LAUSR

Background Bipolar Disorder (BD) is a complex and highly heritable psychiatric disorder with a world-wide prevalence near 1%. There is converging evidence from genetic, molecular, and clinical studies of BD that implicate numerous neurotransmitter and immune signaling abnormalities. These abnormalities have been described previously in Schizophrenia (SZ), which has close genetic and molecular ties to BD. Methods The purpose of this investigation was to uncover generalizable biomarkers for BD using a cross-study analysis of six microarray data sets comprising peripheral blood transcriptomes for patients with a DSM-diagnosis of BD (n=77) and unaffected comparison subjects (n=81); furthermore, we sought to compare transcriptomic signatures between BD and SZ (obtained from a prior study). We performed a combined-subject differential expression mega-analysis with regression models applied per gene, each adjusted for clinical factors and study heterogeneity. In addition, we surveyed gene sets and gene networks for consistent differential expression in BD. Results Three genes were associated with BD at a level of significance that withstood rigorous statistical correction for multiple testing. In addition, differential expression of gene sets in BD was found; functions of these gene sets included innate immunity, energy production in mitochondrial complexes, and metabolism of RNA and proteins, among other biological pathways previously related to BD or psychosis. Lastly, we deployed a machine-learning pipeline, which discriminated BD patients from unaffected comparison subjects and SZ patients with high accuracy based on 77 genes (mean AUCROC=0.849, 95% CI=0.837 – 0.859). Discussion Our study provides strong evidence in support of candidate biomarkers for BD and introduces potentially generalizable blood-based classifiers for BD. Our findings have relevance for cross-disorder genomic analyses. This work warrants expansion to identifying gene signatures that discriminate other adult and childhood neuropsychiatric disorders.