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利用人群中的遗传变异来识别因果变异。

Leveraging genetic variability across populations for the identification of causal variants.

机构信息

The Blavatnik School of Computer Science, Tel-Aviv University, Israel.

出版信息

Am J Hum Genet. 2010 Jan;86(1):23-33. doi: 10.1016/j.ajhg.2009.11.016.


DOI:10.1016/j.ajhg.2009.11.016
PMID:20085711
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2801753/
Abstract

Genome-wide association studies have been performed extensively in the last few years, resulting in many new discoveries of genomic regions that are associated with complex traits. It is often the case that a SNP found to be associated with the condition is not the causal SNP, but a proxy to it as a result of linkage disequilibrium. For the identification of the actual causal SNP, fine-mapping follow-up is performed, either with the use of dense genotyping or by sequencing of the region. In either case, if the causal SNP is in high linkage disequilibrium with other SNPs, the fine-mapping procedure will require a very large sample size for the identification of the causal SNP. Here, we show that by leveraging genetic variability across populations, we significantly increase the localization success rate (LSR) for a causal SNP in a follow-up study that involves multiple populations as compared to a study that involves only one population. Thus, the average power for detection of the causal variant will be higher in a joint analysis than that in studies in which only one population is analyzed at a time. On the basis of this observation, we developed a framework to efficiently search for a follow-up study design: our framework searches for the best combination of populations from a pool of available populations to maximize the LSR for detection of a causal variant. This framework and its accompanying software can be used to considerably enhance the power of fine-mapping studies.

摘要

在过去的几年中,全基因组关联研究已经广泛开展,这导致了许多与复杂性状相关的基因组区域的新发现。通常情况下,与疾病相关的 SNP 并不是因果 SNP,而是由于连锁不平衡而成为其替代物。为了确定实际的因果 SNP,需要进行精细映射的后续研究,要么使用密集的基因分型,要么对该区域进行测序。在这两种情况下,如果因果 SNP 与其他 SNP 高度连锁不平衡,则精细映射过程将需要非常大的样本量来识别因果 SNP。在这里,我们表明,通过利用跨人群的遗传变异性,我们可以显著提高后续研究中因果 SNP 的定位成功率 (LSR),与仅涉及一个人群的研究相比,涉及多个人群的后续研究的 LSR 更高。因此,与每次仅分析一个人群的研究相比,联合分析中检测因果变异的平均功效更高。基于这一观察结果,我们开发了一个框架来有效地搜索后续研究设计:我们的框架从可用人群中搜索最佳人群组合,以最大化检测因果变异的 LSR。该框架及其配套软件可用于大大提高精细映射研究的功效。

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本文引用的文献

[1]
Designing genome-wide association studies: sample size, power, imputation, and the choice of genotyping chip.

PLoS Genet. 2009-5

[2]
Rapid and accurate multiple testing correction and power estimation for millions of correlated markers.

PLoS Genet. 2009-4

[3]
Linkage effects and analysis of finite sample errors in the HapMap.

Hum Hered. 2009

[4]
A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1).

Nat Genet. 2009-5

[5]
FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation.

Hum Mol Genet. 2009-5-1

[6]
Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1.

Nat Genet. 2009-3

[7]
Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

Nat Genet. 2008-6

[8]
Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.

Nat Genet. 2008-5

[9]
1000 Genomes project.

Nat Biotechnol. 2008-3

[10]
Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33.

Proc Natl Acad Sci U S A. 2008-3-18

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