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

Sébastien Jacquemont; Alexandre Reymond; Flore Zufferey; Louise Harewood; Robin Walters; Zoltán Kutalik; Danielle Martinet; Yiping Shen; Armand Valsesia; Noam Beckmann; Gudmar Thorleifsson; Marco Belfiore; Sonia Bouquillon; Dominique Campion; Nicole de Leeuw; Bert de Vries; Tõnu Esko; Bridget Fernandez; Fernando Fernández-Aranda; José Manuel Fernández-Real; Mònica Gratacòs; Audrey Guilmatre; Juliane Hoyer; Marjo-Riitta Jarvelin; Frank Kooy; Ants Kurg; Cédric Le Caignec; Katrin Männik; Orah Platt; Damien Sanlaville; Mieke van Haelst; Sergi Villatoro Gomez; Faida Walha; Bai-Lin Wu; Yongguo Yu; Azzedine Aboura; Marie-Claude Addor; Yves Alembik; Stylianos Antonarakis; Benoît Arveiler; Magalie Barth; Nathalie Bednarek; Frédérique Béna; Sven Bergmann; Mylène Beri; Laura Bernardini; Bettina Blaumeiser; Dominique Bonneau; Armand Bottani; Odile Boute; Han 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; Christèle Dubourg; Julia El-Sayed Moustafa; Paul Elliott; Brigitte 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 Grabe; Agnès Guichet; Olivier Guillin; Anna-Liisa Hartikainen; Délphine Heron; Loyse Hippolyte; Muriel Holder; Georg Homuth; Bertrand Isidor; Sylvie Jaillard; Zdenek Jaros; Susana Jiménez-Murcia; Géraldine Joly Helas

doi:10.1038/nature10406

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

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

Sébastien Jacquemont, Alexandre Reymond, Flore Zufferey, Louise Harewood, Robin Walters, Zoltán Kutalik, Danielle Martinet, Yiping Shen, Armand Valsesia, Noam Beckmann, …

