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

Gordon Gong, Gleb Haynatzki, Hong Wen Deng, Robert R.recker, John Mordeson, Shih Chuan Cheng, Nelson Fong

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 (E4 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 E4 in Africans, Asians, and Caucasians. This suggests that the AD-E4 allelic LD predates the divergence of peoples occurring 100 000 years ago. With the age of AD-E4 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.

Original languageEnglish (US)
Pages (from-to)1233-1240
Number of pages8
JournalChinese Medical Journal
Volume115
Issue number8
StatePublished - Aug 1 2002

Fingerprint

Chromosome Mapping
Linkage Disequilibrium
Alzheimer Disease
Genes
Apolipoproteins E
Gene-Environment Interaction
Mutation
Penetrance
Genetic Selection
Prednisolone
Gene Frequency
Transgenic Mice
Genetic Recombination
Alleles

Keywords

  • Complex trait
  • Linkage disequilibrium mapping
  • Mutation
  • Penetrance
  • Phenocopies
  • Selection
  • Susceptibility genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gong, G., Haynatzki, G., Deng, H. W., R.recker, R., Mordeson, J., Cheng, S. C., & Fong, N. (2002). Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease. Chinese Medical Journal, 115(8), 1233-1240.

Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease. / Gong, Gordon; Haynatzki, Gleb; Deng, Hong Wen; R.recker, Robert; Mordeson, John; Cheng, Shih Chuan; Fong, Nelson.

In: Chinese Medical Journal, Vol. 115, No. 8, 01.08.2002, p. 1233-1240.

Research output: Contribution to journalArticle

Gong, G, Haynatzki, G, Deng, HW, R.recker, R, Mordeson, J, Cheng, SC & Fong, N 2002, 'Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease', Chinese Medical Journal, vol. 115, no. 8, pp. 1233-1240.
Gong, Gordon ; Haynatzki, Gleb ; Deng, Hong Wen ; R.recker, Robert ; Mordeson, John ; Cheng, Shih Chuan ; Fong, Nelson. / Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease. In: Chinese Medical Journal. 2002 ; Vol. 115, No. 8. pp. 1233-1240.
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