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迈向对候选因果变异更精细的定位。

Towards improved fine-mapping of candidate causal variants.

作者信息

Li Zheng, Zhou Xiang

机构信息

Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.

Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

出版信息

Nat Rev Genet. 2025 Jul 28. doi: 10.1038/s41576-025-00869-4.


DOI:10.1038/s41576-025-00869-4
PMID:40721533
Abstract

Fine-mapping in genome-wide association studies aims to identify potentially causal genetic variants among a set of candidate variants that are often highly correlated with each other owing to linkage disequilibrium. A variety of statistical approaches are used in fine-mapping, almost all of which are based on a multiple regression framework to model the relationship between genotype and phenotype, while accommodating specific assumptions about the distribution of variant effect sizes and using different inference algorithms. Owing to their modelling flexibility and the ease of making inferential statements, these approaches are predominantly Bayesian in nature. Recently, these approaches have been improved by refining modelling assumptions, integrating additional information, accommodating summary statistics, and developing scalable computational algorithms that improve computation efficiency and fine-mapping resolution.

摘要

全基因组关联研究中的精细定位旨在从一组候选变异中识别潜在的因果遗传变异,这些候选变异由于连锁不平衡往往彼此高度相关。精细定位中使用了多种统计方法,几乎所有方法都基于多元回归框架来模拟基因型与表型之间的关系,同时纳入关于变异效应大小分布的特定假设并使用不同的推理算法。由于其建模灵活性和进行推理陈述的便利性,这些方法本质上主要是贝叶斯方法。最近,通过完善建模假设、整合额外信息、纳入汇总统计数据以及开发可提高计算效率和精细定位分辨率的可扩展计算算法,这些方法得到了改进。

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本文引用的文献

[1]
Fine-mapping in admixed populations using CARMA-X, with applications to Latin American studies.

Am J Hum Genet. 2025-5-1

[2]
Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels.

Nat Genet. 2025-3

[3]
Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders.

Cell. 2025-3-6

[4]
Genomic language models: opportunities and challenges.

Trends Genet. 2025-4

[5]
Fine-mapping causal tissues and genes at disease-associated loci.

Nat Genet. 2025-1

[6]
The impact of common and rare genetic variants on bradyarrhythmia development.

Nat Genet. 2025-1

[7]
FABIO: TWAS fine-mapping to prioritize causal genes for binary traits.

PLoS Genet. 2024-12-2

[8]
Fine-Mapping the Results From Genome-Wide Association Studies of Primary Biliary Cholangitis Using SuSiE and h2-D2.

Genet Epidemiol. 2025-1

[9]
Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases.

Nat Genet. 2024-9

[10]
Finemap-MiXeR: A variational Bayesian approach for genetic finemapping.

PLoS Genet. 2024-8

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