Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Abstract

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Recent Advances in the Genetics of Schizophrenia

“…The same group also developed an analytical framework to use summary statistics data from this GWAS to identify and rank common gene/functional pathways between schizophrenia, BD, and major depressive disorder (MDD). They reported associations for the histone methylation pathway as well as for immune and neuronal signaling and postsynaptic density [92]. Li et al[93] have recently added 30 new loci to the PGC results by adding a large Chinese sample of ∼36,000 individuals and combining them with the PGC data in meta-analysis.…”

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia

“…In addition, studies have also utilized sub-GWAS significant associations to generate polygenic risk scores, thereby allowing the profiling of genome-wide risk in individuals and across neuropsychiatric disorders (Purcell et al 2009), and to identify neuronal, immune and histone biological pathways enriched for association with psychiatric disorders using geneset analyses (O`Dushlaine 2015;Harrison 2015).…”

Gastroenterology issues in schizophrenia: Why the gut matters

“…This causal interface most likely occurs during prenatal or early postnatal brain development when neurons are migrating and synapses are being formed and pruned. Abundant and converging evidence from both genetic and environmental studies points to immune system aberrations as contributing a substantial risk for development of the disorder [6][7][8][9][10].…”