A Comprehensive Evaluation of Cross-Omics Blood-Based Biomarkers for Neuropsychiatric Disorders

The identification of peripheral multi-omics biomarkers of brain disorders has long been hindered by insufficient sample size and confounder influence. This study aimed to compare biomarker potential for different molecules and diseases. We leveraged summary statistics of five blood quantitative trait loci studies (N = 1980 to 22,609) and genome-wide association studies (N = 9725 to 500,199) from 14 different brain disorders, such as Schizophrenia (SCZ) and Alzheimer's Disease (AD). We applied summary-based and two-sample Mendelian Randomization to estimate the associations between blood molecules and brain disorders. We identified 524 RNA, 807 methylation sites, 29 proteins, seven cytokines, and 22 metabolites having a significant association with at least one of 14 brain disorders. Simulation analyses indicated that a cross-omics combination of biomarkers had better performance for most disorders, and different disorders could associate with different omics. We identified an 11-methylation-site model for SCZ diagnosis (Area Under Curve, AUC = 0.74) by analyzing selected candidate markers in published datasets (total N = 6098). Moreover, we constructed an 18-methylation-sites model that could predict the prognosis of elders with mild cognitive impairment (hazard ratio = 2.32). We provided an association landscape between blood cross-omic biomarkers and 14 brain disorders as well as a suggestion guide for future clinical discovery and application.