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

The International Schizophrenia Consortium (ISC)

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173 Citations (Scopus)


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 (P0.05) 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 (n6909)) and validation (Genetic Association Information Network (n2729)) 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 (P0.03-0.001); 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 (n4847)) (P0.01). 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.

Original languageEnglish
Pages (from-to)286-292
Number of pages7
JournalMolecular Psychiatry
Issue number3
Early online date16 Feb 2010
Publication statusPublished - 2011

Bibliographical note

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.


  • bipolar disorder
  • GWAS
  • neuronal cell adhesion
  • pathways
  • schizophrenia


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