The Effects of 16p11.2 Gene Dosage on Brain Structure

Thursday, May 11, 2017: 12:00 PM-1:40 PM
Golden Gate Ballroom (Marriott Marquis Hotel)
S. Martin1, B. Rodriguez-Herreros2, J. Nielsen3, C. Moreau4, A. Maillard5, A. Pain6, C. Modenato7, S. Richetin8, N. R. R. Zürcher9, N. Hadjikhani10, A. Reymond11, R. L. Buckner12,13,14, B. Draganski7 and S. Jacquemont15, (1)Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, (2)CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC, Canada, (3)Harvard University, Cambridge, MA, (4)CHU Sainte Justine, University of Montreal, Montreal, QC, Canada, (5)Service de Génétique Médicale, Lausanne University Hospital, Pully, SWITZERLAND, (6)Genetics, University of Lausanne, Lausanne, Switzerland, (7)Department for Clinical Neurosciences, University of Lausanne, Lausanne, Switzerland, (8)Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, (9)Swiss Federal Institute of Technology (EPFL), Lausanne, SWITZERLAND, (10)MGH/ Martinos Center for Biomedical Imaging/ Harvard Medical School, Charlestown, MA, (11)University of Lausanne, Lausanne, SWITZERLAND, (12)Department of Radiology, Harvard Medical School, Boston, MA, (13)Psychology Department, Harvard University, Boston, MA, (14)Center for Brain Sciences, Harvard University, Cambridge, MA, (15)University of Montreal, Montreal, QC, CANADA
Background:  Copy Number Variants - CNVs are major contributors to neurodevelopmental disorders. Carriers of the deletion or duplication at the 16p11.2 locus (29.6-30.2 Mb-Hg 19) have a 10-fold increased risk of developing autism spectrum disorder (ASD) and present an inverse gene dosage on Body Mass Index and head circumference. Some recent neuroimaging studies have revealed an association between the number of 16p11.2 genomic copies and global brain metrics, as well as regional structural changes in the reward system, language circuitry and social cognition.


Our goals for this study were to 1) Replicate and extend previously published findings on a larger dataset of families with 16p11.2 CNV by pooling new and previously published data; 2) Demonstrate that individuals, who share the same autism risk factor, show robust brain alterations through different cohorts and scanning sites.

Methods: Participants, above 6 years old, were evaluated in the European 16p11.2 consortium and the American Simons VIP study. 361 participants were examined on a 3T whole body MRI scanner on 7 different sites. T1-weighted anatomical images were acquired using a multi-echo magnetization prepared rapid gradient echo sequences (ME-MPRAGE) on 264 participants and a single-echo MPRAGE sequences on 97 participants. Data analyses were performed using the SPM12 and FreeSurfer software packages.

Results:  We analyzed MRI data in 78 16p11.2 deletion carriers, 71 duplication carriers, 72 familial controls, as well as 140 extra-familial controls. 11 deletion and 8 duplication carriers met criteria for ASD (13%). Intracranial Volume correlated negatively with the number of genomic copies at the 16p11.2 locus in the European and American cohorts. Both gray and white matter total volumes contributed to this effect. Using Voxel-Based Morphometry in both cohorts, we found a negative relationship between the number of 16p11.2 genomic copies and the volume of bilateral insula, putamen, superior temporal gyri, orbital part of inferior frontal gyri, lingual gyri, and some cerebellar lobules. Both cohorts also presented a positive relationship between the number of genomic copies and the volume of bilateral middle temporal gyri.
We did not find any interaction between the genetic status and the two cohorts, the 7 sites or the gender. Results were also stable across the 7 iterative analyses successively leaving out one of the scanning sites. Subdividing the genetic group in 2 categorical age groups showed the same profile of structural brain abnormalities.

Conclusions:  These results demonstrate that different ascertainment methods in Europe and the USA led to the same brain differences. The robustness and power of this combined dataset and the relevance of the global and regional findings show that multisite MRI studies are extremely powerful, especially when neurobiological heterogeneity can be reduced by focusing on individuals who share a common ASD risk factor.

See more of: Genetics
See more of: Genetics