Novel loci and potential mechanisms of major depressive disorder, bipolar disorder, and schizophrenia

Different psychiatric disorders share genetic relationships and pleiotropic loci to certain extent. We integrated and analyzed datasets related to major depressive disorder (MDD), bipolar disorder (BIP), and schizophrenia (SCZ) from the Psychiatric Genomics Consortium using multitrait analysis of genome-wide association analysis (MTAG). MTAG significantly increased the effective sample size from 99,773 to 119,754 for MDD, from 909,061 to 1,450,972 for BIP, and from 856,677 to 940,613 for SCZ. We discovered 7, 32, and 43 novel lead single nucleotide polymorphisms (SNPs) and 1, 6, and 3 novel causal SNPs for MDD, BIP, and SCZ, respectively, after fine-mapping. We identified rs8039305 in the FURIN gene as a novel pleiotropic locus across the three disorders. We performed marker analysis of genomic annotation (MAGMA) and Hi-C-coupled MAGMA (H-MAGMA) based gene-set analysis and identified 101 genes associated with the three disorders, which were enriched in the regulation of postsynaptic membranes, postsynaptic membrane dopaminergic synapses, and Notch signaling pathway. Next, we performed Mendelian randomization analysis using different tools and detected a causal effect of BIP on SCZ. Overall, we demonstrated the usage of combined genome-wide association studies summary statistics for exploring potential novel mechanisms of the three psychiatric disorders, providing an alternative approach to integrate publicly available summary data.