Genome-wide analysis of common structural variants in Alzheimer's disease identifies a risk-associated regulatory CCG repeat in FAM193B.

IF 20.3 1区医学 Q1 NEUROSCIENCES

Nature neuroscience Pub Date : 2026-10-12 DOI:10.1038/s41593-026-02481-z

Han Cao, Yifan Fu, Xiaopu Zhou, Yangyang Duan, Fanny C F Ip, Yu Chen, Shenyuan Hu, Si Chai Liu, Timothy C Y Kwok, Kin Y Mok, Tom H Cheung, John Hardy, Amy K Y Fu, Nancy Y Ip

{"title":"Genome-wide analysis of common structural variants in Alzheimer's disease identifies a risk-associated regulatory CCG repeat in FAM193B.","authors":"Han Cao, Yifan Fu, Xiaopu Zhou, Yangyang Duan, Fanny C F Ip, Yu Chen, Shenyuan Hu, Si Chai Liu, Timothy C Y Kwok, Kin Y Mok, Tom H Cheung, John Hardy, Amy K Y Fu, Nancy Y Ip","doi":"10.1038/s41593-026-02481-z","DOIUrl":null,"url":null,"abstract":"Although Alzheimer's disease (AD) has a polygenic architecture, with numerous associated single-nucleotide polymorphisms (SNPs) identified, the contribution of structural variants (SVs) is unclear. In this study, using long-read (n = 11) and short-read (n = 3,190) sequencing data from the Chinese population, we show that common SVs contribute to AD heritability beyond common SNPs. We identify an expanded CCG repeat in the FAM193B promoter that shows a genome-wide significant association with increased AD risk (odds ratio = 2.20 per 10-repeat increase, P = 5.5 × 10-13). The expanded FAM193B-CCG repeat increases FAM193B expression and mediates the pleiotropic association between brain FAM193B expression and AD risk. Analyses of postmortem human brains and cultured neuronal cells show that elevated neuronal FAM193B expression is associated with DNA damage and cell death-related pathways. These findings establish the common FAM193B-CCG repeat as an AD risk genetic factor and highlight the contribution of common SVs to AD heritability.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3000,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41593-026-02481-z","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Although Alzheimer's disease (AD) has a polygenic architecture, with numerous associated single-nucleotide polymorphisms (SNPs) identified, the contribution of structural variants (SVs) is unclear. In this study, using long-read (n = 11) and short-read (n = 3,190) sequencing data from the Chinese population, we show that common SVs contribute to AD heritability beyond common SNPs. We identify an expanded CCG repeat in the FAM193B promoter that shows a genome-wide significant association with increased AD risk (odds ratio = 2.20 per 10-repeat increase, P = 5.5 × 10^-13). The expanded FAM193B-CCG repeat increases FAM193B expression and mediates the pleiotropic association between brain FAM193B expression and AD risk. Analyses of postmortem human brains and cultured neuronal cells show that elevated neuronal FAM193B expression is associated with DNA damage and cell death-related pathways. These findings establish the common FAM193B-CCG repeat as an AD risk genetic factor and highlight the contribution of common SVs to AD heritability.

查看原文本刊更多论文

阿尔茨海默病常见结构变异的全基因组分析确定了FAM193B中风险相关的调节CCG重复序列。

尽管阿尔茨海默病（AD）具有多基因结构，并发现了许多相关的单核苷酸多态性（snp），但结构变异（SVs）的作用尚不清楚。在这项研究中，我们使用来自中国人群的长读（n = 11）和短读（n = 3190）测序数据，发现共同的sv对AD遗传力的贡献超过了共同的snp。我们在FAM193B启动子中发现了一个扩展的CCG重复序列，显示出与AD风险增加的全基因组显著相关（比值比= 2.20 / 10重复增加，P = 5.5 × 10-13）。扩增的FAM193B- ccg重复序列增加了FAM193B的表达，并介导了大脑FAM193B表达与AD风险之间的多效性关联。对死后人脑和培养的神经元细胞的分析表明，神经元FAM193B表达升高与DNA损伤和细胞死亡相关通路有关。这些发现确定了常见的FAM193B-CCG重复序列是AD的风险遗传因素，并强调了常见SVs对AD遗传力的贡献。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Nature neuroscience 医学-神经科学

CiteScore

38.60

自引率

1.20%

发文量

212

审稿时长

1 months

期刊介绍： Nature Neuroscience, a multidisciplinary journal, publishes papers of the utmost quality and significance across all realms of neuroscience. The editors welcome contributions spanning molecular, cellular, systems, and cognitive neuroscience, along with psychophysics, computational modeling, and nervous system disorders. While no area is off-limits, studies offering fundamental insights into nervous system function receive priority. The journal offers high visibility to both readers and authors, fostering interdisciplinary communication and accessibility to a broad audience. It maintains high standards of copy editing and production, rigorous peer review, rapid publication, and operates independently from academic societies and other vested interests. In addition to primary research, Nature Neuroscience features news and views, reviews, editorials, commentaries, perspectives, book reviews, and correspondence, aiming to serve as the voice of the global neuroscience community.