Division of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
EMBO Rep. 2023 Jan 9;24(1):e55197. doi: 10.15252/embr.202255197. Epub 2022 Nov 11.
Transposable elements (TEs) are active in neuronal cells raising the question whether TE insertions contribute to risk of neuropsychiatric disease. While genome-wide association studies (GWAS) serve as a tool to discover genetic loci associated with neuropsychiatric diseases, unfortunately GWAS do not directly detect structural variants such as TEs. To examine the role of TEs in psychiatric and neurologic disease, we evaluated 17,000 polymorphic TEs and find 76 are in linkage disequilibrium with disease haplotypes (P < 10 ) defined by GWAS. From these 76 polymorphic TEs, we identify potentially causal candidates based on having insertions in genomic regions of regulatory chromatin and on having associations with altered gene expression in brain tissues. We show that lead candidate insertions have regulatory effects on gene expression in human neural stem cells altering the activity of a minimal promoter. Taken together, we identify 10 polymorphic TE insertions that are potential candidates on par with other variants for having a causal role in neurologic and psychiatric disorders.
转座元件 (TEs) 在神经元细胞中活跃，这引发了一个问题，即 TE 插入是否会导致神经精神疾病的风险增加。全基因组关联研究 (GWAS) 是一种发现与神经精神疾病相关的遗传位点的工具，但不幸的是，GWAS 不能直接检测到 TE 等结构变异。为了研究 TEs 在精神和神经疾病中的作用，我们评估了 17000 个多态性 TEs，并发现其中 76 个与 GWAS 定义的疾病单倍型相关联 (P < 10)。在这 76 个多态性 TEs 中，我们根据插入基因组调节染色质区域和与脑组织中基因表达改变的关联，确定了潜在的因果候选者。我们表明，主要候选插入物对人类神经干细胞中的基因表达具有调节作用，改变了最小启动子的活性。总的来说，我们确定了 10 个多态性 TE 插入物，它们是潜在的候选者，与其他变体一样，在神经和精神疾病中具有因果作用。