Nature (London), Vol.478(7367), pp.97-102

06/10/2011

DOI: https://doi.org/10.1038/nature10406

PMID: 21881559

Résumé

Endocrinology and metabolism

Genetics

Human health and pathology

Life Sciences

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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Titre: Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus
Créateurs - sans rôle: Sébastien Jacquemont - Service de génétique médicale
Alexandre Reymond - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
Flore Zufferey - Service de génétique médicale
Louise Harewood - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
Robin Walters - Department of Genomics of Common Disease
Zoltán Kutalik - Department of Medical Genetics
Danielle Martinet - Service de génétique médicale
Yiping Shen - Laboratory Medicine
Armand Valsesia - Department of Medical Genetics
Noam Beckmann - Service de génétique médicale
Gudmar Thorleifsson - deCODE Genetics
Marco Belfiore - Service de génétique médicale
Sonia Bouquillon - Laboratoire de Génétique Médicale [Hôpital Jeanne de Flandre]
Dominique Campion - Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
Nicole de Leeuw - Department of human genetics
Bert de Vries - Department of human genetics
Tõnu Esko - Estonian Genome and Medicine
Bridget Fernandez - Disciplines of Genetics and Medicine
Fernando Fernández-Aranda - Institut d'Investigació Biomédica de Bellvitge
José Manuel Fernández-Real - Section of Diabetes, Endocrinology and Nutrition
Mònica Gratacòs - Center for Genomic Regulation
Audrey Guilmatre - Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
Juliane Hoyer - Institute of Human Genetics [Erlangen, Allemagne]
Marjo-Riitta Jarvelin - Department of child and adolescent health
Frank Kooy - Department of Medical Genetics
Ants Kurg - Institute of Molecular and Cell Biology
Cédric Le Caignec - CHU Trousseau [APHP]
Katrin Männik - Institute of Molecular and Cell Biology
Orah Platt - Laboratory Medicine
Damien Sanlaville - Service de cytogénétique constitutionnelle
Mieke van Haelst - Department of Genomics of Common Disease
Sergi Villatoro Gomez - Center for Genomic Regulation
Faida Walha - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
Bai-Lin Wu - Laboratory Medicine
Yongguo Yu - Laboratory Medicine
Azzedine Aboura - Département de génétique
Marie-Claude Addor - Service de génétique médicale
Yves Alembik - Service de cytogénétique
Stylianos Antonarakis - Génétique médicale
Benoît Arveiler - Maladies Rares: Génétique et Métabolisme
Magalie Barth - Service de génétique [Angers]
Nathalie Bednarek - Université de Reims Champagne-Ardenne
Frédérique Béna - Génétique médicale
Sven Bergmann - Department of Medical Genetics
Mylène Beri - Service de Génétique [CHRU Nancy]
Laura Bernardini - Mendel Laboratory
Bettina Blaumeiser - Department of Medical Genetics
Dominique Bonneau - Service de génétique [Angers]
Armand Bottani - Génétique médicale
Odile Boute - Service de Génétique clinique
Han Brunner - Department of human genetics
Dorothée Cailley - Service de génétique médicale
Patrick Callier - Laboratoire de cytogénétique (CHU de Dijon)
Jean Chiesa - Laboratoire de Cytogénétique
Jacqueline Chrast - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
Lachlan Coin - Department of Genomics of Common Disease
Charles Coutton - Département de génétique et procréation
Jean-Marie Cuisset - Service de Neuropédiatrie
Jean-Christophe Cuvellier - Service de Neuropédiatrie
Albert David - CHU Trousseau [APHP]
Bénédicte de Freminville - Service de génétique
Bruno Delobel - Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul]
Marie-Ange Delrue - Service de génétique médicale
Bénédicte Demeer - Service de génétique médicale
Dominique Descamps - Centre Hospitalier de Béthune
Gérard Didelot - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
Klaus Dieterich - Service de Génétique Clinique
Vittoria Disciglio - Department of Biotechnology
Martine Doco-Fenzy - Service de Génétique
Séverine Drunat - Département de génétique
Bénédicte Duban-Bedu - Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul]
Christèle Dubourg - Institut de génétique et de développement de Rennes
Julia El-Sayed Moustafa - Department of Genomics of Common Disease
Paul Elliott - Department of Epidemiology and Public Health
Brigitte Faas - Department of human genetics
Laurence Faivre - Department of Experimental Cardiology
Anne Faudet - CHU Pitié-Salpêtrière [AP-HP]
Florence Fellmann - Service de génétique médicale
Alessandra Ferrarini - Service de génétique médicale
Richard Fisher - Institute of human genetics
Elisabeth Flori - Service de cytogénétique
Lukas Forer - Division of genetic epidemiology
Dominique Gaillard - Service de Génétique
Marion Gerard - Département de génétique
Christian Gieger - Institute of Experimental Medicine
Stefania Gimelli - Génétique médicale
Giorgio Gimelli - Laboratorio di citogenetica
Hans Grabe - Department of Psychiatry and Psychotherapy
Agnès Guichet - Service de génétique [Angers]
Olivier Guillin - Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
Anna-Liisa Hartikainen - Department of Obstetrics and Gynecology
Délphine Heron - CHU Pitié-Salpêtrière [AP-HP]
Loyse Hippolyte - Service de génétique médicale
Muriel Holder - Service de Génétique clinique
Georg Homuth - Interfaculty Institute for Genetics and Functional Genomics
Bertrand Isidor - CHU Trousseau [APHP]
Sylvie Jaillard - Institut de génétique et de développement de Rennes
Zdenek Jaros - Abteilung für Kinder und Jugendheilkunde
Susana Jiménez-Murcia - Institut d'Investigació Biomédica de Bellvitge
Géraldine Joly Helas - Service de génétique [Rouen]
Détails de publication: Nature (London), Vol.478(7367), pp.97-102
Éditeur: Nature Publishing Group
Nombre de pages: 6
Identifiants: 99163341709311
Unité académique: Institut des Biomolécules Max Mousseron - IBMM
Langue: English
Type de ressource: Journal article