Guo Michael H, Lee Wan-Ping, Vardarajan Badri, Schellenberg Gerard D, Phillips-Cremins Jennifer
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
medRxiv. 2023 Nov 16:2023.11.16.23298623. doi: 10.1101/2023.11.16.23298623.
Studies of the genetics of Alzheimer's disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, most of the disease heritability has yet to be uncovered, suggesting that there is substantial genetic risk conferred by other forms of genetic variation. There are over one million short tandem repeats (STRs) in the genome, and their link to AD risk has not been assessed. As pathogenic expansions of STR cause over 30 neurologic diseases, it is important to ascertain whether STRs may also be implicated in AD risk. Here, we genotyped 321,742 polymorphic STR tracts genome-wide using PCR-free whole genome sequencing data from 2,981 individuals (1,489 AD case and 1,492 control individuals). We implemented an approach to identify STR expansions as STRs with tract lengths that are outliers from the population. We then tested for differences in aggregate burden of expansions in case versus control individuals. AD patients had a 1.19-fold increase of STR expansions compared to healthy elderly controls (p=8.27×10, two-sided Mann Whitney test). Individuals carrying > 30 STR expansions had 3.62-fold higher odds of having AD and had more severe AD neuropathology. AD STR expansions were highly enriched within active promoters in post-mortem hippocampal brain tissues and particularly within SINE-VNTR-Alu (SVA) retrotransposons. Together, these results demonstrate that expanded STRs within active promoter regions of the genome promote risk of AD.
阿尔茨海默病（AD）的遗传学研究主要集中在单核苷酸变异和短插入/缺失上。然而，大部分疾病遗传力仍未被揭示，这表明其他形式的基因变异也会带来相当大的遗传风险。基因组中存在超过一百万个短串联重复序列（STR），但其与AD风险的关联尚未得到评估。由于STR的致病性扩增会导致30多种神经系统疾病，因此确定STR是否也与AD风险有关至关重要。在这里，我们使用来自2981名个体（1489例AD病例和1492例对照个体）的无PCR全基因组测序数据，对全基因组范围内的321742个多态性STR区域进行了基因分型。我们采用了一种方法来识别STR扩增，即将长度超出群体范围的STR视为扩增。然后，我们测试了病例组和对照组个体中扩增总体负担的差异。与健康老年对照组相比，AD患者的STR扩增增加了1.19倍（p = 8.27×10，双侧曼-惠特尼检验）。携带>30个STR扩增的个体患AD的几率高3.62倍，且AD神经病理学更严重。AD的STR扩增在死后海马脑组织的活性启动子中高度富集，特别是在SINE-VNTR-Alu（SVA）逆转座子中。总之，这些结果表明基因组活性启动子区域内的STR扩增会增加AD风险。
