A hypothesis-driven pathway analysis reveals myelin-related pathways that contribute to the risk of schizophrenia and bipolar disorder

Abstract

Schizophrenia (SZ) and bipolar disorder (BD) are both severe neuropsychiatric disorders with a strong and potential overlapping genetic background. Multiple lines of evidence, including genetic studies, gene expression studies and neuroimaging studies, have suggested that both disorders are closely related to myelin and oligodendrocyte dysfunctions. In the current study, we hypothesized that the holistic effect of the myelin-related pathway contributes to the genetic susceptibility to both SZ and BD. We extracted pathway data from the canonical pathway database, Gene Ontology (GO), and selected a 'compiled' pathway based on previous literature. We then performed hypothesis-driven pathway analysis on GWAS data from the Psychiatric Genomics Consortium (PGC). As a result, we identified three myelin-related pathways with a joint effect significantly associated with both disorders: 'Myelin sheath' pathway (P(SZ) = 2.45E-7, P(BD) = 1.22E-3), 'Myelination' pathway (P(SZ) = 2.10E-4, P(BD) = 2.53E-24), and 'Compiled' pathway (P(SZ) = 4.57E-8, P(BD) = 2.61E-9). In comparing the SNPs and genes in these three pathways across the two diseases, we identified a substantial overlap in nominally associated SNPs and genes, which could be susceptibility SNPs and genes for both disorders. From these observations, we propose that myelin-related pathways may be involved in the etiologies of both SZ and BD.

Keywords: Bipolar disorder; Genome-wide association study; Myelin; Pathway-based analysis; Schizophrenia.