PNAS：张和平教授发现研究基因及其与环境关系的新方法

生物谷

多基因（Multiple genes），gene-by-gene相互作用，gene-by-environment相互作用被认为是了解大多数复杂疾病的重要理论研究，然而要辨别这些相互关系十分困难，虽然

近期在识别复杂基因的遗传变异方面取得了一些成功，但是目前要辨认出基因与基因之间，基因与环境之间的相互作用依然存在许多困难。

来自耶鲁大学医学院传染病学与公共健康学系，江西师范法大学的研究人员为了克服这些困难，提出了一个forest-based方法，以及一个变异重要性（variable importance）的概念。这一研究成果公布在《美国国家科学院院刊》（PNAS）杂志上。

领导这一研究的是张和平教授，他于1991年获斯坦福大学博士学位，现任耶鲁大学生物统计学系终身教授。

原始出处:

Published online before print November 28, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0709868104

A forest-based approach to identifying gene and gene–gene interactions

Xiang Chen*, Ching-Ti Liu*, Meizhuo Zhang*, and Heping Zhang*, ${dagger}$ , ${ddagger}$

*Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520-8034; and ${dagger}$ Jiangxi Normal University, Jiangxi 330027, China

Communicated by Herman Chernoff, Harvard University, Cambridge, MA, October 18, 2007 (received for review July 30, 2007)

Abstract

Multiple genes, gene-by-gene interactions, and gene-by-environment interactions are believed to underlie most complex diseases. However, such interactions are difficult to identify. Although there have been recent successes in identifying genetic variants for complex diseases, it still remains difficult to identify gene–gene and gene–environment interactions. To overcome this difficulty, we propose a forest-based approach and a concept of variable importance. The proposed approach is demonstrated by simulation study for its validity and illustrated by a real data analysis for its use. Analyses of both real data and simulated data based on published genetic models show the effectiveness of our approach. For example, our analysis of a published data set on age-related macular degeneration (AMD) not only confirmed a known genetic variant (P value = 2E-6) for AMD, but also revealed an unreported haplotype surrounding single-nucleotide polymorphism (SNP) rs10272438 on chromosome 7 that was significantly associated with AMD (P value = 0.0024). These significance levels are obtained after the consideration for a large number of SNPs. Thus, the importance of this work is twofold: it proposes a powerful and flexible method to identify high-risk haplotypes and their interactions and reveals a potentially protective variant for AMD.

age-related macular degeneration | genomewide association | haplotype | single-nucleotide polymorphism | tree and forest methods

附：

Heping Zhang
Associate Professor Biostatistics, Child Study, and Statistics
Department of Epidemiology and Public Health
Yale University School of Medicine

New Haven, CT 06520-8034
Office phone: 785-6272
Office location: LEPH 202
Email: heping.zhang@yale.edu

Research Interests
Recursive Partitioning (Trees and Splines) in Health Sciences Nonparametric Analysis of Longitudinal (continuous and discrete) Data Linkage and Association Analyses, Mapping Quantitative Trait Loci FMR Imaging Analysis

Education
Ph.D. in Statistics, with minor in Computer Sciences
Stanford University, Stanford, 1991

Selected Publications and Related Software
Confidence regions in linear functional relationship. Annals of Statistics, 22, 49-66, 1994.

Maximum correlation and splines. Technometrics,36, 196-201, 1994. Software (MASAL) is available.

Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science, 268, 1584--1589, 1995. (with N. Risch) Software is available.

A tree-based method in prospective studies. Statistics in Medicine, 15, 37--50, 1996. (with T. Holford and M. Bracken) Software (RTREE) is available.

Multivariate adaptive splines for longitudinal data (MASAL). Journal of Computational and Graphic Statistics, 6, 74-91, 1997. Software is available.

Classification trees for multiple binary responses. Journal of the American Statistical Association, 93, 180-193, 1998. Software (CTMBR) is available.

Recursive Partitioning in the Health Sciences. Springer, New York, 1999. (with B. Singer) Survial tree program (STREE) is available.