Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.
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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 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, Murphy Clodagh, 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, International 22q11.2DS Brain and Behavior Consortium
Аннотация
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.