Multi-omics of human plasma reveals molecular features of dysregulated inflammation and accelerated aging in schizophrenia

Anaamika Campeau,Toer Stevens,Leigh-Ana Rossitto,Michael Meehan,Dilip V Jeste,David J Gonzalez,Rebecca Daly,Pieter Dorrestein,Robert H Mills,Tanya T Nguyen,Vivian Hook

doi:10.1038/s41380-021-01339-z

Abstract

Schizophrenia is a devastating psychiatric illness that detrimentally affects a significant portion of the worldwide population. Aging of schizophrenia patients is associated with reduced longevity, but the potential biological factors associated with aging in this population have not yet been investigated in a global manner. To address this gap in knowledge, the present study assesses proteomics and metabolomics profiles in the plasma of subjects afflicted with schizophrenia compared to non-psychiatric control patients over six decades of life. Global, unbiased analyses of circulating blood plasma can provide knowledge of prominently dysregulated molecular pathways and their association with schizophrenia, as well as features of aging and gender in this disease. The resulting data compiled in this study represent a compendium of molecular changes associated with schizophrenia over the human lifetime. Supporting the clinical finding of schizophrenia’s association with more rapid aging, both schizophrenia diagnosis and age significantly influenced the plasma proteome in subjects assayed. Schizophrenia was broadly associated with prominent dysregulation of inflammatory and metabolic system components. Proteome changes demonstrated increased abundance of biomarkers for risk of physiologic comorbidities of schizophrenia, especially in younger individuals. These findings advance our understanding of the molecular etiology of schizophrenia and its associated comorbidities throughout the aging process.

Highlights

Schizophrenia is a major psychiatric illness that affects ~1% of the population worldwide
Multi-omic analysis to assess broad-scale alterations related to schizophrenia In this study, we analyzed the plasma of 54 persons with schizophrenia (SZs) and 51 age-comparable non-psychiatric comparison subjects (NCs) through three mass spectrometry-based approaches analyzing proteins, post-translational modifications (PTMs) of proteins, and metabolites (Fig. 1a)
To achieve a global perspective on the circulating molecular factors contributing to altered physiology in individuals with schizophrenia, we undertook a mass spectrometry-based multi-omic analysis of blood plasma samples collected from individuals diagnosed with schizophrenia (SZs) and non-psychiatric control subjects (NCs) representing individuals from six decades of life

Summary

INTRODUCTION

Schizophrenia is a major psychiatric illness that affects ~1% of the population worldwide. Previous studies have centered on understanding singular molecular entities (e.g., protein or metabolite) or functional pathways and their relationships to disease risk in schizophrenia These studies have identified inflammatory drivers associated with schizophrenia, such as Vcam, C-reactive protein (CRP), and various cytokines [6, 10, 11]. A growing number of investigations focus on leveraging emerging -omics technologies to uncover previously unknown mechanisms of disease and to define biomarkers associated with clinical variables [15] Such studies hold promise for their ability to reveal a wealth of information on the biological underpinnings of the disease, but for the new strategies they might portend for managing the metabolic and inflammatory dysfunction associated with schizophrenia and its treatment. The resulting data reveal a compendium of age-defined molecular factors associated with heightened disease risk in individuals with schizophrenia, including increased broad-scale inflammatory factors and metabolic dysfunction

MATERIALS AND METHODS

Campeau et al 3

RESULTS

DISCUSSION