Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease.
OBJECTIVE
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 ( epsilon 4 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 theta between marker and disease loci will be either overestimated or estimated with little bias. Therefore, an upper limit of theta can be obtained. AD has been found to be associated with the marker allele epsilon 4 in Africans, Asians, and Caucasians. This suggests that the AD- epsilon 4 allelic LD predates the divergence of peoples occurring 100 000 years ago. With the age of AD- epsilon 4 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.
Gong
Gordon
G
Creighton University Osteoporosis Research Center, 601 North 30th Street, Suite 6730, Omaha, NE 68131, USA. gdgong@creighton.edu
Haynatzki
Gleb
G
Deng
Hong-Wen
HW
Recker
Robert R
RR
Mordeson
John
J
Cheng
Shih-Chuan
SC
Fong
Nelson
N
D000544:Alzheimer Disease / Q000235:genetics*; D002874:Chromosome Mapping; D016001:Confidence Intervals; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D009154:Mutation