Short tandem repeats (STRs) contribute significantly to genetic diversity in humans, including disease-causing variation. Although the effect of STR variation on gene expression has been extensively assessed, their impact on epigenetics has been poorly studied and limited to specific genomic regions. Here, we investigated the hypothesis that some STRs act as independent regulators of local DNA methylation in the human genome and modify risk of common human traits. To address these questions, we first analyzed two independent data sets comprising PCR-free whole-genome sequencing (WGS) and genome-wide DNA methylation levels derived from whole-blood samples in 245 (discovery cohort) and 484 individuals (replication cohort). Using genotypes for 131,635 polymorphic STRs derived from WGS using HipSTR, we identified 11,870 STRs that associated with DNA methylation levels (mSTRs) of 11,774 CpGs (Bonferroni P < 0.001) in our discovery cohort, with 90% successfully replicating in our second cohort. Subsequently, through fine-mapping using CAVIAR we defined 585 of these mSTRs as the likely causal variants underlying the observed associations (fm-mSTRs) and linked a fraction of these to previously reported genome-wide association study signals, providing insights into the mechanisms underlying complex human traits. Furthermore, by integrating gene expression data, we observed that 12.5% of the tested fm-mSTRs also modulate expression levels of nearby genes, reinforcing their regulatory potential. Overall, our findings expand the catalog of functional sequence variants that affect genome regulation, highlighting the importance of incorporating STRs in future genetic association analysis and epigenetics data for the interpretation of trait-associated variants.

中文翻译：

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短串联重复变异对局部 DNA 甲基化影响的全基因组评估

短串联重复序列 (STR) 对人类遗传多样性做出了重大贡献，包括致病变异。尽管 STR 变异对基因表达的影响已被广泛评估，但其对表观遗传学的影响研究甚少，且仅限于特定的基因组区域。在这里，我们研究了这样的假设：一些 STR 作为人类基因组中局部 DNA 甲基化的独立调节因子，并改变常见人类特征的风险。为了解决这些问题，我们首先分析了两个独立的数据集，包括来自 245 名（发现队列）和 484 名个体（复制队列）全血样本的无 PCR 全基因组测序 (WGS) 和全基因组 DNA 甲基化水平。使用 HipSTR 对源自 WGS 的 131,635 个多态性 STR 进行基因型分析，我们在我们的发现队列中鉴定出 11,870 个 STR 与 11,774 个 CpG (Bonferroni P < 0.001) 的 DNA 甲基化水平 (mSTR) 相关，其中 90% 在我们的第二个队列中成功复制。随后，通过使用 CAVIAR 进行精细绘图，我们将其中 585 个 mSTR 定义为观察到的关联 (fm-mSTR) 背后可能的因果变异，并将其中的一小部分与之前报告的全基因组关联研究信号联系起来，从而提供了对潜在机制的见解复杂的人类特征。此外，通过整合基因表达数据，我们观察到 12.5% 的测试 fm-mSTR 还调节附近基因的表达水平，增强其调节潜力。总体而言，我们的研究结果扩展了影响基因组调控的功能序列变异的目录，强调了将 STR 纳入未来遗传关联分析和表观遗传学数据中以解释性状相关变异的重要性。