Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SINE-VNTR-Alu (SVA) elements, a class of great ape-specific transposable elements with gene-regulatory roles, which represents a major source of structural variability in the human population. We highlight the presence of structurally variable SVAs (SV-SVAs) in neurological disease–associated loci, and we further associate SV-SVAs to disease-associated SNPs and differential gene expression using luciferase assays and expression quantitative trait loci data. Finally, we genetically deleted SV-SVAs in the BIN1 and CD2AP Alzheimer's disease–associated risk loci and in the BCKDK Parkinson's disease–associated risk locus and assessed multiple aspects of their gene-regulatory influence in a human neuronal context. Together, this study reveals a novel layer of genetic variation in transposable elements that may contribute to identification of the structural variants that are the actual drivers of disease associations of GWAS loci.

中文翻译：

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转座因子结构变异的隐藏层揭示了人类疾病风险基因座中潜在的遗传修饰因子

全基因组关联研究 (GWAS) 在发现疾病相关基因座方面提供了丰富的信息，但并非旨在捕获人类基因组中的所有结构变异。使用长读长测序数据，我们发现 SINE-VNTR- Alu (SVA) 元件中存在广泛的结构变异，这是一类具有基因调节作用的类猿特异性转座因子，是人类结构变异的主要来源. 我们强调了神经疾病相关基因座中结构可变的 SVA (SV-SVA) 的存在，并且我们使用荧光素酶测定和表达数量性状基因座数据进一步将 SV-SVA 与疾病相关的 SNP 和差异基因表达联系起来。最后，我们在BIN1和CD2AP阿尔茨海默病相关风险位点和BCKDK帕金森病相关风险位点，并评估了它们在人类神经元环境中的基因调控影响的多个方面。总之，这项研究揭示了转座因子中新的遗传变异层，这可能有助于识别结构变异，这些变异是 GWAS 基因座疾病关联的实际驱动因素。