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来自16905名阿尔茨海默病测序项目受试者的全基因组序列数据的结构变异检测与关联分析

Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects.

作者信息

Wang Hui, Dombroski Beth A, Cheng Po-Liang, Tucci Albert, Si Ya-Qin, Farrell John J, Tzeng Jung-Ying, Leung Yuk Yee, Malamon John S, Wang Li-San, Vardarajan Badri N, Farrer Lindsay A, Schellenberg Gerard D, Lee Wan-Ping

机构信息

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.

Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.

出版信息

medRxiv. 2023 Sep 13:2023.09.13.23295505. doi: 10.1101/2023.09.13.23295505.

DOI:10.1101/2023.09.13.23295505
PMID:37745545
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10516060/
Abstract

Structural variations (SVs) are important contributors to the genetics of numerous human diseases. However, their role in Alzheimer's disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. Here, we analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP, N=16,905 subjects) and identified 400,234 (168,223 high-quality) SVs. We found a significant burden of deletions and duplications in AD cases (OR=1.05, =0.03), particularly for singletons (OR=1.12, =0.0002) and homozygous events (OR=1.10, <0.0004). On AD genes, the ultra-rare SVs, including protein-altering SVs in , , , and , were associated with AD (SKAT-O =0.004). Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, e.g., a deletion (chr2:105731359-105736864) in complete LD (R=0.99) with rs143080277 (chr2:105749599) in . We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics.

摘要

结构变异（SVs）是多种人类疾病遗传学的重要贡献因素。然而，由于准确检测SVs存在挑战，它们在阿尔茨海默病（AD）中的作用在很大程度上仍未得到研究。在此，我们分析了来自阿尔茨海默病测序项目（ADSP，N = 16,905名受试者）的全基因组测序数据，并鉴定出400,234个（168,223个高质量）SVs。我们发现AD病例中缺失和重复的负担显著（优势比=1.05，P = 0.03），特别是对于单倍型（优势比=1.12，P = 0.0002）和纯合事件（优势比=1.10，P < 0.0004）。在AD基因上，超罕见的SVs，包括APP、PSEN1、PSEN2和APOE中的蛋白质改变型SVs，与AD相关（SKAT - O P = 0.004）。21个SVs与已知的AD风险变异处于连锁不平衡（LD）状态，例如，一个缺失（chr2:105731359 - 105736864）与APP中的rs143080277（chr2:105749599）完全处于LD状态（R = 0.99）。我们还鉴定出16个与AD相关的SVs和13个与AD相关的病理/认知内表型相关的SVs。我们的研究结果证明了SVs对AD遗传学的广泛影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59f2/10516060/3ed65fe9aaee/nihpp-2023.09.13.23295505v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59f2/10516060/8363bc0384f5/nihpp-2023.09.13.23295505v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59f2/10516060/ecb3e4065a9e/nihpp-2023.09.13.23295505v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59f2/10516060/3da8c9c0480e/nihpp-2023.09.13.23295505v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59f2/10516060/3ed65fe9aaee/nihpp-2023.09.13.23295505v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59f2/10516060/8363bc0384f5/nihpp-2023.09.13.23295505v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59f2/10516060/ecb3e4065a9e/nihpp-2023.09.13.23295505v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59f2/10516060/3da8c9c0480e/nihpp-2023.09.13.23295505v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59f2/10516060/3ed65fe9aaee/nihpp-2023.09.13.23295505v1-f0004.jpg

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