Involvement of the long intergenic non-coding RNA LINC00461 in schizophrenia

Shuquan Rao,Hongbao Cao,Fuquan Zhang,Ancha Baranova,Lin Tian

doi:10.1186/s12888-022-03718-4

Abstract

ObjectiveLINC00461 is a highly conserved intergenic non-protein coding RNA that was implicated in schizophrenia at the genome-wide level. We aim to explore potential mechanisms underlying the involvement of LINC00461 in schizophrenia.MethodsWe performed a meta-analysis to investigate the association of LINC00461 rs410216 with schizophrenia, and evaluate the effects of the rs410216 on hippocampal volume and function using the functional magnetic resonance imaging (fMRI) analysis. We utilized the GTEx dataset to profile the expression distribution of LINC00461 across different brain regions, and to investigate the potential impact of the risk SNPs on the expression of LINC00461 and other nearby genes. We compared blood expression levels of LINC00461 between schizophrenia patients and controls.ResultsHere we show that single-nucleotide polymorphisms (SNPs) located in regulatory elements spanning the LINC00461 region are significantly associated with schizophrenia (index SNP rs410216, Pmeta = 1.43E-05); subjects carrying the risk allele of rs410216 showed decreased hippocampal volume. However, no significant association of the rs410216 variant with hippocampal activation was observed. Moreover, the expression level of LINC00461 mRNA was significantly lower in first-onset schizophrenia patients, and the risk allele also predicts a lower transcriptional level of LINC00461 in the hippocampus.ConclusionTogether, these convergent lines of evidence implicate inadequate LINC00461 expression in the hippocampus in the development of schizophrenia, providing novel insight into the genetic architecture and biological etiology of schizophrenia.

Highlights

Schizophrenia is a severe mental disorder with high heritability and strong genetic heterogeneity
We reveal that the risk allele carriers predict lower mRNA levels of LINC00461, but not other nearby genes, in the hippocampus
The remaining five single-nucleotide polymorphisms (SNPs) showed moderate to strong Linkage disequilibrium (LD) with the index SNP, rs410216

Summary

Introduction

Schizophrenia is a severe mental disorder with high heritability and strong genetic heterogeneity. Despite considerable heritability [1], the mechanism of schizophrenia remains elusive due to the phenotypic uncertainties and etiological heterogeneity. Accumulating studies point to structural and functional abnormalities in the hippocampus using imaging and postmortem studies. Protein-coding genes are cardinal forces influencing disease etiology, accumulating evidence strongly suggests that long noncoding RNA (lncRNA) may facilitate deciphering the disease pathogenesis [5]. The lncRNA LINC00461 is a feasible target in the pathogenesis of schizophrenia due to the. LINC00461 is predominantly expressed in the brain (Supplementary Fig. 1). The sequence and expression pattern of LINC00461 were highly conserved across diverse species [7], suggesting its crucial roles in the regulation of brain functions. LINC00461 is one of the most pleiotropic genome-wide risk genes for major psychiatric traits [8], including schizophrenia [9]

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Conclusion