埃克塞特大学Robin N. Beaumont团队在研究中取得进展。他们通过全基因组测序分析确定了与循环蛋白水平相关的罕见、大效应非编码变异和调控区域。该项研究成果发表在2025年2月24日出版的《自然—遗传学》上。

为了开始解决这些挑战，该课题组人员对全基因组测序数据进行了cis关联分析，其中包括11亿个变异，1.23亿非编码聚合测试和约50,000名英国生物银行参与者的2907种循环蛋白水平。课题组人员鉴定出604个独立的、罕见的非编码单变与循环蛋白水平相关。与蛋白质编码变异不同，罕见的非编码遗传变异几乎同样可能增加或降低蛋白质水平。罕见的非编码聚合测试确定了357个条件独立的相关区域。其中，74例（21%）无法通过单变异检测检测到。他们的发现对于鉴定与常见人类表型相关的罕见非编码遗传变异及其作用具有重要意义，包括检测非编码变异总量的重要性。

据了解，罕见的非编码遗传变异对常见表型的贡献在很大程度上是未知的，这是由于历史上缺乏群体规模的全基因组测序数据，以及将非编码变异分类为功能相似的群体的困难。

附：英文原文

Title: Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels

Author: Hawkes, Gareth, Chundru, Kartik, Jackson, Leigh, Patel, Kashyap A., Murray, Anna, Wood, Andrew R., Wright, Caroline F., Weedon, Michael N., Frayling, Timothy M., Beaumont, Robin N.

Issue&Volume: 2025-02-24

Abstract: The contribution of rare noncoding genetic variation to common phenotypes is largely unknown, as a result of a historical lack of population-scale whole-genome sequencing data and the difficulty of categorizing noncoding variants into functionally similar groups. To begin addressing these challenges, we performed a cis association analysis using whole-genome sequencing data, consisting of 1.1 billion variants, 123 million noncoding aggregate-based tests and 2,907 circulating protein levels in ~50,000 UK Biobank participants. We identified 604 independent rare noncoding single-variant associations with circulating protein levels. Unlike protein-coding variation, rare noncoding genetic variation was almost as likely to increase or decrease protein levels. Rare noncoding aggregate testing identified 357 conditionally independent associated regions. Of these, 74 (21%) were not detectable by single-variant testing alone. Our findings have important implications for the identification, and role, of rare noncoding genetic variation associated with common human phenotypes, including the importance of testing aggregates of noncoding variants.

DOI: 10.1038/s41588-025-02095-4

Source: https://www.nature.com/articles/s41588-025-02095-4