Type

Journal Article

Authors

Derek Morris
Aiden Peter Corvin
Michael Gill

Subjects

Psychiatry

Topics
factor analysis neuroscience genome wide association schizophrenia risk analysis functional groups the european union genetics

Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. (2011)

Abstract 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. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). The genotyping of the samples was provided through the Genetic Association Information Network (GAIN). The data set(s) used for the analyses described in this manuscript were obtained from the GAIN Database found at http://view.ncbi.nlm.nih.gov/dbgap, controlled through dbGaP accession number phs000021.v2.p1. Samples and associated phenotype data for the genome-wide association of schizophrenia study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: PV Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL, USA). We gratefully acknowledge financial support of the NWO/VIDI (452-05-318 to DP), TOP ZonMW (40-00812-98-07-032 to LNC and MV), NWO-ALW Pilot grant (051.07.004 to MV), FP7 HEALTH-F2-2009-241498 (Eurospin consortium), Neuroscience Campus Amsterdam and the European Union Seventh Framework Program under grant agreement no. HEALTHF2-2009-242167 ('SynSys' project). ABS and MV are supported by the Centre for Medical Systems Biology (CMSB). PMV acknowledges funding from the Australian National Health and Medical Research Council (NHMRC grants 389892 and 613672). Collaboration between DP and PMV was supported through a Visiting Professorship grant from the Royal Netherlands Academy of Arts and Sciences (KNAW).
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Full list of authors on original publication

Derek Morris, Aiden Peter Corvin, Michael Gill

Experts in our system

1
Derek Morris
Trinity College Dublin
Total Publications: 150
 
2
Aiden Corvin
Trinity College Dublin
Total Publications: 190
 
3
Michael Gill
Trinity College Dublin
Total Publications: 260