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Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility

O'Dushlaine, C, Kenny, E, Heron, E, Donohoe, G, Gill, M, Morris, D, Corvin, A, O'Donovan, Michael Conlon, Kirov, George, Craddock, Nicholas John, Holmans, Peter Alan, Williams, Nigel Melville, Georgieva, Lyudmila and Owen, Michael John 2011. Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Molecular Psychiatry 16 (3) , pp. 286-292. 10.1038/mp.2010.7

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Abstract

Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant (P<0.05) to nonsignificant SNPs in a given pathway to identify the 'enrichment' for association signals. We applied this approach to the discovery (the International Schizophrenia Consortium (n=6909)) and validation (Genetic Association Information Network (n=2729)) of schizophrenia genome-wide association study (GWAS) data sets. We investigated each of the 212 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes in the discovery sample. Nominally significant pathways were tested in the validation sample, and five pathways were found to be significant (P=0.03-0.001); only the cell adhesion molecule (CAM) pathway withstood conservative correction for multiple testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium (n=4847)) (P=0.01). At a gene level, CAM genes associated in all three samples (NRXN1 and CNTNAP2), which were previously implicated in specific language disorder, autism and schizophrenia. The CAM pathway functions in neuronal cell adhesion, which is critical for synaptic formation and normal cell signaling. Similar pathways have also emerged from a pathway analysis of autism, suggesting that mechanisms involved in neuronal cell adhesion may contribute broadly to neurodevelopmental psychiatric phenotypes.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Additional Information: Michael C O’Donovan, George K Kirov, Nick J Craddock, Peter A Holmans, Nigel M Williams, Lucy Georgieva, Ivan Nikolov, N Norton, H Williams, Draga Toncheva, Vihra Milanova and Michael J Owen are collaborators on this article
Publisher: Nature Publishing Group
ISSN: 1359-4184
Last Modified: 21 Jun 2019 19:48
URI: http://orca-mwe.cf.ac.uk/id/eprint/81081

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