title: The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity.
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 diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.
authors.affiliation: Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: A M
authors.initials: AM
authors.lastname: Maillard
authors.affiliation: LREN-Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Ruef
authors.affiliation: 1] Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland [2] LREN-Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Pizzagalli
authors.affiliation: 1] Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland [2] Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Migliavacca
authors.affiliation: Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Hippolyte
authors.affiliation: LREN-Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Adaszewski
authors.affiliation: 1] LREN-Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland [2] Department of Neurology, Max-Planck Institute for Human Cognitive and Brain Science, Leipzig, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dukart
authors.affiliation: Department of Psychiatry, CERY Hospital Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Ferrari
authors.affiliation: Department of Psychiatry, CERY Hospital Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Conus
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Männik
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Zazhytska
authors.affiliation: Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Siffredi
authors.affiliation: Department of Radiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Maeder
authors.affiliation: 1] Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland [2] Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland [3] Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: Z
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: LREN-Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Kherif
authors.affiliation: 1] Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland [2] Athinoula A. Martinos Center for Biomedical Imaging, Massachussetts General Hospital, Harvard Medical School, Charlestown, MA, USA [3] Gillberg Neuropsychiatry Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Hadjikhani
authors.affiliation: 1] Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland [2] Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland [3] Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: J S
authors.initials: JS
authors.lastname: Beckmann
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Reymond
authors.affiliation: 1] LREN-Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland [2] Department of Neurology, Max-Planck Institute for Human Cognitive and Brain Science, Leipzig, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Draganski
authors.affiliation: Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Jacquemont
mesh_terms: D000293:Adolescent; D000328:Adult; D000886:Anthropometry; D029681:Arabidopsis Proteins / Q000378:metabolism; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D015992:Body Mass Index; D001921:Brain / Q000473:pathology*; D001931:Brain Mapping; D002648:Child; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D056726:Genetic Association Studies; D006801:Humans; D019751:Intramolecular Transferases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D029681:Arabidopsis Proteins; D019751:Intramolecular Transferases; C568454:marneral synthase, Arabidopsis