背景:Tourette综合征(TS)是一种神经发育障碍,以运动和发声抽动为特征。先前已使用全基因组关联研究(GWAS)在欧洲血统人群中鉴定了与TS相关的几个易感基因座。然而,TS的确切致病机制尚不清楚;此外,以前TS的GWAS结果是基于西方人群,这可能无法转化为其他人群。因此,我们对台湾TS和慢性抽动障碍(CTD)患者进行了GWAS,旨在阐明该人群中TS的遗传基础和潜在危险因素。
方法:GWAS是对台湾TS/CTDs队列进行的,样本量为1,007名TS患者和25,522名血统匹配的对照。此外,计算并评估多基因风险评分.
结果:全基因组显著基因座,rs12313062(p=1.43×10-8)等9个单核苷酸多态性,在染色体12q23.2中鉴定,与DRAM1相关,并且是在TS/CTDs组中鉴定出的新的易感基因座。DRAM1是一种由p53调控的溶酶体跨膜蛋白,可调节自噬和凋亡,与自噬破坏相关的神经精神疾病的潜在影响。
结论:这项研究在台湾人群中进行了首次针对TS的GWAS,鉴定染色体12q23.2上与DRAM1相关的重要基因座。这些发现为TS的神经生物学提供了新的见解,并为该领域的未来研究提供了潜在的方向。
BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Several susceptibility loci associated with TS have been identified previously in populations of European descent using genome-wide association studies (GWAS). However, the exact pathogenic mechanism underlying TS is unknown; additionally, the results of previous GWAS for TS were based on Western populations, which may not translate to other populations. Therefore, we conducted a GWAS in
Taiwanese patients with TS and chronic tic disorders (CTDs), with an aim to elucidate the genetic basis and potential risk factors for TS in this population.
METHODS: GWAS was performed on a
Taiwanese TS/CTDs cohort with a sample size of 1,007 patients with TS and 25,522 ancestry-matched controls. Additionally, polygenic risk score was calculated and assessed.
RESULTS: Genome-wide significant locus, rs12313062 (p=1.43 × 10-8) and other 9 single nucleotide polymorphisms, were identified in chromosomes 12q23.2, associated with DRAM1 and was a novel susceptibility locus identified in TS/CTDs group. DRAM1, a lysosomal transmembrane protein regulated by p53, modulates autophagy and apoptosis, with potential implications for neuropsychiatric conditions associated with autophagy disruption.
CONCLUSIONS: This
study conducted the first GWAS for TS in a
Taiwanese population, identifying a significant locus on chromosome 12q23.2 associated with DRAM1. These findings provide novel insights into the neurobiology of TS and potential directions for future research in this area.