Multivariate analysis of genome-wide data to identify potential pleiotropic genes for five major psychiatric disorders using MetaCCA

Background: Genome-wide association studies have been extensively applied in identifying SNP associated with major psychiatric disorders. However, the SNPs identified by the prevailing univariate approach only explain a small percentage of the genetic variance of traits, and the extensive data have shown the major psychiatric disorders have common biological mechanisms and the overlapping pathophysiological pathways.

Methods: We applied the genetic pleiotropy-informed metaCCA method on summary statistics data from the Psychiatric Genomics Consortium Cross-Disorder Group to examine the overlapping genetic relations between the five major psychiatric disorders. Furthermore, to refine all genes, we performed gene-based association analyses for the five disorders respectively using VEGAS2. Gene enrichment analysis was applied to explore the potential functional significance of the identified genes.

Results: After metaCCA analysis, 1147 SNPs reached the Bonferroni corrected threshold (p < 1.06 × 10^-6) in the univariate SNP-multivariate phenotype analysis, and 246 genes with a significance threshold (p < 3.85 × 10^-6) were identified as potentially pleiotropic genes in the multivariate SNP-multivariate phenotype analysis. By screening the results of gene-based p-values, we identified 37 putative pleiotropic genes which achieved significance threshold in metaCCA analyses and were also associated with at least one disorder in the VEGAS2 analyses.

Limitations: Alternative approaches and experimental studies may be applied to check whether novel genes could still be identified/substantiated with these methods.

Conclusions: The metaCCA method identified novel variants associated with psychiatric disorders by effectively incorporating information from different GWAS datasets. Our analyses may provide insights for some common therapeutic approaches of these five major psychiatric disorders based on the pleiotropic genes and common mechanisms identified.