复现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.
发表日期：2023 Jul 26
作者：
Ronen E Mukamel, Robert E Handsaker, Maxwell A Sherman, Alison R Barton, Margaux L A Hujoel, Steven A McCarroll, Po-Ru Loh
来源：
CELL
摘要：
在人类基因组中，许多区域由于串联重复变量序列（VNTRs）的可变数目而在个体之间长度不同。为了评估VNTRs对整个基因组的表型影响，我们采用了一种统计外推方法，估计了418,136个与英国生物库（UK Biobank）无关的参与者和838个GTEx（Genotype-Tissue Expression）参与者的9,561个常染色体VNTR基因座的长度。关联和统计精细定位分析确定了58个VNTRs，在UK Biobank中似乎影响了一个复杂特征，其中18个VNTRs还似乎调控了附近基因的表达或剪接。在TMCO1和EIF3H的非编码VNTRs上，出现了已知最大的与青光眼和结直肠癌风险相关的常见人类遗传变异贡献。这两个VNTRs中的每个VNTR与个体之间的风险范围相差2倍以上。这些结果揭示了非编码VNTRs在人类健康和基因调控中所起的重要作用，这一作用在以前没有得到充分认识。版权所有© 2023年作者。Elsevier Inc.发表，保留所有权利。
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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.