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

Molecular Psychiatry volume 16, pages 286–292 (2011)Cite this article

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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.

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Acknowledgements

We thank all the participating patients, institutions and medical staff, without whose contribution this work would not have been possible. We acknowledge the support of our funders, in particular Science Foundation Ireland and the Health Research Board. We appreciate the useful comments made by anonymous reviewers.

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Author notes

  1. C O'Dushlaine and E Kenny: These authors contributed equally to this work.

  2. See Appendix.

Authors and Affiliations

  1. Department of Psychiatry, Trinity College Dublin, Dublin, Ireland

    C O'Dushlaine, E Kenny, E Heron, G Donohoe, M Gill, D Morris & A Corvin

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The International Schizophrenia Consortium

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Correspondence to A Corvin.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Appendix

Appendix

The International Schizophrenia Consortium: Trinity College Dublin—Derek W Morris, Colm T O’Dushlaine, Elaine Kenny, Emma M Quinn, Michael Gill, Aiden Corvin; Cardiff University—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, Michael J Owen; Karolinska Institutet/University of North Carolina at Chapel Hill—Christina M Hultman, Paul Lichtenstein, Emma F Thelander, Patrick Sullivan; University College London—Andrew McQuillin, Khalid Choudhury, Susmita Datta, Jonathan Pimm, Srinivasa Thirumalai, Vinay Puri, Robert Krasucki, Jacob Lawrence, Digby Quested, Nicholas Bass, Hugh Gurling; University of Aberdeen—Caroline Crombie, Gillian Fraser, Soh Leh Kuan, Nicholas Walker, David St Clair; University of Edinburgh—Douglas HR Blackwood, Walter J Muir, Kevin A McGhee, Ben Pickard, Pat Malloy, Alan W Maclean, Margaret Van Beck; Queensland Institute of Medical Research—Naomi R Wray, Peter M Visscher, Stuart Macgregor; University of Southern California—Michele T Pato, Helena Medeiros, Frank Middleton, Celia Carvalho, Christopher Morley, Ayman Fanous, David Conti, James A Knowles, Carlos Paz Ferreira, Antonio Macedo, M Helena Azevedo, Carlos N Pato; Massachusetts General Hospital—Jennifer L Stone, Douglas M Ruderfer, Manuel AR Ferreira, Stanley Center for Psychiatric Research and Broad Institute of MIT and Harvard—Shaun M Purcell, Jennifer L Stone, Kimberly Chambert, Douglas M Ruderfer, Finny Kuruvilla, Stacey B Gabriel, Kristin Ardlie, Mark J Daly, Edward M Scolnick, Pamela Sklar.

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O'Dushlaine, C., Kenny, E., Heron, E. et al. Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Mol Psychiatry 16, 286–292 (2011). https://doi.org/10.1038/mp.2010.7

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