Peripheral lncRNA-IL1RAP Dysregulation in Schizophrenia: A Multi-Omics Bridge Between Immunity and Diagnosis

Schizophrenia (SCZ) is frequently accompanied by peripheral immune dysregulation, yet robust and reproducible blood-based molecular markers remain limited.

We sought a compact long non-coding RNA (lncRNA) signal in peripheral blood leukocytes (PBL) and examined how it aligns with immune-linked transcriptional programs and cellular compartments, using bulk RNA sequencing (RNA-seq), targeted validation, and a healthy-donor peripheral blood mononuclear cell (PBMC) single-cell reference for localization.

PBL from 50 first-episode or unmedicated SCZ patients and 50 matched controls underwent RNA-seq. We performed reference-guided transcript annotation and generated lncRNA and mRNA count matrices. Differential expression was assessed with edgeR (TMM normalization). Candidate lncRNAs were prioritized using sample-level lncRNA-mRNA co-variation, followed by qRT-PCR validation in an independent cohort and evaluation with a two-feature logistic regression model using repeated 10-fold cross-validation. Pathway-scale analyses and weighted gene co-expression network analysis (WGCNA) summarized coordinated programs. Single-cell data from healthy donors were used for expression localization only, not case-control testing.

We observed a small set of dysregulated lncRNAs alongside broader mRNA changes. Two candidates at the CCR3 and IL1RAP loci (TCONS_00134168/lncRNA-CCR3 and TCONS_00138311/lncRNA-IL1RAP) showed consistent case-control directionality and were supported by qRT-PCR. The two-lncRNA model showed strong internal discrimination (AUC = 0.933) but weaker, uncertain performance in a small external qRT-PCR set (AUC = 0.656). Enrichment analyses highlighted synapse-related annotations, RNA processing/translation, and immune signaling, with recurrent involvement of IL1RAP-linked IL-1 branches. WGCNA placed lncRNA-IL1RAP and IL1RAP within diagnosis-inversely associated co-expression programs, whereas lncRNA-CCR3 showed a more transcript-specific pattern. In the healthy-reference single-cell atlas, IL1B/IL1RAP/HSF1 signals were most prominent in the monocyte/macrophage compartment.

Together, these findings support an exploratory two-lncRNA candidate marker concept, while underscoring the need for larger multi-center validation and targeted mechanistic follow-up without implying causality.