Cited by 228Schizophrenia research and treatmentGenetic Associations and EpidemiologyBipolar Disorder and Treatment

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

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O'Dushlaine, C, Kenny, E, Heron, E, Donohoe, G, Gill, M, Morris, D, The International Schizophrenia Consortium, Corvin, A·2011·Molecular Psychiatry

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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Crossref · 10.1038/mp.2010.7

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Authors
O'Dushlaine, C., Kenny, E., Heron, E., Donohoe, G., Gill, M., Morris, D., The International Schizophrenia Consortium, & Corvin, A.
Affiliations
Trinity College Dublin (IE)
Corresponding author
Corvin, A
Venue
Molecular Psychiatry
Published
2010-02-16
Volume
16
Issue
3
Pages
286-292
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
OpenAlex
W2037995604
Cited by
228
References
41
Citations by year
2026: 2 · 2025: 7 · 2024: 6 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 12 · 2019: 13 · 2018: 6 · 2017: 10 · 2016: 13 · 2015: 25 · 2014: 23 · 2013: 30 · 2012: 29
FWCI
21.39
Type
journal article
Language
en
Open access
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • HAL (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
  • Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Keywords
schizophrenia, bipolar disorder, adhesion molecules, neuronal adhesion, pathway enrichment, NRXN1, CNTNAP2, synaptogenesis, genetic susceptibility
MeSH terms
Bipolar Disorder, Calcium-Binding Proteins, Female, Humans, Male, Membrane Proteins, Nerve Tissue Proteins, Schizophrenia, Signal Transduction, Cell Adhesion Molecules, Neuronal, Neural Cell Adhesion Molecules, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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