An investigation of immune mechanisms in major psychiatric disorders.

Abstract

Schizophrenia and major depressive disorder (MDD) are severe psychiatric disorders with well-established genetic components, such as copy number variants (CNVs). Another risk component for psychiatric disorders is environmental factors. Recent evidence presents prenatal influenza exposure as a risk factor for psychiatric disorders, particularly schizophrenia. It is suggested that the mechanism behind the risk of prenatal infection involves molecular mimicry, a theoretical process in which autoimmune cross-reactivity may occur as a result of sufficiently immune system-triggering similarity between peptides of an infectious agent and the host. Previous studies attempted to pinpoint specific peptides through which this autoimmune mechanism may occur in psychiatric disorders, including recent findings of over-enriched sequences of the viral subunit hemagglutinin aligned against human axon guidance proteins. However, associations between individual influenza subunit peptides including hemagglutinin and schizophrenia-implicated CNV peptides have never been explored. In this study, peptide alignment software based on the Batch Peptide Match kit was used to compare sequence alignment rates between proteins encoded by 142 CNVs linked to schizophrenia and subunits of the prototypical (1918) pandemic influenza virus, a demonstrably psychotogenic strain. This was done against control groups of peptides from genes expressed by human tissues not relevant to the disorder. In order to explore whether molecular mimicry risk extends beyond schizophrenia, we also performed sequence alignments between the same viral subunits and peptides from genes implicated in MDD from two recent genome-wide association studies (GWAS). Significant frequencies of peptide alignments were found between schizophrenia-implicated CNV peptides and two influenza A H1N1 subunits, matrix protein 1 (p=1x10-5) and nonstructural protein 1 (p=1x10-8). No significant matches with MDD-implicated GWAS peptides were found. Hemagglutinin, which previously showed peptide matching with proteins relevant to schizophrenia in a similar study, also showed alignments in our dataset, but were statistically not significant and had an overall depletion effect (OR<0.8). Given the growth of evidence supporting the role of prenatal influneza infection in schizophrenia risk, employing research techniques using specific viral subunits, such as artificial inoculation of animal models and stem cells, may elucidate pathogenic pathways in influenza molecular mimicry, and could prove vital for future attempts at mitigating this risk.