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.

中文翻译：

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在 1p31.1 GWAS 风险基因座中鉴定与重度抑郁症相关的功能性人类独特的 351-bp Alu 插入多态性。

全基因组关联研究 (GWAS) 报告了与重度抑郁症 (MDD) 相关的大量单核苷酸多态性 (SNP)，但 GWAS 风险基因座的潜在功能变化尚不清楚。在这里，我们表明欧洲 MDD 全基因组风险相关等位基因 rs12129573 在 1p31.1 与汉族 MDD 相关，并且该 SNP 与人类独特的 Alu 插入多态性 (rs70959274) 处于强连锁不平衡 (LD)在长链非编码 RNA (lncRNA) LINC01360 (Long Intergenic Non-Protein Coding RNA 1360) 的 5' 侧翼区域中，在目前可用的表达数据集中，它优选在人类睾丸中表达。rs12129573 的风险等位基因几乎完全与这种 Alu 插入的缺失有关。Alu 插入多态性 (rs70959274) 与 LINC01360 的较低 RNA 水平显着相关，并可能通过调节其内部 CpG 位点的甲基化而充当转录沉默子。荧光素酶测定证实，在 rs70959274 处存在 Alu 插入会抑制人类细胞中的转录活性，并且通过 CRISPR/Cas9 定向基因组编辑删除 Alu 插入会增加 LINC01360 的 RNA 表达。人类细胞中 Alu 插入的缺失也会导致与 MDD 相关的基因表达、生物学过程和途径的失调，例如 DRD2 和 FLOT1 的 mRNA 水平的改变，参与突触传递、神经发生、学习或记忆的基因转录，和 PI3K-Akt 信号通路。总之，