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Genetics and Epigenetics

16p11.2 Locus modulates response to satiety before the onset of obesity

International Journal of Obesity volume 40, pages 870–876 (2016)Cite this article

Subjects

Abstract

Background:

The 600 kb BP4-BP5 copy number variants (CNVs) at the 16p11.2 locus have been associated with a range of neurodevelopmental conditions including autism spectrum disorders and schizophrenia. The number of genomic copies in this region is inversely correlated with body mass index (BMI): the deletion is associated with a highly penetrant form of obesity (present in 50% of carriers by the age of 7 years and in 70% of adults), and the duplication with being underweight. Mechanisms underlying this energy imbalance remain unknown.

Objective:

This study aims to investigate eating behavior, cognitive traits and their relationships with BMI in carriers of 16p11.2 CNVs.

Methods:

We assessed individuals carrying a 16p11.2 deletion or duplication and their intrafamilial controls using food-related behavior questionnaires and cognitive measures. We also compared these carriers with cohorts of individuals presenting with obesity, binge eating disorder or bulimia.

Results:

Response to satiety is gene dosage-dependent in pediatric CNV carriers. Altered satiety response is present in young deletion carriers before the onset of obesity. It remains altered in adolescent carriers and correlates with obesity. Adult deletion carriers exhibit eating behavior similar to that seen in a cohort of obesity without eating disorders such as bulimia or binge eating. None of the cognitive measures are associated with eating behavior or BMI.

Conclusions:

These findings suggest that abnormal satiety response is a strong contributor to the energy imbalance in 16p11.2 CNV carriers, and, akin to other genetic forms of obesity, altered satiety responsiveness in children precedes the increase in BMI observed later in adolescence.

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Acknowledgements

We thank all participants and their families for their contribution. The ECHO study group members are very grateful to NHS (National Health Service) medical genetics clinics, Unique—The Rare Chromosome Disorder Support Group, a UK registered charity, and to UK-based 16p11.2 online support groups for advertising the study and referring participants. We acknowledge Hayley Moss, Maria Niarchou and Aimée Davies for their contribution in the recruitment and assessment of the participants. SJRAC is supported by a MRC doctoral training grant at the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. KM was awarded a fellowship from the Swiss Scientific Exchange NMS Program, SJ is recipient of an SNSF Professorship fund. This work is supported by grants from the Simons Foundation (SFARI274424 to AR), the Swiss National Science Foundation 31003A_160203 (AR) and SNSF Sinergia grants CRSII33-133044 (AR and SJ). The Swiss University Study of Nutrition (SUN) project is funded by the Swiss National Science Foundation (SNSF) (grant number 100014132045/1) and by the German Federal Ministry of Education and Research (BMBF) (grant number 01EO1001). The CIBERobn is an initiative of ISCIII. Partial funding was obtained by Fondo Investigación Sanitaria (FIS; PI11/210/; PI14/290).

16P11.2 EUROPEAN CONSORTIUM

Addor, M-C, Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland; Andrieux, J, Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, France; Baujat, G, Centre de Référence Département de Génétique, Hôpital Necker-Enfants malades, Paris, France; Belfiore, M, Laboratoire de cytogénétique, Service de Génétique Médicale, CHUV, Lausanne, Switzerland; Bonneau, D, Service de génétique médicale, CHU-Angers, France; Bouquillon, S, Institut de Génétique Médicale, Hôpital Jeanne de Flandre, Lille, France; Boute, O, Hôpital Jeanne de Flandre, CHRU de Lille, France; Brusco, A, University of Torino, Department of Medical Sciences, Turin, Italy; Bussat, J, Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne University, Switzerland; Campion, D, Service de psychiatrie, Centre hospitalier de Rouvray, Sotteville lès Rouen, France; Delrue, M-A, Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme, Service de Génétique Médicale, CHU-Bordeaux, France; Dervaux, G, Unité de Médecine et Chirurgie de l'obésité, Centre Hospitalier de Béthune, France; Doco-Fenzy, M, Service de Génétique, CHU, EA3801 SFR-CAP Santé Reims, France; Edery, P, Service de Génétique, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant et Centre de Recherche en Neurosciences de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France; Fagerberg, C, Department of Clinical Genetics, Odense Universitetshospital, Odense, Denmark; Fellmann, F, Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland; Ferrarini, A, Department of Pediatrics, San Giovanni Hospital, Bellinzona, Switzerland; Forzano, F, SSD Genetica Medica, E Ospedali Galliera, Genova, Italy; Gérard, M, Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France; Giachino, D, Genetica Medica, Azienda Ospedaliera Universitaria San Luigi Gonzaga Orbassano, Torino, Italy; Gilbert-Dussardier, B, Service de Génétique Médicale, Centre de Référence Anomalies du Développement-Ouest, CHU de Poitiers; EA 3808, Université de Poitiers, France; Héron, D, Département de Génétique, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France; Holder, M, Hôpital Jeanne de Flandre, CHRU de Lille, France; Jacquette, A, Département de Génétique, groupe hospitalier Pitié-Salpétrière, Paris, France; Journel, H, Génétique médicale, Centre Hospitalier Bretagne Atlantique, Vannes, France; Kutalik, Z, IUMSP, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Lacombe, D, Department of Medical Genetics, CHU of Bordeaux, Université de Bordeaux, France; Lazaro, L, CH Côte-Basque, Service de pédiatrie, Bayonne, France; Lemaître, M-P, Service de Neuropédiatrie, Centre Hospitalier Régional Universitaire, Lille, France; Lespinasse, J, Service génétique médicale, CH Chambéry, France; Macé, A, Department of Medical Genetics, University of Lausanne, Switzerland; Mandrile, G, Genetica Medica, Azienda Ospedaliera Universitaria San Luigi Gonzaga Orbassano, Torino, Italy; Martinet, D, Laboratoire de cytogénétique, Service de Génétique Médicale, CHUV, Lausanne, Switzerland; Minet, J-C, Department of Pediatrics, Hôpital du Jura, Délémont, Switzerland; Moerman, A, Institut de Génétique Médicale, Hôpital Jeanne de Flandre, Lille, France; Morice-Picard, F, Department of Medical Genetics, Centre Hospitalier Universitaire de Bordeaux, GH Pellegrin, Bordeaux, France; Motte, J, Neurologie Pédiatrique, Pôle Femme-Mère-Enfant, American Memorial Hospital, Reims, France; Olivier-Faivre, L, Centre de référence Anomalies du développement et Syndromes Malformatifs de l’Interrégion Est, Hôpital d’Enfants, CHU de Dijon et Université de Bourgogne, Dijon, France; Pasquier, L, Service de Génétique Clinique, Hôpital sud, CHU de Rennes, Université Rennes 1, UMR 6290 CNRS, Groupe GPLD, Rennes, France; Petit, F, Hôpital Jeanne de Flandre, CHRU de Lille, France; Plessis, G, Service de Génétique clinique, CHU Caen, France; Ragona, F, Department of Pediatric Neuroscience, IRCCS Foundation Neurological Institute C Besta, Milan, Italy; Ramelli, G-P, Department of Pediatrics, San Giovanni Hospital, Bellinzona, Switzerland; Van Haelst, MM, Department of Medical Genetics, University Medical Center, Utrecht, Netherlands; Van Maldergem, L, Centre de Génétique humaine, CHU-Besançon, France.

