当前位置： SCI文献检索 > BMC GENOMICS期刊下所有文献 > Construction of gene clusters resembling genetic causal mechanisms for common complex disease with an application to young-onset hypertension.

Construction of gene clusters resembling genetic causal mechanisms for common complex disease with an application to young-onset hypertension.

Abstract：

BACKGROUND:Lack of power and reproducibility are caveats of genetic association studies of common complex diseases. Indeed, the heterogeneity of disease etiology demands that causal models consider the simultaneous involvement of multiple genes. Rothman's sufficient-cause model, which is well known in epidemiology, provides a framework for such a concept. In the present work, we developed a three-stage algorithm to construct gene clusters resembling Rothman's causal model for a complex disease, starting from finding influential gene pairs followed by grouping homogeneous pairs. RESULTS:The algorithm was trained and tested on 2,772 hypertensives and 6,515 normotensives extracted from four large Caucasian and Taiwanese databases. The constructed clusters, each featured by a major gene interacting with many other genes and identified a distinct group of patients, reproduced in both ethnic populations and across three genotyping platforms. We present the 14 largest gene clusters which were capable of identifying 19.3% of hypertensives in all the datasets and 41.8% if one dataset was excluded for lack of phenotype information. Although a few normotensives were also identified by the gene clusters, they usually carried less risky combinatory genotypes (insufficient causes) than the hypertensive counterparts. After establishing a cut-off percentage for risky combinatory genotypes in each gene cluster, the 14 gene clusters achieved a classification accuracy of 82.8% for all datasets and 98.9% if the information-short dataset was excluded. Furthermore, not only 10 of the 14 major genes but also many other contributing genes in the clusters are associated with either hypertension or hypertension-related diseases or functions. CONCLUSIONS:We have shown with the constructed gene clusters that a multi-causal pie-multi-component approach can indeed improve the reproducibility of genetic markers for complex disease. In addition, our novel findings including a major gene in each cluster and sufficient risky genotypes in a cluster for disease onset (which coincides with Rothman's sufficient cause theory) may not only provide a new research direction for complex diseases but also help to reveal the disease etiology.

journal_name

BMC Genomics

journal_title

BMC genomics

authors

Lynn KS,Lu CH,Yang HY,Hsu WL,Pan WH

doi

10.1186/1471-2164-14-497

subject

Has Abstract

pub_date

2013-07-23 00:00:00

pages

497

issn

1471-2164

pii

1471-2164-14-497

journal_volume

pub_type

杂志文章

在线工具

Construction of gene clusters resembling genetic causal mechanisms for common complex disease with an application to young-onset hypertension.