Jadhav Bharati, Garg Paras, van Vugt Joke J F A, Ibanez Kristina, Gagliardi Delia, Lee William, Shadrina Mariya, Mokveld Tom, Dolzhenko Egor, Martin-Trujillo Alejandro, Gies Scott L, Rocca Clarissa, Barbosa Mafalda, Jain Miten, Lahiri Nayana, Lachlan Katherine, Houlden Henry, Paten Benedict, Veldink Jan, Tucci Arianna, Sharp Andrew J
medRxiv. 2023 Dec 12:2023.05.03.23289461. doi: 10.1101/2023.05.03.23289461.
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 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 expansions compared to controls. With a population prevalence that is at least 5-fold higher than the TRE that causes fragile X syndrome, expansions represent a significant cause of neurodevelopmental delay.
富含鸟嘌呤-胞嘧啶的串联重复序列扩增（TREs）通常与DNA甲基化、基因沉默和叶酸敏感的脆性位点相关，并构成多种先天性和迟发性疾病的基础。通过结合DNA甲基化谱分析和串联重复序列基因分型，我们在来自英国生物银行的168641名个体中鉴定出24个甲基化的TREs，并使用全表型组关联研究（PheWAS）研究了它们对人类性状的影响，确定了156个显著的TRE-性状关联，涉及17种不同的TREs。其中，某基因启动子中的GCC扩增与完成中等教育的概率降低2.4倍有关，效应大小与几种复发性致病微缺失相当。在一个由6371名有疑似遗传病因的神经发育问题先证者组成的队列中，与对照组相比，我们观察到某扩增有显著富集。某扩增的人群患病率至少比导致脆性X综合征的TRE高5倍，是神经发育延迟的一个重要原因。
