Identification of a functional human-unique 351-bp Alu insertion polymorphism associated with major depressive disorder in the 1p31.1 GWAS risk loci

Abstract

Genome-wide association studies (GWAS) have reported substantial single-nucleotide polymorphisms (SNPs) associated with major depressive disorder (MDD), but the underlying functional variations in the GWAS risk loci are unclear. Here we show that the European MDD genome-wide risk-associated allele of rs12129573 at 1p31.1 is associated with MDD in Han Chinese, and this SNP is in strong linkage disequilibrium (LD) with a human-unique Alu insertion polymorphism (rs70959274) in the 5′ flanking region of a long non-coding RNA (lncRNA) LINC01360 (Long Intergenic Non-Protein Coding RNA 1360), which is preferably expressed in human testis in the currently available expression datasets. The risk allele at rs12129573 is almost completely linked with the absence of this Alu insertion. The Alu insertion polymorphism (rs70959274) is significantly associated with a lower RNA level of LINC01360 and acts as a transcription silencer likely through modulating the methylation of its internal CpG sites. Luciferase assays confirm that the presence of Alu insertion at rs70959274 suppresses transcriptional activities in human cells, and deletion of the Alu insertion through CRISPR/Cas9-directed genome editing increases RNA expression of LINC01360. Deletion of the Alu insertion in human cells also leads to dysregulation of gene expression, biological processes and pathways relevant to MDD, such as the alterations of mRNA levels of DRD2 and FLOT1, transcription of genes involved in synaptic transmission, neurogenesis, learning or memory, and the PI3K-Akt signaling pathway. In summary, we identify a human-unique DNA repetitive polymorphism in robust LD with the MDD risk-associated SNP at the prominent 1p31.1 GWAS loci, and offer insights into the molecular basis of the illness.

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Fig. 1: Genetic associations of SNPs spanning 1p31.1 region with major depressive disorder (MDD) in European populations, and schematic of rs12129573 and Alu polymorphism (rs70959274) locations in human genome.
Fig. 2: Molecular characterization of the linked rs12129573 and rs70959274.
Fig. 3: Effects of rs70959274 on LINC01360 transcriptional activities and gene expression.
Fig. 4

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W.L., L.L., X.X. and M.L. designed the study and interpreted the results. W.L., W.L., X.C. and Z.Y. conducted the SNP and Alu genotyping, the primary functional assays, including molecular cloning, cell line experiments, and analysis of those data. H.L. performed the bioinformatics analysis based on RNA-sequencing data. H.C. and X.X. contributed to design the CRISPR/Cas9 experiments. W.L., X.S., M.S., D.S.Z., X.L., C.Z., M.S., L.Z., Y.Y., Y.Z., J.Z., Y.G.Y., Y.F. and L.L. contributed to collection of clinical samples. X.X. and M.L. drafted the manuscript, and all authors contributed to the final version of the paper.

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Correspondence to Luxian Lv or Ming Li or Xiao Xiao.

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Liu, W., Li, W., Cai, X. et al. Identification of a functional human-unique 351-bp Alu insertion polymorphism associated with major depressive disorder in the 1p31.1 GWAS risk loci. Neuropsychopharmacol. 45, 1196–1206 (2020). https://doi.org/10.1038/s41386-020-0659-2

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