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

The International Schizophrenia Consortium (ISC)

Research output: Contribution to journalArticle

150 Citations (Scopus)

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 (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
Volume16
Issue number3
Early online date16 Feb 2010
DOIs
Publication statusPublished - 2011

Fingerprint

Bipolar Disorder
Cell Adhesion
Schizophrenia
Cell Adhesion Molecules
Cell Membrane
Autistic Disorder
Single Nucleotide Polymorphism
Genes
Language Disorders
Information Services
Genome-Wide Association Study
Psychiatry
Genome
Phenotype

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. / The International Schizophrenia Consortium (ISC).

In: Molecular Psychiatry, Vol. 16, No. 3, 2011, p. 286-292.

Research output: Contribution to journalArticle

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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 (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.",
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