澳大利亚昆士兰大学Loic Yengo研团队取得一项新突破。他们开发出人类表型缺失遗传性的估计和定位。这一研究成果发表在2025年11月12日出版的国际学术期刊《自然》上。

在这里，该课题组分析了来自英国生物银行347630名欧洲血统个体的全基因组序列（WGS）数据，以量化40100万个单核苷酸和短indel变异（次要等位基因频率（MAF）大于0.01%）与34种复杂性状和疾病的遗传力有关。平均而言，该研究组发现WGS捕获了大约88%的基于家系的狭义遗传力：即20%来自罕见变异（MAF<）1%)， 68%来自常见变异（MAF≥1%）。

该课题组人员发现编码和非编码遗传变异分别占基于WGS的罕见变异遗传力的21%和79%。研究人员发现15个性状在基于WGS的遗传力估计和基于系谱的遗传力估计之间没有显著差异，这表明它们的遗传力完全被WGS数据所解释。最后，研究组对所有34种表型进行了全基因组关联分析，总体上确定了11243种常见变异关联和886种罕见变异关联。总之，他们的研究提供了对罕见变异遗传力的高精度估计，解释了许多表型的遗传力，并证明了脂质性状超过25%的罕见变异遗传力可以映射到少于50万个完全测序的基因组的特定位点。

据悉，罕见的编码变异塑造了人类表型的个体间差异。然而，罕见的非编码变异对这些差异的贡献仍然没有得到很好的描述。

附：英文原文

Title: Estimation and mapping of the missing heritability of human phenotypes

Author: Wainschtein, Pierrick, Zhang, Yuanxiang, Schwartzentruber, Jeremy, Kassam, Irfahan, Sidorenko, Julia, Fiziev, Petko P., Wang, Huanwei, McRae, Jeremy, Border, Richard, Zaitlen, Noah, Sankararaman, Sriram, Goddard, Michael E., Zeng, Jian, Visscher, Peter M., Farh, Kyle Kai-How, Yengo, Loic

Issue&Volume: 2025-11-12

Abstract: Rare coding variants shape inter-individual differences in human phenotypes1. However, the contribution of rare non-coding variants to those differences remains poorly characterized. Here we analyse whole-genome sequence (WGS) data from 347,630 individuals with European ancestry in the UK Biobank2,3 to quantify the relative contribution of 40million single-nucleotide and short indel variants (with a minor allele frequency (MAF) larger than 0.01%) to the heritability of 34 complex traits and diseases. On average across phenotypes, we find that WGS captures approximately 88% of the pedigree-based narrow sense heritability: that is, 20% from rare variants (MAF<1%) and 68% from common variants (MAF≥1%). We show that coding and non-coding genetic variants account for 21% and 79% of the rare-variant WGS-based heritability, respectively. We identified 15 traits with no significant difference between WGS-based and pedigree-based heritability estimates, suggesting their heritability is fully accounted for by WGS data. Finally, we performed genome-wide association analyses of all 34 phenotypes and, overall, identified 11,243 common-variant associations and 886 rare-variant associations. Altogether, our study provides high-precision estimates of rare-variant heritability, explains the heritability of many phenotypes and demonstrates for lipid traits that more than 25% of rare-variant heritability can be mapped to specific loci using fewer than 500,000 fully sequenced genomes.

DOI: 10.1038/s41586-025-09720-6

Source: https://www.nature.com/articles/s41586-025-09720-6