美国再生元遗传学中心Olivier Delaneau小组取得一项新突破。他们开发出英国生物银行166740例全基因组数据中非编码区罕见变异与血液性状的关联研究。相关论文发表在2025年8月6日出版的《自然—遗传学》杂志上。

在这里，该团队利用血液基因调控和缺失评分的知识来选择与血液相关性状相关的非编码变异。整合WGS和42个血细胞计数以及166740个UK Biobank样本的生物标志物测量，小组进行了变异崩溃测试，确定了数百个涉及非编码变异的基因性状关联。

然而，该课题组证明了这些非编码罕见变异关联中的大多数(1)再现了先前研究中已知的关联，(2)是由附近常见和罕见变异之间的连锁不平衡驱动的。这项研究强调了罕见变异分析中普遍存在的挑战，以及在解释非编码罕见变异关联结果时需要谨慎。

据了解，拥有全基因组测序（WGS）的大型生物库现在能够将非编码罕见变异与复杂的人类特征联系起来。鉴于98%的基因组可供探索，非编码变异的选择仍然是这些分析中一个关键但尚未解决的挑战。

附：英文原文

Title: Noncoding rare variant associations with blood traits in 166,740 UK Biobank genomes

Author: Ribeiro, Diogo M., Hofmeister, Robin J., Rubinacci, Simone, Delaneau, Olivier

Issue&Volume: 2025-08-06

Abstract: Large biobanks with whole-genome sequencing (WGS) now enable the association of noncoding rare variants with complex human traits. Given that >98% of the genome is available for exploration, the selection of noncoding variants remains a critical yet unresolved challenge in these analyses. Here we leverage knowledge of blood gene regulation and deleteriousness scores to select noncoding variants pertinent for association with blood-related traits. Integrating WGS and 42 blood cell count and biomarker measurements for 166,740 UK Biobank samples, we perform variant collapsing tests, identifying hundreds of gene–trait associations involving noncoding variants. However, we demonstrate that most of these noncoding rare variant associations (1) reproduce associations known from previous studies and (2) are driven by linkage disequilibrium between nearby common and rare variants. This study underscores the prevailing challenges in rare variant analysis and the need for caution when interpreting noncoding rare variant association results.

DOI: 10.1038/s41588-025-02288-x

Source: https://www.nature.com/articles/s41588-025-02288-x