A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 as a significant cause of intellectual disability.
A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 as a significant cause of intellectual disability.
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一项针对甲基化 GC 重复序列的全表组关联研究发现，AFF3 中的 GCC 重复序列扩展是智力障碍的一个重要原因。
DOI：
10.1101/2023.05.03.23289461
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Lahiri,Nayan
中科院分区：
文献类型：
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作者：
Jadhav,Bharati;Garg,Paras;vanVugt,JokeJFA;Ibanez,Kristina;Gagliardi,Delia;Lee,William;Shadrina,Mariya;Mokveld,Tom;Dolzhenko,Egor;Martin-Trujillo,Alejandro;Gies,ScottL;Rocca,Clarissa;Barbosa,Mafalda;Jain,Miten;Lahiri,Nayan
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 PheWAS 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 linked 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 to controls. With a population prevalence that is at least 5-fold higher than TREs causing fragile X syndrome, AFF3 expansions represent a significant cause of neurodevelopmental delay in humans.
