Journal articles

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}

* 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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Genetics

Life Sciences [q-bio] / Human health and pathology / Endocrinology and metabolism

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https://www.hal.inserm.fr/inserm-00619240
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Submitted on : Monday, March 5, 2012 - 7:00:05 AM
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