Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Nature Year : 2011

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 G. Walters (3) , Zoltán Kutalik (4, 5) , Danielle Martinet (1) , Yiping Shen (6, 7) , Armand Valsesia (4, 5, 8) , Noam D. Beckmann (1) , Gudmar Thorleifsson (9) , Marco Belfiore (1) , Sonia Bouquillon (10) , Dominique Campion (11, 12) , Nicole de Leeuw (13) , Bert B. A. de Vries (13) , Tõnu Esko (12, 14) , Bridget A. 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 R. Kooy (21) , Ants Kurg (14) , Cédric Le Caignec (22) , Katrin Männik (14) , Orah S. Platt (6) , Damien Sanlaville (23) , Mieke M. 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 E. 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 G. 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 S. El-Sayed Moustafa (3) , Paul Elliott (52) , Brigitte H. W. 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 J. 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 V. A. M. Knoers (24) , David A. Koolen (13) , Peter M. 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 D. Macdermot (72) , Pall Magnusson (73) , Christian R. Marshall (74) , Michèle Mathieu-Dramard (46) , Mark I. 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 S. Ried (58) , Claudine Rieubland (89) , Wendy Roberts (90) , Katharina M. Roetzer (66) , Caroline Rooryck (30, 31) , Massimiliano Rossi (23) , Evald Saemundsen (91) , Véronique Satre (40, 41) , Claudia Schurmann (62) , Engilbert Sigurdsson (92) , Dimitri J. Stavropoulos (93) , Hreinn Stefansson (9) , Carola Tengström (94) , Unnur Thorsteinsdóttir (9) , Francisco J. 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 T. Vulto-van Silfhout (13) , Gérard Waeber (97) , Carina Wallgren-Pettersson (99) , Robert M. Witwicki (2) , Simon Zwolinksi (56) , Joris Andrieux (10) , Xavier Estivill (18) , James F. Gusella (7) , Omar Gustafsson (9) , Andres Metspalu (12, 14) , Stephen W. Scherer (100) , Kari Stefansson (9) , Alexandra I. F. Blakemore (3) , Jacques S. Beckmann (1, 4) , Philippe Froguel (3, 101)
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 - Institut d'Investigació Biomèdica de Bellvitge = Bellvitge Biomedical Research Institute
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 CHU Trousseau [APHP]
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 CHU Pitié-Salpêtrière [AP-HP]
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
Sébastien Jacquemont
Bénédicte Demeer
Dominique Descamps
Klaus Dieterich
Séverine Drunat
Laurence Faivre
Boris Keren
Alessandra Renieri
Sophie Visvikis-Siest
Omar Gustafsson
  • Function : Author
Kari Stefansson
  • Function : Author

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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inserm-00619240 , version 1 (05-03-2012)

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Sébastien Jacquemont, Alexandre Reymond, Flore Zufferey, Louise Harewood, Robin G. Walters, et al.. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.. Nature, 2011, 478 (7367), pp.97-102. ⟨10.1038/nature10406⟩. ⟨inserm-00619240⟩
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