Dissecting Schizophrenia Biology Using Pleiotropy with Cognitive Genomics

Abstract Background Given the increasingly large number of loci discovered by psychiatric GWAS, specification of the key biological pathways underlying these loci has become a priority for the field. We have previously leveraged the pleiotropic genetic relationships between schizophrenia and two cognitive phenotypes (educational attainment and cognitive task performance) to differentiate two subsets of illness-relevant SNPs: (1) those with "concordant" alleles, which are associated with reduced cognitive performance and educational attainment and increased schizophrenia risk; and (2) those with "discordant" alleles linked to reduced educational and/or cognitive levels but lower schizophrenia susceptibility. Methods In the present study, we extend our prior work, utilizing larger input GWAS datasets and a more powerful statistical approach to pleiotropic meta-analysis, the Pleiotropic Locus Exploration and Interpretation using Optimal test (PLEIO). Results Our pleiotropic meta-analysis of schizophrenia and the two cognitive phenotypes revealed 768 significant loci (166 novel). Among these, 347 loci harbored concordant SNPs, 270 encompassed discordant SNPs, and 151 “dual” loci contained concordant and discordant SNPs. Competitive gene-set analysis using MAGMA linked concordant SNP loci with neurodevelopmental pathways (e.g., neurogenesis), whereas discordant loci were associated with mature neuronal synaptic functions. These distinctions were also observed in BrainSpan analysis of temporal enrichment patterns across developmental periods, with concordant loci containing more prenatally expressed genes than discordant loci. Dual loci were enriched for genes related to mRNA translation initiation, representing a novel finding in the schizophrenia literature. Conclusions Pleiotropic analysis permits not only enhanced statistical power for locus discovery, but also the ability to parse distinct biological processes associated with endophenotypes.