Family-based RNA sequencing in bipolar disorder points to novel candidate genes and dysregulated pathways

Genetic risk variants in bipolar disorder (BD) may lead to substantial gene expression changes. Transcriptomic studies employing multiplex BD families are extremely scarce. Here, we performed RNAseq on total mRNA of 31 lymphoblastoid cell lines from a cohort of eight multiplex BD families. We conducted differential gene expression and Weighted Gene Co-expression Network Analysis (WGCNA) for candidate genes and pathways identification. The results were validated by three methods: i) replication in an independent cohort using brain-derived RNAseq data from 71 BD and 252 control individuals; ii) MAGMA gene-based association using GWAS summary statistics data; iii) gene prioritization via Polygenic Priority Score (PoPS). DEGs and co-expression modules were examined for biological enrichments and validated through gene-set analysis. We found 60 significant DEGs after comparing 16 BD cases and 15 unaffected relatives, with the long non-coding RNA (lncRNA) LINC01237 being the most significant ( adjP = 4.1E-07). Five DEGs were prioritized, including ENSG00000279277 , a lncRNA mapping in a BD GWAS locus. Enrichment analyses linked DEGs to nervous system and gated channel activities. WGCNA identified five BD-associated expression modules, with the most significant module related to ion transmembrane transport, corpus callosum hypoplasia, and a protein network related to solute carriers. This study suggests that lncRNAs may play a role in BD pathophysiology. Additionally, alterations in ion homeostasis, driven by the dysregulation of gated channels, appear a plausible impaired process in BD.