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

Abstract

Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants each of small effect. Identifying if risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the SNP ratio test (SRT) which compares the ratio of nominally significant (p<0.05) to non-significant SNPs in a given pathway to identify `enrichment? for association signals. We applied this approach to discovery (the International Schizophrenia Consortium (ISC) (n=6,909)) and validation (Genetic Association Information Network (GAIN) (n=2,729)) schizophrenia genome-wide association study (GWAS) datasets. We investigated each of the 212 experimentally validated pathways described in Kyoto Encyclopaedia of Genes and Genomes (KEGG) in the discovery sample. Nominally significant pathways were tested in validation sample, five pathways were significant (p=0.03-0.001); only the Cell Adhesion Molecules (CAM) pathway withstood conservative correction for multiple-testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium (WTCCC) (n=4,847)) (p=0.01). At a gene-level CAM genes associated in all three samples (NRXN1 and CNTNAP2) have previously been implicated in specific language disorder, autism and schizophrenia. The Cell Adhesion Molecules (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.