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The 16p11.2 Locus Modulates Brain Structures Common to Autism, Schizophrenia and Obesity

Saturday, May 16, 2015: 11:30 AM-1:30 PM
Imperial Ballroom (Grand America Hotel)
A. M. Maillard1, A. Ruef2, F. Pizzagalli3, E. Migliavacca4, L. Hippolyte3, S. Adaszewski3, J. Dukart3, C. Ferrari3, P. Conus3, K. Männik4, M. Zazhytska4, V. Siffredi3, P. Maeder3, Z. Kutalik3, F. Kherif3, N. Hadjikhani5,6,7, J. Beckmann3, A. Reymond8, B. Draganski3,9 and S. Jacquemont1, (1)Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland, (2)LREN - Département des neurosciences cliniques, Lausanne University Hospital, Lausanne, Switzerland, (3)Lausanne University Hospital, Lausanne, Switzerland, (4)University of Lausanne, Lausanne, Switzerland, (5)Massachussetts General Hospital, Charlestown, MA, (6)Brain Mind Institute, EPFL, Lausanne, Switzerland, (7)University of Gothenburg, Gothenburg, Sweden, (8)Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, (9)Max Plank Institute, Leipzig, Germany
Background:  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).

Objectives:  The aim of this study is to investigate variation in brain anatomy in 16p11.2 deletion and duplication carriers.

Methods:  We acquired T1 - and diffusion-weighted images. Analysis was performed using voxel-based statistical methods in SPM8

Results: Beyond gene dosage effects on global cortical surface, grey and white matter volumes, we show that the number of genomic copies is negatively correlated to grey 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.

Conclusions:  This study identifies an intermediate phenotype under gene dosage influence in 16p11.2 carriers. 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.

See more of: Brain Structure
See more of: Brain Structure (MRI, neuropathology)