Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome

Objective:Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., “second hits”) that may contribute to schizophrenia expression.Method:Through an inte...

Full description

Saved in:

Bibliographic Details
Published in:	American Journal of Psychiatry Vol. 174; no. 11; pp. 1054 - 1063
Main Authors:	Bassett, Anne S, Lowther, Chelsea, Merico, Daniele, Costain, Gregory, Chow, Eva W. C, van Amelsvoort, Therese, McDonald-McGinn, Donna, Gur, Raquel E, Swillen, Ann, Van den Bree, Marianne, Murphy, Clodagh, Murphy, Kieran, Gothelf, Doron, Bearden, Carrie E, Eliez, Stephan, Kates, Wendy, Philip, Nicole, Sashi, Vandana, Campbell, Linda, Vorstman, Jacob, Cubells, Joseph, Repetto, Gabriela M, Simon, Tony, Boot, Erik, Heung, Tracy, Evers, Rens, Vingerhoets, Claudia, van Duin, Esther, Zackai, Elaine, Vergaelen, Elfi, Devriendt, Koen, Vermeesch, Joris R, Owen, Michael, Michaelovosky, Elena, Kushan, Leila, Schneider, Maude, Fremont, Wanda, Busa, Tiffany, Hooper, Stephen, McCabe, Kathryn, Duijff, Sasja, Isaev, Karin, Pellecchia, Giovanna, Wei, John, Gazzellone, Matthew J, Scherer, Stephen W, Emanuel, Beverly S, Guo, Tingwei, Morrow, Bernice E, Marshall, Christian R
Format:	Journal Article
Language:	English
Published:	United States American Psychiatric Association 01-11-2017
Subjects:	Adult Autism Spectrum Disorder - genetics Autism Spectrum Disorder - psychology Autistic Disorder - genetics Autistic Disorder - psychology Chromosome Deletion Chromosome Disorders - genetics Chromosome Disorders - psychology Chromosomes Chromosomes, Human, Pair 16 - genetics Deoxyribonucleic acid DiGeorge Syndrome - genetics DiGeorge Syndrome - psychology DNA DNA Copy Number Variations Female Genes Genomes Humans Intellectual Disability - genetics Intellectual Disability - psychology Male Middle Aged Risk factors Schizophrenia Schizophrenia - genetics Psychosis Microdeletion Velocardiofacial Syndrome 22q11 Deletion Syndrome Schizophrenia DiGeorge Syndrome Structural Variants
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Objective:Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., “second hits”) that may contribute to schizophrenia expression.Method:Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia.Results:Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci.Conclusions:The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.
ISSN:	0002-953X 1535-7228
DOI:	10.1176/appi.ajp.2017.16121417