Author information

Author notes

  1. S Jacquemont

    Present address: 21Current address: Département de Pédiatrie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.,

  2. A M Maillard and L Hippolyte: These authors contributed equally to this work.

  3. The 16p11.2 European Consortium collaborators are listed before references.

Authors and Affiliations

  1. Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

    A M Maillard, L Hippolyte, B Rodriguez-Herreros, A Pain, S Martin-Brevet, R Etienne, J S Beckmann & S Jacquemont

  2. LREN—Département des Neurosciences Cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

    B Rodriguez-Herreros, S Martin-Brevet & B Draganski

  3. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK

    S J R A Chawner & M B M van den Bree

  4. Department of Psychology, Clinical Psychology and Psychotherapy, University of Fribourg, Fribourg, Switzerland

    D Dremmel, S Kurz & S Munsch

  5. CIBER Fisiopatologia Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Barcelona, Spain

    Z Agüera, A B Fagundo, S Jimenez-Murcia & F Fernandez-Aranda

  6. Department of Psychiatry, Bellvitge University Hospital-IDIBELL, Barcelona, Spain

    Z Agüera, A B Fagundo, S Jimenez-Murcia & F Fernandez-Aranda

  7. Department of Medical Psychology and Medical SocCiology, Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig Medical Center, Leipzig, Germany

    A Hilbert

  8. Department of Neurology, Max-Planck Institute for Human Cognitive and Brain Science, Leipzig, Germany

    B Draganski

  9. Clinical Sciences Department, School of Medicine, Barcelona, Spain

    S Jimenez-Murcia & F Fernandez-Aranda

  10. Estonian Genome Center, Tartu University Hospital, Tartu, Estonia

    K Männik, A Metspalu & A Reigo

  11. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

    K Männik & A Reymond

  12. Service de Génétique Médicale, CHU-Nantes, Nantes, France

    B Isidor, C Le Caignec & A David

  13. INSERM UMR957, Faculté de Médecine, Nantes, France

    C Le Caignec

  14. Département de Génétique et de Cytogénétique, AP-HP, Hôpital Pitié-Salpêtrière, Unité Fonctionnelle de Génétique Clinique, Paris, France

    C Mignot

  15. Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France

    C Mignot

  16. Groupe de Recherche Clinique Déficience Intellectuelle et Autisme, UPMC, Paris, France

    C Mignot

  17. Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Paris, France

    B Keren

  18. SIB Swiss Institute of Bioinformatics,, Lausanne, Switzerland

    J S Beckmann

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  1. A M Maillard
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  2. L Hippolyte
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  3. B Rodriguez-Herreros
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  8. A Pain
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  9. S Martin-Brevet
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  10. A Hilbert
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  11. S Kurz
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  12. R Etienne
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  14. S Jimenez-Murcia
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  15. K Männik
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  16. A Metspalu
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  18. B Isidor
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  19. C Le Caignec
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  20. A David
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  21. C Mignot
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  22. B Keren
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  23. M B M van den Bree
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  24. S Munsch
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  25. F Fernandez-Aranda
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  26. J S Beckmann
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  27. A Reymond
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  28. S Jacquemont
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16p11.2 European Consortium

Corresponding author

Correspondence to S Jacquemont.

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Maillard, A., Hippolyte, L., Rodriguez-Herreros, B. et al. 16p11.2 Locus modulates response to satiety before the onset of obesity. Int J Obes 40, 870–876 (2016). https://doi.org/10.1038/ijo.2015.247

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