31085
Enigma-CNV: Unraveling the Effects on Brain Structure of Rare Copy Number Variants Involved in Autism and Other Neurodevelopmental Diseases

Panel Presentation
Saturday, May 4, 2019: 1:30 PM
Room: 517C (Palais des congres de Montreal)
I. E. Sønderby1, D. van der Meer2, S. Djurovic3, I. Agartz4, L. T. Westlye3, S. Jacquemont5, P. M. Thompson6, O. A. Andreassen7 and .. for the ENIGMA-CNV working group8, (1)CoE NORMENT, University of Oslo, Oslo, Norway, (2)Oslo University, Oslo, Norway, (3)NORMENT, Oslo, Norway, (4)Dep of Psychiatric Reseach, Diakonhjemmet Hospital, Oslo, Norway, (5)CHU Sainte Justine, University of Montreal, Montreal, QC, Canada, (6)Stevens Neuroimaging & Informatics Institute, University of Southern California, Los Angeles, CA, (7)NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine,, University og Oslo, Oslo, Norway, (8)UCLA, Oslo, CA
Background: Many recurrent copy number variants (CNVs) dispose to autism, including the 16p11.2 proximal and distal CNV, 1q21.1, 15q11.2 and 16p13.11 CNV. Although many CNVs are highly penetrant, their low frequency makes them challenging to study. ENIGMA-CNV is an international effort launched to create the statistical power to identify the effect of CNVs on brain MRI measures. The study currently includes n~17,000 participants with CNVs and structural brain data. The 1q21.1 CNV predisposes to e.g. delayed development, autism and schizophrenia. Deletion carriers display microcephaly and duplications carriers macrocephaly. Frequency of the deletion in UK biobank: 0.027 %.

Objectives: Our aim is to identify the effect of CNVs on brain MRI measures.

Methods: Structural T1-MRI data from ENIGMA-CNV and the UK biobank were analyzed (FreeSurfer) and CNVs called (PennCNV). Subcortical volumes, cortical area and thickness were normalized correcting for age, age squared, gender, scanner and intracranial volume (ICV). Dose response (deletion = 1, non-carrier = 2, duplication = 3) was analyzed in a linear model on the normalized brain values.

Results: We found a positive dose-response effect of copy number on intracranial volume (β=1.52, P=1.4E-26) and total surface area (β=0.81, P = 1.5E-08) with the highest effect on the frontal lobe and a small, significant negative dose response on caudate and hippocampus (β=-0.44, P=0.0026; β -0.5, P=0.00064) (deletion=30, non-carriers=24,575, duplications=19). In addition, in the largest analysis to date on 15q11.2 (119 deletions, 154 duplications, 37,871 non-carriers), we showed a positive dose response for cortical surface area (β=0.19, P=2.9E-3) and a negative dose response for average cortical thickness (β=-0.25, P=1.3E-4).

Conclusions: The mechanism behind the head circumference change in 1q21.1 distal CNV carriers seems to be an increase in cortical surface area which may indicate an effect on early development of the (dorsal) telencephalon. Together with other results both from ENIGMA-CNV and others, this indicates that each recurrent CNV has its own specific brain structural signature independent of its phenotypic outcome. These results underline the value of large-scale collaboration such as ENIGMA-CNV for studies of rare genetic variants implicated in autism and brain pathology.

All contributors to ENIGMA-CNV working group can be found at: http://enigma.ini.usc.edu/ongoing/enigma-cnv/enigma-cnv-co-authors/.

See more of: Human and Animal Models: Impact of High-Risk Copy Number Variants on Brain Structure, Functional Connectivity, and Sexual Development.
See more of: Biomarkers (molecular, phenotypic, neurophysiological, etc)