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

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dc.contributor.authorBassett, Anne
dc.contributor.authorLowther, Chelsea
dc.contributor.authorMerico, Daniele
dc.contributor.authorCostain, Gregory
dc.contributor.authorChow, Eva
dc.contributor.authorvan Amelsvoort, Therese
dc.contributor.authorMcDonald-McGinn, Donna
dc.contributor.authorGur, Raquel
dc.contributor.authorSwillen, Ann
dc.contributor.authorVan den Bree, Marianne
dc.contributor.authorMurphy, Kieran
dc.contributor.authorGothelf, Doron
dc.contributor.authorBearden, Carrie
dc.contributor.authorEliez, Stephan
dc.contributor.authorKates, Wendy
dc.contributor.authorPhilip, Nicole
dc.contributor.authorSashi, Vandana
dc.contributor.authorCampbell, Linda
dc.contributor.authorVorstman, Jacob
dc.contributor.authorCubells, Joseph
dc.contributor.authorRepetto, Gabriela
dc.contributor.authorSimon, Tony
dc.contributor.authorBoot, Erik
dc.contributor.authorHeung, Tracy
dc.contributor.authorEvers, Rens
dc.contributor.authorVingerhoets, Claudia
dc.contributor.authorvan Duin, Esther
dc.contributor.authorZackai, Elaine
dc.contributor.authorVergaelen, Elfi
dc.contributor.authorDevriendt, Koen
dc.contributor.authorVermeesch, Joris
dc.contributor.authorOwen, Michael
dc.contributor.authorMurphy, Clodagh
dc.contributor.authorMichaelovosky, Elena
dc.contributor.authorKushan, Leila
dc.contributor.authorSchneider, Maude
dc.contributor.authorFremont, Wanda
dc.contributor.authorBusa, Tiffany
dc.contributor.authorHooper, Stephen
dc.contributor.authorMcCabe, Kathryn
dc.contributor.authorDuijff, Sasja
dc.contributor.authorIsaev, Karin
dc.contributor.authorPellecchia, Giovanna
dc.contributor.authorWei, John
dc.contributor.authorGazzellone, Matthew
dc.contributor.authorScherer, Stephen
dc.contributor.authorEmanuel, Beverly
dc.contributor.authorGuo, Tingwei
dc.contributor.authorMorrow, Bernice
dc.contributor.authorMarshall, Christian
dc.contributor.authorInternational 22q11.2DS Brain and Behavior Consortium
dc.date.accessioned2018-01-09T19:00:12Z
dc.date.available2018-01-09T19:00:12Z
dc.date.issued2017
dc.description.abstractOBJECTIVE: 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.
dc.format.extent10
dc.identifier.citationBassett AS, Lowther C, Merico D, Costain G, Chow EWC, van Amelsvoort T, McDonald-McGinn D, Gur RE, Swillen A, Van den Bree M, Murphy K, Gothelf D, Bearden CE, Eliez S, Kates W, Philip N, Sashi V, Campbell L, Vorstman J, Cubells J, Repetto GM, Simon T, Boot E, Heung T, Evers R, Vingerhoets C, van Duin E, Zackai E, Vergaelen E, Devriendt K, Vermeesch JR, Owen M, Murphy C, Michaelovosky E, Kushan L, Schneider M, Fremont W, Busa T, Hooper S, McCabe K, Duijff S, Isaev K, Pellecchia G, Wei J, Gazzellone MJ, Scherer SW, Emanuel BS, Guo T, Morrow BE, Marshall CR; International 22q11.2DS Brain and Behavior Consortium. Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome. Am J Psychiatry. 2017 Nov 1;174(11):1054-1063
dc.identifier.urihttp://hdl.handle.net/11447/1869
dc.identifier.urihttp://dx.doi.org/10.1176/appi.ajp.2017.16121417
dc.language.isoen_US
dc.publisherAmerican Psychiatric Association
dc.subject22q11 Deletion Syndrome
dc.subjectDiGeorge Syndrome
dc.subjectMicrodeletion
dc.subjectPsychosis
dc.subjectSchizophrenia
dc.subjectStructural Variants
dc.subjectVelocardiofacial Syndrome
dc.titleRare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome
dc.typeArtículo

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