Journal article

The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity

AM Maillard, A Ruef, F Pizzagalli, E Migliavacca, L Hippolyte, S Adaszewski, J Dukart, C Ferrari, P Conus, K Maennik, M Zazhytska, V Siffredi, P Maeder, Z Kutalik, F Kherif, N Hadjikhani, JS Beckmann, A Reymond, B Draganski, S Jacquemont

MOLECULAR PSYCHIATRY | NATURE PUBLISHING GROUP | Published : 2015

Abstract

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ..

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Grants

Awarded by Swiss National Science Foundation (SNSF) Sinergia grant


Awarded by Simons Foundation Autism Research Initiative


Awarded by European Union


Awarded by SNSF (NCCR Synapsy)


Awarded by Deutsche Forschungsgemeinschaft


Awarded by SNSF


Funding Acknowledgements

We thank the participants, families and referring providers (see Supplementary Table 1) for their contribution. We are very grateful to Richard S. Frackowiak for his valuable comments and edits on the manuscript. We acknowledge Stephanie Selmoni, Nathalie Isidor and Ana Machado for their contribution in the recruitment of the participants as well as Guillaume Sierro and Melody Laser for their help scanning the participants. This work was supported by the Leenaards Foundation Prize (SJ, AR and NH), a Swiss National Science Foundation (SNSF) Sinergia grant CRIS FN CRSII33-133044 (AR, SJ), and the Simons Foundation Autism Research Initiative SFARI274424 (AR) the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 604102. BD was supported by the SNSF (NCCR Synapsy, project grant Nr 320030_135679 and SPUM 33CM30_140332/1), Foundation Parkinson Switzerland, Foundation Synapsis, Novartis Foundation for medical-biological research and Deutsche Forschungsgemeinschaft (Kfo 247). LREN is supported by the Roger de Spoelberch and the Partridge Foundations. SJ was supported by a professorship grant from the SNSF PP00P3_144902/2. KM is a grantee of a scholarship from the Swiss Scientific Exchange NMS Program and MZ by a fellowship from the doctoral school of the Faculty of Biology and Medicine, University of Lausanne. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Participants were scanned at the 'Centre d'Imagerie BioMedicale' (CIBM) which is a research initiative of the following partners: University of Lausanne, Swiss Federal Institute of Technology Lausanne, University of Geneva, Centre Hospitalier Universitaire Vaudois, Hopitaux Universitaires de Geneve and the Leenaards and the Jeantet Foundations. We thank the participants and their families for their contribution. 16p11.2 European Consortium contributing members: M-C Addor, Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne. J Andrieux, Institut de Genetique Medicale, Hopital Jeanne de Flandre, Lille. B Arveiler, Univ. Bordeaux, Maladies Rares: Genetique et Metabolisme, Service de Genetique Medicale, CHU-Bordeaux, Bordeaux. G Baujat, Centre de Reference Departement de Genetique, Hopital Necker-Enfants malades, Paris. F Bena, Service of Genetic Medicine, University Hospitals of Geneva, Geneva. D Bonneau, Service de genetique medicale, CHU-Angers, Angers. S Bouquillon, Institut de Genetique Medicale, Hopital Jeanne de Flandre, Lille. O Boute, Hopital Jeanne de Flandre, CHRU de Lille, Lille. A Brusco, University of Torino, Department of Medical Sciences, Turin. D Campion, Service de psychiatrie, Centre hospitalier de Rouvray, Sotteville les Rouen. A David, Service de Genetique Medicale, CHU-Nantes, Nantes. M-A Delrue, Univ. Bordeaux, Maladies Rares: Genetique et Metabolisme, Service de Genetique Medicale, CHU-Bordeaux, Bordeaux. M Doco-Fenzy, Service de Genetique, CHU, EA3801 SFR-CAP Sante Reims. C Fagerberg, Department of Clinical Genetics, Odense University Hospital, Odense. L Faivre, Hopital d'Enfants, CHU Dijon. F Forzano, SSD Genetica Medica, EO Ospedali Galliera, Genova. D Giachino, Genetica Medica, Azienda Ospedaliera Universitaria San Luigi Gonzaga Orbassano, Torino. A Guichet, Service de genetique medicale, CHU-Angers. O Guillin, Service de psychiatrie, Centre hospitalier de Rouvray, Sotteville les Rouen. D Heron, Departement de Genetique, Hopital Pitie-Salptriere, Universite Pierre et Marie Curie, Paris.B Isidor, Service de Genetique Medicale, CHU-Nantes, Nantes. A Jacquette, Departement de Genetique, groupe hospitalier Pitie-Salpetriere, Paris. H Journel, Genetique medicale, Centre Hospitalier Bretagne Atlantique, Vannes. B Keren, Departement de Genetique Cytogenetique et Embryologie AP-HP, Hopital Pitie-Salpetriere, Universite Pierre et Marie Curie, Paris. D Lacombe, Univ. Bordeaux, Maladies Rares: Genetique et Metabolisme, Service de Genetique Medicale, CHU-Bordeaux, Bordeaux. C Le Caignec, Service de Genetique Medicale, CHU Nantes, Nantes. M-P Lemaitre, Service de Neuropediatrie, Centre Hospitalier Regional Universitaire, Lille. J Lespinasse, Service genetique medicale, CH Chambery. G Mandrile, Genetica Medica, Azienda Ospedaliera Universitaria San Luigi Gonzaga Orbassano, Torino. M Mathieu-Dramard, Service de Genetique Clinique, CHU Amiens, Amiens. C Mignot, Service de Genetique Clinique, CHU La Pitie Salpetriere, France; Service de Neuropediatrie, APHP, Hopital Armand Trousseau. F Petit, Hopital Jeanne de Flandre, CHRU de Lille, Lille. G Plessis, Service de Genetique, CHU Clemenceau, Caen. F Prieur, Service de genetique medicale, CHU St Etienne C Rooryck, Univ. Bordeaux, Maladies Rares: Genetique et Metabolisme, Service de Genetique Medicale, CHU-Bordeaux, Bordeaux. D Sanlaville, Service de Cytogenetique Constitutionnelle, Hospices Civils de Lyon, CHU de Lyon and Centre de Recherche en Neuroscience de Lyon, Lyon. MM Van Haelst, Department of Medical Genetics, University Medical Center, Utrecht. L Van Maldergem, Centre de Genetique humaine, CHU-Besancon.