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Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease

中华医学杂志（英文版）2002，Vol.115Issue(8)：1233-1240,8.

Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease

作者信息

1. Creighton University Osteoporosis Research Center, 601 North 30th Street, Suite 6730, Omaha, NE 68131,USA;Creighton University Osteoporosis Research Center, 601 North 30th Street, Suite 6730, Omaha, NE 68131,USA;Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China;Creighton University Osteoporosis Research Center, 601 North 30th Street, Suite 6730, Omaha, NE 68131,USA;Department of Mathematics and Computer Science, Creighton University, 2500 California Plaza, Omaha, NE,68178;Department of Mathematics and Computer Science, Creighton University, 2500 California Plaza, Omaha, NE,68178;Department of Mathematics and Computer Science, Creighton University, 2500 California Plaza, Omaha, NE,68178
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摘要

Abstract

Objectives To formulate an equation for fine mapping of disease loci under complex conditions and determine the marker-disease distance in a specific case using this equation. Methods Lewontin's linkage disequilibrium (LD) measure D' was used to formulate an equation for mapping disease genes in the presence of phenocopies, locus heterogeneity, gene-gene and gene-environment interactions, incomplete penetrance, uncertain liability and threshold, incomplete initial LD, natural selection, recurrent mutation, high disease allele frequency and unknown mode of inheritance. This equation was then used to determine the distance between a marker (ε4 within the apolipoprotein E gene, APOE) and Alzheimer's disease (AD) loci using published data.Results An equation was formulated for mapping disease genes under the above conditions. If these conditions are present but ignored, then recombination fraction θ between marker and disease loci will be either overestimated or estimated with little bias. Therefore, an upper limit of θ can be obtained. AD has been found to be associated with the marker allele ε4 in Africans, Asians, and Caucasians. This suggests that the AD-ε4 allelic LD predates the divergence of peoples occurring 100·!000 years ago. With the age of AD-ε4 allelic LD so estimated, the maximal distance was calculated to be 23.2 kb (mean 5.8 kb).Conclusions (1) A method is developed for LD mapping of susceptibility genes. (2) A mutation within the APOE gene itself, among others, is responsible for the susceptibility to AD, which is supported by recent evidence from studies using transgenic mice.

关键词

linkage disequilibrium mapping/complex trait/phenocopies/penetrance/mutation/selection/susceptibility genes

Key words

linkage disequilibrium mapping/complex trait/phenocopies/penetrance/mutation/selection/susceptibility genes

分类

医药卫生

引用本文复制引用

..Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease[J].中华医学杂志（英文版）,2002,115(8):1233-1240,8.

基金项目

This publication was supported by revenue from the Nebraska Tobacco Settlement awarded to Creighton University by the State of Nebraska, LB692. Its contents are solely the responsibility of the authors and do not necessarily represent the official views o （）

中华医学杂志（英文版）

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ISSN：0366-6999

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