 2 Flore Zufferey 1 Louise Harewood 2 Robin Walters 3 Zoltán Kutalik 4, 5 Danielle Martinet 1 Yiping Shen 6, 7 Armand Valsesia 4, 5, 8 Noam Beckmann 1 Gudmar Thorleifsson 9 Marco Belfiore 1 Sonia Bouquillon 10 Dominique Campion 11, 12 Nicole de Leeuw 13 Bert de Vries 13 Tõnu Esko 12, 14 Bridget Fernandez 15 Fernando Fernández-Aranda 16 José Manuel Fernández-Real 17 Mònica Gratacòs 18 Audrey Guilmatre 11, 12 Juliane Hoyer 19 Marjo-Riitta Jarvelin 20 Frank Kooy 21 Ants Kurg 14 Cédric Le Caignec 22 Katrin Männik 14 Orah Platt 6 Damien Sanlaville 23 Mieke van Haelst 3, 24 Sergi Villatoro Gomez 18 Faida Walha 2 Bai-Lin Wu 6, 25 Yongguo Yu 6, 26 Azzedine Aboura 27 Marie-Claude Addor 1 Yves Alembik 28 Stylianos Antonarakis 29 Benoît Arveiler 30, 31 Magalie Barth 32 Nathalie Bednarek 33 Frédérique Béna 29 Sven Bergmann 4, 5, 34 Mylène Beri 35 Laura Bernardini 36 Bettina Blaumeiser 21 Dominique Bonneau 32 Armand Bottani 29 Odile Boute 37 Han Brunner 13 Dorothée Cailley 31 Patrick Callier 38 Jean Chiesa 39 Jacqueline Chrast 2 Lachlan Coin 3 Charles Coutton 40, 41, 42 Jean-Marie Cuisset 43 Jean-Christophe Cuvellier 43 Albert David 22 Bénédicte de Freminville 44 Bruno Delobel 45 Marie-Ange Delrue 31, 30 Bénédicte Demeer 46 Dominique Descamps 47 Gérard Didelot 2 Klaus Dieterich 48 Vittoria Disciglio 49 Martine Doco-Fenzy 50 Séverine Drunat 27 Bénédicte Duban-Bedu 45 Christèle Dubourg 51 Julia El-Sayed Moustafa 3 Paul Elliott 52 Brigitte Faas 13, 53 Laurence Faivre 54 Anne Faudet 55 Florence Fellmann 1 Alessandra Ferrarini 1 Richard Fisher 56 Elisabeth Flori 28 Lukas Forer 57 Dominique Gaillard 50 Marion Gerard 27 Christian Gieger 58 Stefania Gimelli 29, 59 Giorgio Gimelli 60 Hans Grabe 61 Agnès Guichet 32 Olivier Guillin 11 Anna-Liisa Hartikainen 59 Délphine Heron 55 Loyse Hippolyte 1 Muriel Holder 37 Georg Homuth 62 Bertrand Isidor 22 Sylvie Jaillard 51 Zdenek Jaros 63 Susana Jiménez-Murcia 16 Géraldine Joly Helas 64 Philippe Jonveaux 35 Satu Kaksonen 65 Boris Keren 55 Anita Kloss-Brandstätter 57 Nine Knoers 24 David Koolen 13 Peter Kroisel 66 Florian Kronenberg 57 Audrey Labalme 23 Emilie Landais 50 Elisabetta Lapi 67 Valérie Layet 68 Solenn Legallic 11 Bruno Leheup 69 Barbara Leube 70 Suzanne Lewis 71 Josette Lucas 51 Kay Macdermot 72 Pall Magnusson 73 Christian Marshall 74 Michèle Mathieu-Dramard 46 Mark Mccarthy 75, 76 Thomas Meitinger 77 Maria Antonietta Mencarelli 49 Giuseppe Merla 78 Alexandre Moerman 37 Vincent Mooser 79 Fanny Morice-Picard 30, 31 Mafalda Mucciolo 49 Matthias Nauck 80 Ndeye Coumba Ndiaye 81 Ann Nordgren 82 Laurent Pasquier 51 Florence Petit 37 Rolph Pfundt 13 Ghislaine Plessis 83 Evica Rajcan-Separovic 84 Gian Paolo Ramelli 85 Anita Rauch 86 Roberto Ravazzolo 87 Andre Reis 19 Alessandra Renieri 49 Cristobal Richart 88 Janina Ried 58 Claudine Rieubland 89 Wendy Roberts 90 Katharina Roetzer 66 Caroline Rooryck 30, 31 Massimiliano Rossi 23 Evald Saemundsen 91 Véronique Satre 40, 41 Claudia Schurmann 62 Engilbert Sigurdsson 92 Dimitri Stavropoulos 93 Hreinn Stefansson 9 Carola Tengström 94 Unnur Thorsteinsdóttir 9 Francisco Tinahones 95 Renaud Touraine 44 Louis Vallée 43 Ellen van Binsbergen 24 Nathalie van der Aa 21 Catherine Vincent-Delorme 96 Sophie Visvikis-Siest 81 Peter Vollenweider 97 Henry Völzke 98 Anneke Vulto-van Silfhout 13 Gérard Waeber 97 Carina Wallgren-Pettersson 99 Robert Witwicki 2 Simon Zwolinksi 56 Joris Andrieux 10 Xavier Estivill 18 James Gusella 7 Omar Gustafsson 9 Andres Metspalu 12, 14 Stephen Scherer 100 Kari Stefansson 9 Alexandra Blakemore 3 Jacques Beckmann 1, 4, * Philippe Froguel 3, 101
* Corresponding author
1 Service de génétique médicale
2 CIG - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
3 Department of Genomics of Common Disease
4 Department of Medical Genetics
5 SIB - Swiss Institute of Bioinformatics [Lausanne]
6 Laboratory Medicine
7 Center for Human Genetic Research
8 Ludwig Institute for Cancer Research
9 deCODE Genetics
10 Laboratoire de Génétique Médicale
