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Mol Psychiatry. 2018 Jun 13. doi: 10.1038/s41380-018-0078-5. [Epub ahead of print]

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size.

Author information

1
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
2
Department of Mental Health, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
3
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
4
Interdepartmental Neuroscience Program, University of California, Los Angeles, Los Angeles, CA, USA.
5
Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA.
6
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
7
Department of Psychiatry & Neuropsychology, Maastricht University, Maastricht, Netherlands.
8
Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, USA.
9
Department of Psychology, Syracuse University, Syracuse, NY, USA.
10
PRC GrowUpWell, University of Newcastle, Newcastle, Australia.
11
School of Psychology, University of Newcastle, Newcastle, Australia.
12
UC Davis MIND Institute and Department of Psychiatry and Behavioral Sciences, Davis, CA, USA.
13
Sackler Institute for Translational Neurodevelopment and Department of Forensic and Neurodevelopmental Sciences, King's College London, Institute of Psychiatry, Psychology & Neuroscience, London, UK.
14
Behavioural Genetics Clinic, Adult Autism Service, Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley Foundation NHS Trust, London, UK.
15
National Autism Unit, Bethlem Royal Hospital, Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley Foundation NHS Trust, London, UK.
16
Hospital for Sick Children, Toronto, ON, Canada.
17
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
18
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
19
Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
20
The Dalglish Family 22q Clinic, Department of Psychiatry, and Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
21
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
22
Department of Psychiatry, University of Pennsylvania, and the Lifespan Brain Institute, Penn Medicine and the Children's Hospital of Philadelphia, Philadelphia, PA, USA.
23
Department of Radiology, Division of Neuroradiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
24
Department of Psychology, Brigham Young University, Provo, UT, USA.
25
Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
26
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
27
Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
28
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
29
Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
30
Division of Clinical Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
31
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA.
32
Imaging Genetics and Neuroinformatics Lab, Department of Psychology, Georgia State University, Atlanta, GA, USA.
33
Mind Research Network, Albuquerque, NM, USA.
34
Departments of Neurology, Psychiatry, Radiology, Engineering, Pediatrics and Ophthalmology, University of Southern California, California, CA, USA.
35
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA. CBearden@mednet.ucla.edu.
36
Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA. CBearden@mednet.ucla.edu.

Abstract

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

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