重复多态性是青光眼和结直肠癌的顶级遗传风险位点的基础。
Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer.
机构信息
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
出版信息
Cell. 2023 Aug 17;186(17):3659-3673.e23. doi: 10.1016/j.cell.2023.07.002. Epub 2023 Jul 31.
Many regions in the human genome vary in length among individuals due to variable numbers of tandem repeats (VNTRs). To assess the phenotypic impact of VNTRs genome-wide, we applied a statistical imputation approach to estimate the lengths of 9,561 autosomal VNTR loci in 418,136 unrelated UK Biobank participants and 838 GTEx participants. Association and statistical fine-mapping analyses identified 58 VNTRs that appeared to influence a complex trait in UK Biobank, 18 of which also appeared to modulate expression or splicing of a nearby gene. Non-coding VNTRs at TMCO1 and EIF3H appeared to generate the largest known contributions of common human genetic variation to risk of glaucoma and colorectal cancer, respectively. Each of these two VNTRs associated with a >2-fold range of risk across individuals. These results reveal a substantial and previously unappreciated role of non-coding VNTRs in human health and gene regulation.
由于串联重复数（VNTRs）的可变数量，人类基因组的许多区域在个体之间的长度存在差异。为了评估 VNTRs 在全基因组范围内的表型影响，我们应用了一种统计推断方法来估计 418,136 名无亲缘关系的英国生物库参与者和 838 名 GTEx 参与者的 9561 个常染色体 VNTR 基因座的长度。关联和统计精细映射分析确定了 58 个 VNTRs，这些 VNTRs 似乎在英国生物库中影响复杂性状，其中 18 个似乎也调节附近基因的表达或剪接。TMCO1 和 EIF3H 上的非编码 VNTRs 似乎分别为青光眼和结直肠癌风险的常见人类遗传变异提供了最大的已知贡献。这两个 VNTR 中的每一个与个体之间的风险范围超过 2 倍相关。这些结果揭示了非编码 VNTRs 在人类健康和基因调控中的重要且以前未被认识到的作用。
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