SU17 - ALTERED BRAIN CONNECTIVITY IN PATIENTS WITH 16P11.2

Abstract

Background Copy Number Variants (CNVs) at the 16p11.2 BP4-BP5 locus are among the most common genetic risk factors associated with neurodevelopmental disorders [1]. Deletion (DEL) have been associated with Autism Spectrum Disorder (ASD) and Duplication (DUP) with Schizophrenia and ASD. Voxel-based morphometry studies have revealed a robust association between the number of 16p11.2 genomic copies and global brain volume, as well as regional structural changes in key areas of the reward system, language circuitry and social cognition [2]. Our goal is to examine the effect of 16p11.2 CNVs on functional brain organization and its relationship with alterations in brain structure. Methods This study was conducted in a cohort of 20 16p11.2 DEL carriers, 19 DUP carriers and 74 controls (CON) [3]. Mean age was 23.8 yrs±14.9. Resting-state fMRI and structural scans were acquired at two sites on Siemens 3 T TIM Trio scanners using the same sequences (EPI: TR=3000; TE=30; scan time=06:12, flip angle=90). fMRI data were corrected for slice timing and subject motion and registered to MNI space [4] using the NIAK pipeline [5]. Timepoints with excessive head-motion (> 0.5mm) were removed [6]. Subjects with low time points ( Pairwise functional connectivity was estimated as the correlation between the average time series of 64 brain regions [7]. We then fitted a linear model to each connection with the CNV status, subject motion, sex and recording site as explanatory factors. Differences between CNV status groups were then tested by post-hoc contrasts. Each contrast was controlled for false discovery rate (FDR) across all connections at q Results Connectivity of regions in the basal ganglia, medial temporal gyrus and precuneus showed significant differences for the DEL vs CON, and DEL vs DUP contrasts. Specifically, connections among basal ganglia regions (caudate, thalamus, putamen) and between basal ganglia regions and superior and inferior temporal gyri showed significant overconnectivity in DEL group compared to both CON and DUP. Finally, connections between the caudate, superior frontal gyrus and inferior parietal lobule were found to be stronger in DEL than DUP. No significant differences of functional connectivity were found for the DUP vs CON contrast. We examined in a larger normative dataset whether changes in global brain volumes may mediate these changes but found no relationship between brain volume and connections altered in deletion carriers. Discussion Our results are concordant with previous findings of structural brain alterations in 16p11.2 DEL carriers. Striato-striatal and striato-cortical over-connectivity in the DEL carriers is consistent with previous reports of aberrant functional connectivity in ASD [10]. As previously observed the effect size of the duplication on brain structure and cognitive traits is smaller than the effects of the deletion. A larger sample size is likely required to observe the changes in connectivity associated with the duplication. 1. 10.1038/nature13908 2. 10.1038/mp.2014.145 3. 10.1016/j.neuron.2012.02.014 4. 10.1016/j.neuroimage.2010.07.033 5. niak.simexp-lab.org 6. 10.1016/j.neuroimage.2011.10.018 7. 10.6084/m9.figshare.1285615 8. www.jstor.org/stable/2346101 9. 10.1016/j.neuroimage.2015.07.071 10. 10.1016/j.biopsych.2010.10.029