High-depth whole-genome sequencing identifies structure variants, copy number variants and short tandem repeats associated with Parkinson's disease.

IF 6.7 1区 医学 Q1 NEUROSCIENCES NPJ Parkinson's Disease Pub Date : 2024-07-23 DOI:10.1038/s41531-024-00722-1
Chaodong Wang, Hankui Liu, Xu-Ying Li, Jinghong Ma, Zhuqin Gu, Xiuli Feng, Shu Xie, Bei-Sha Tang, Shengdi Chen, Wei Wang, Jian Wang, Jianguo Zhang, Piu Chan
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Abstract

While numerous single nucleotide variants and small indels have been identified in Parkinson's disease (PD), the contribution of structural variants (SVs), copy number variants (CNVs), and short tandem repeats (STRs) remains poorly understood. Here we investigated the association using the high-depth whole-genome sequencing data from 466 Chinese PD patients and 513 controls. Totally, we identified 29,561 SVs, 32,153 CNVs, and 174,905 STRs, and found that CNV deletions were significantly enriched in the end-proportion of autosomal chromosomes in PD. After genome-wide association analysis and replication in an external cohort of 352 cases and 547 controls, we validated that the 1.6 kb-deletion neighboring MUC19, 12.4kb-deletion near RXFP1 and GGGAAA repeats in SLC2A13 were significantly associated with PD. Moreover, the MUC19 deletion and the SLC2A13 5-copy repeat reduced the penetrance of the LRRK2 G2385R variant. Moreover, genes with these variants were dosage-sensitive. These data provided novel insights into the genetic architecture of PD.

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高深度全基因组测序确定了与帕金森病相关的结构变异、拷贝数变异和短串联重复序列。
虽然在帕金森病(PD)中发现了许多单核苷酸变异和小的嵌合体,但对结构变异(SV)、拷贝数变异(CNV)和短串联重复序列(STR)的贡献仍然知之甚少。在此,我们利用来自 466 名中国帕金森病患者和 513 名对照者的高深度全基因组测序数据研究了这一关联。我们共鉴定出 29,561 个 SVs、32,153 个 CNVs 和 174,905 个 STRs,并发现 CNV 缺失明显富集于 PD 常染色体的末端部分。经过全基因组关联分析以及在由352例病例和547例对照组成的外部队列中进行复制,我们验证了邻近MUC19的1.6kb缺失、RXFP1附近的12.4kb缺失以及SLC2A13中的GGGAAA重复序列与帕金森病显著相关。此外,MUC19缺失和SLC2A13的5拷贝重复降低了LRRK2 G2385R变异的穿透性。此外,具有这些变异的基因对剂量敏感。这些数据为了解帕金森病的遗传结构提供了新的视角。
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来源期刊
NPJ Parkinson's Disease
NPJ Parkinson's Disease Medicine-Neurology (clinical)
CiteScore
9.80
自引率
5.70%
发文量
156
审稿时长
11 weeks
期刊介绍: npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.
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