美国麻省理工学院和哈佛大学布罗德研究所Hilary K. Finucane和Elle M. Weeks共同合作，近期取得重要共组进展。他们研究利用基因特征的多基因富集来预测复杂性状和疾病背后的基因。相关研究成果2023年7月13日在线发表于《自然—遗传学》杂志上。

据介绍，全基因组关联研究（GWAS）是了解复杂人类特征和疾病生物学的宝贵工具，但直接指向致病基因的相关变异很少。

研究人员引入了一种新的方法，即多基因优先评分（PoPS），该方法可以学习性状相关的基因特征，如细胞类型特异性表达，以优先考虑GWAS基因座上的基因。使用具有精细映射编码变体基因的大型评估集，研究人员发现，PoPS和最接近的基因各自优于其他基因优先方法，但通过将PoPS与正交方法相结合，观察到最佳的整体性能。使用这种组合方法，研究人员在113个复杂性状和疾病中高精度地优先选择10642个独特的基因-性状对，不仅发现了已建立的基因-特征关系，而且在未解决的基因座上提名了新的基因，如用于估计肾小球滤过率的LGR4基因和用于深静脉血栓形成的CCR7基因。

总的来说，这一研究证明了PoPS为基因优先工具箱提供了一个强大的补充。

附：英文原文

Title: Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases

Author: Weeks, Elle M., Ulirsch, Jacob C., Cheng, Nathan Y., Trippe, Brian L., Fine, Rebecca S., Miao, Jenkai, Patwardhan, Tejal A., Kanai, Masahiro, Nasser, Joseph, Fulco, Charles P., Tashman, Katherine C., Aguet, Francois, Li, Taibo, Ordovas-Montanes, Jose, Smillie, Christopher S., Biton, Moshe, Shalek, Alex K., Ananthakrishnan, Ashwin N., Xavier, Ramnik J., Regev, Aviv, Gupta, Rajat M., Lage, Kasper, Ardlie, Kristin G., Hirschhorn, Joel N., Lander, Eric S., Engreitz, Jesse M., Finucane, Hilary K.

Issue&Volume: 2023-07-13

Abstract: Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene–trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene–trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.

DOI: 10.1038/s41588-023-01443-6

Source: https://www.nature.com/articles/s41588-023-01443-6