11 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
12 Estonian Genome and Medicine
13 Department of human genetics
14 Institute of Molecular and Cell Biology
15 Disciplines of Genetics and Medicine
16 IDIBELL - Department of Psychiatry
17 Section of Diabetes, Endocrinology and Nutrition
18 CRG-UPF - Center for Genomic Regulation
19 Institute of Human Genetics [Erlangen, Allemagne]
20 Department of child and adolescent health
21 Department of Medical Genetics
22 Service d'ORL et de Chirurgie Cervicofaciale
23 Service de cytogénétique constitutionnelle
24 Department of Medical Genetics
25 Institutes of Biomedical Science
26 Shanghai Children's Medical Center
27 Département de génétique
28 Service de cytogénétique
29 Génétique médicale
30 MRGM - Maladies Rares - Génétique et Métabolisme
31 Service de génétique médicale
32 Service de génétique [Angers]
33 URCA - Université de Reims Champagne-Ardenne
34 Department of Molecular Genetics
35 Service de Génétique [CHRU Nancy]
36 Mendel Laboratory
37 Service de Génétique clinique
38 Laboratoire de cytogénétique (CHU de Dijon)
39 Laboratoire de Cytogénétique
40 Département de génétique et procréation
41 AGIM - AGeing and IMagery
42 Laboratoire de biochimie et génétique moléculaire
43 Service de Neuropédiatrie
44 Service de génétique
45 Centre de Génétique Chromosomique
46 Service de génétique médicale
47 CH Béthune - Centre Hospitalier de Béthune
48 Service de Génétique Clinique
49 Department of Biotechnology
50 Service de Génétique
51 IGDR - Institut de Génétique et Développement de Rennes
52 Department of Epidemiology and Public Health
53 Department of Human Genetics [Nijmegen]
54 Department of Experimental Cardiology
55 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
56 Institute of human genetics
57 Division of genetic epidemiology
58 Institute of Experimental Medicine
59 Department of Obstetrics and Gynecology
60 Laboratorio di citogenetica
61 Department of Psychiatry and Psychotherapy
62 Interfaculty Institute for Genetics and Functional Genomics
63 Abteilung für Kinder und Jugendheilkunde
64 Service de génétique [Rouen]
65 The Habilitation Unit of Folkhalsan
66 Institute of human genetics
67 Medical Genetics Unit
68 Unité de Cytogénétique et Génétique Médicale
69 Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy]
70 Institute of Human Genetics and Anthropology
71 Department of Medical Genetics
72 North West Thames Regional Genetics Service
73 Child and Adolescent Psychiatry
74 Program in Genetics and Genomic Biology
75 OCDEM - Oxford Centre for Diabetes, Endocrinology and Metabolism
76 The Wellcome Trust Centre for Human Genetics [Oxford]
77 Institute of Human Genetics
78 Medical Genetics Unit
79 Genetics, GlaxoSmithKline R&D
80 Institute of Clinical Chemistry and Laboratory Medicine
81 GC - Génétique cardiovasculaire
82 Molecular Medicine and Surgery department
83 Service de Génétique [CHU Caen]
84 Department of Pathology
85 Division of pediatrics
86 Institute of Medical Genetics
87 Department of pediatrics and CEBR
88 Department of Internal Medicine
89 Division of Human Genetics
90 Autism Research Unit
91 State Diagnostic
92 University of Iceland [Reykjavik]
93 Department of Pediatric Laboratory Medicine
94 Genetic Services
95 Department of Endocrinology and Nutrition
96 Centre de Maladies Rares
97 Department of Internal Medicine
98 Institute for Community Medicine
99 Department of Medical and Clinical Genetics [Helsinki]
100 The Centre for Applied Genomics, Toronto
101 IBL - Institut de biologie de Lille - UMS 3702
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.
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Sébastien Jacquemont, Alexandre Reymond, Flore Zufferey, Louise Harewood, Robin Walters, et al.. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.. Nature, Nature Publishing Group, 2011, 478 (7367), pp.97-102. ⟨10.1038/nature10406⟩. ⟨inserm-00619240⟩

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