Strong synaptic transmission impact by copy number variations in schizophrenia

Abstract

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 × 10 −7 ). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.genetics | genomics | neurobiology

1q21.1 Microduplication expression in adults

“…[17][18][19][20] Other citations involving 1q21.1 duplication cases were also assessed. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] Cases of 1q21.1 duplication in GeneReviews (http://www.ncbi.nlm. nih.gov/books/NBK52787) and the four references provided therein 1,2,10,25 were reviewed as well, but no new subjects or phenotypic data were identified.…”

“…3,35 We systematically reviewed 28 primary reports identified and their accompanying supplemental materials to identify unique individuals and abstract as much information as possible on each subject. 1,2,[5][6][7][8][9][10][11][12][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Any subjects with 1q21.1 duplications that were not 1.0-5.0 Mb (Figure 1) in size were excluded, 12,31 allowing us to include atypical variants that were larger or smaller than the standard duplication classes used in our analyses. We documented the ascertainment criteria, country of origin, authors, and the demographic, clinical, and genotypic characteristics of subjects in different studies, and used these variables to attempt to identify duplicate cases reported in two or more papers.…”

“…Four studies were excluded because the sources of subjects overlapped with those of other reports and/or the origin of cases was not specified. 17,18,32,34 We compiled data for 107 subjects from the remaining 22 studies 1,2,[5][6][7][8][9][10][11][19][20][21][22][23][24][25][26][27][28][29][30]33 for the main analyses in this report.…”

Genetic studies of schizophrenia: an update

“…For the involved genes, the effect is more pronounced [34,[57][58][59] . The large 22q11.21 locus (3 Mb), also known as DiGeorge and velo-cardio-facial syndrome critical region, was first reported to be associated with SCZ in the 1990s [60] , and this was verified in many later studies [38,39,44,46,47,[51][52][53][54][55] . Most of the studies show that deletion of this region increases the risk of SCZ.…”

“…As a result, CNVs can change the dosage of one or more genes in the regions covered affects the NRXN1 gene [35][36][37][38][39][40][41][42] , and 7p36.3 dup only affects the VIPR2 gene [38,43,44] . CNVs that alter the expression of multiple genes include 1q21.1 del/dup (34 genes) [36][37][38][39]41,[45][46][47] , 3q29del/dup (21 genes) [38][39][40]44,48,49] , 15q13.3del (12 genes) [38,39,44,46,47,49] , 16p13.1dup (11 genes) [40,41,50,51] , and 22q11.2del/dup (53 genes) [38,39,44,46,47,[51][52][53][54][55][56] , etc. (see Table 2 for more details).…”