A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability

IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Nature genetics Pub Date : 2024-09-23 DOI:10.1038/s41588-024-01917-1
Bharati Jadhav, Paras Garg, Joke J. F. A. van Vugt, Kristina Ibanez, Delia Gagliardi, William Lee, Mariya Shadrina, Tom Mokveld, Egor Dolzhenko, Alejandro Martin-Trujillo, Scott J. Gies, Gabrielle Altman, Clarissa Rocca, Mafalda Barbosa, Miten Jain, Nayana Lahiri, Katherine Lachlan, Henry Houlden, Benedict Paten, Genomics England Research Consortium, Project MinE ALS Sequencing Consortium, Jan Veldink, Arianna Tucci, Andrew J. Sharp
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Abstract

GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE–trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay. Phenome-wide analysis in the UK Biobank identifies GC-rich tandem repeat expansions associated with a range of traits, including a GCC expansion in AFF3 contributing to intellectual disability.

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富含甲基化的 GC 重复序列的全表型关联研究发现,AFF3 中的 GCC 重复序列扩展与智力残疾有关
富含 GC 的串联重复扩展(TRE)通常与 DNA 甲基化、基因沉默和叶酸敏感脆性位点有关,是多种先天性和晚发性疾病的基础。通过DNA甲基化分析和串联重复基因分型相结合的方法,我们发现了24个甲基化TRE,并在英国生物库的168,641名个体中进行了全表型关联研究,调查了它们对人类性状的影响,发现了156个显著的TRE-性状关联,涉及17个不同的TRE。其中,AFF3 启动子中的 GCC 扩增与完成中等教育的概率降低 2.4 倍有关,其效应大小与几种复发性致病性微缺失相当。在一个由 6371 名疑似遗传病因的神经发育问题患者组成的队列中,我们观察到与对照组相比,AFF3 基因扩增显著增高。与导致脆性X综合征的TRE相比,AFF3扩增的人群发病率至少高出五倍,因此AFF3扩增是导致神经发育迟缓的一个主要原因。
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来源期刊
Nature genetics
Nature genetics 生物-遗传学
CiteScore
43.00
自引率
2.60%
发文量
241
审稿时长
3 months
期刊介绍: Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution
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