The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity. S. Jacquemont1, A. M. Maillard1, A. Ruef2, F. Pizzagalli1,2, E. Migliavacca3, L. Hippolyte1, S. Adaszewski2, J. Dukart2, C. Ferrari4, P. Conus4, K. Männik3, M. Zazhytska3, V. Siffredi1, P. Maeder5, Z. Kutalik6,7,8, F. Kherif2, N. Hadjikhani9,10, J. S. Beckmann1,6,7, A. Reymond3, B. Draganski2,11, 16p11.2 European Consortium 1) Service of Medical Genetics, Centre hospitalier Universitaire Lausanne, Switzerland; 2) LREN- Department of clinical Neurosciences, Centre hospitalier Universitaire Lausanne, Switzerland; 3) Center for integrative Genomics, Univeristy of Lausanne, Switzerland; 4) Department of Psychiatry, CERY, Centre hospitalier Universitaire Lausanne, Switzerland; 5) Department of Radiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; 6) Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; 7) Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland; 8) Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; 9) Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Current affiliation: Guillberg Neuropsychiatry Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 10) Athinoula A. Martinos Center for Biomedical Imaging, Massachussetts General Hospital, Harvard Medical School, Charlestown, MA, USA; 11) Department of Neurology, Max-Planck Institute for Human Cognitive and Brain Science, Leipzig, Germany.
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 intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain volume measures, we find robust patterns of alteration in reward, language and social cognition circuits. Changes in the reward system overlap with patterns of structural abnormalities common to ASD, SZ and obesity. Using measures of peripheral mRNA levels, we demonstrate that expression of 16p11.2 genes modulates brain structure, and confirm the findings related to the number of genomic copies. 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.