Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia

Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ∼1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schiz...

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Bibliographic Details
Published in:	Molecular psychiatry Vol. 17; no. 10; pp. 996 - 1006
Main Authors:	Lips, E S, Cornelisse, L N, Toonen, R F, Min, J L, Hultman, C M, Holmans, P A, O'Donovan, M C, Purcell, S M, Smit, A B, Verhage, M, Sullivan, P F, Visscher, P M, Posthuma, D
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-10-2012 Nature Publishing Group
Subjects:	631/1647/2217 631/443/376 692/499 692/699/476/1799 Adhesion Adult and adolescent clinical studies Behavioral Sciences Biological and medical sciences Biological Psychology Calcium Channels, L-Type - genetics Case-Control Studies Cell adhesion Cell adhesion & migration Cell Adhesion - genetics Drugs Excitability Female GAIN Gene expression gene group analysis Genes Genetic aspects Genetic Predisposition to Disease genome-wide association Genome-Wide Association Study Genomes Genomics Genotype GWAS Heredity Human health and pathology Humans Intracellular Signaling Peptides and Proteins - genetics Intracellular signalling ISC Life Sciences Linkage Disequilibrium Male Medical sciences Medicin och hälsovetenskap Medicine Medicine & Public Health Mental disorders Neural transmission Neurosciences Oligonucleotide Array Sequence Analysis - methods Original original-article Pathology Pharmacotherapy Physiological aspects Polygenic inheritance Polymorphism, Single Nucleotide Psychiatrics and mental health Psychiatry Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Psychoses PubMed - statistics & numerical data Risk Factors Schizophrenia Schizophrenia - epidemiology Schizophrenia - genetics Signal transduction Signal Transduction - genetics synapse Synapses Synapses - genetics White People Netherlands Sweden United States > US Massachusetts ISC GWAS gene group analysis synapse genome-wide association GAIN Schizophrenia Functional analysis Genetic determinism Psychosis Synapse Gene Risk factor Genetics schizophrenia
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Summary:	Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ∼1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia ( P =7.6 × 10 −11 ) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants ( P <0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction ( P =2.0 × 10 −4 ), excitability ( P =9.0 × 10 −4 ) and cell adhesion and trans-synaptic signaling ( P =2.4 × 10 −3 ). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Please see Appendix for consortium authorship.
ISSN:	1359-4184 1476-5578 1476-5578
DOI:	10.1038/mp.2011.117