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E R Martin,
E H Lai,
J R Gilbert,
A R Rogala,
A J Afshari, J Riley,
K L Finch,
J F Stevens,
K J Livak,
B D Slotterbeck,
S H Slifer,
L L Warren,
P M Conneally,
D E Schmechel,
I Purvis,
M A Pericak-Vance,
A D Roses,
J M Vance
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ABSTRACT: There has been great interest in the prospects of using single-nucleotide polymorphisms (SNPs) in the search for complex disease genes, and several initiatives devoted to the identification and mapping of SNPs throughout the human genome are currently underway. However, actual data investigating the use of SNPs for identification of complex disease genes are scarce. To begin to look at issues surrounding the use of SNPs in complex disease studies, we have initiated a collaborative SNP mapping study around APOE, the well-established susceptibility gene for late-onset Alzheimer disease (AD). Sixty SNPs in a 1.5-Mb region surrounding APOE were genotyped in samples of unrelated cases of AD, in controls, and in families with AD. Standard tests were conducted to look for association of SNP alleles with AD, in cases and controls. We also used family-based association analyses, including recently developed methods to look for haplotype association. Evidence of association (P</=.05) was identified for 7 of 13 SNPs, including the APOE-4 polymorphism, spanning 40 kb on either side of APOE. As expected, very strong evidence for association with AD was seen for the APOE-4 polymorphism, as well as for two other SNPs that lie <16 kb from APOE. Haplotype analysis using family data increased significance over that seen in single-locus tests for some of the markers, and, for these data, improved localization of the gene. Our results demonstrate that associations can be detected at SNPs near a complex disease gene. We found that a high density of markers will be necessary in order to have a good chance of including SNPs with detectable levels of allelic association with the disease mutation, and statistical analysis based on haplotypes can provide additional information with respect to tests of significance and fine localization of complex disease genes.
The American Journal of Human Genetics 08/2000; 67(2):383-94. · 10.60 Impact Factor
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E R Martin,
J R Gilbert,
E H Lai, J Riley,
A R Rogala,
B D Slotterbeck,
C A Sipe,
J M Grubber,
L L Warren,
P M Conneally,
A M Saunders,
D E Schmechel,
I Purvis,
M A Pericak-Vance,
A D Roses,
J M Vance
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ABSTRACT: The discussion of the prospects of using a dense map of single nucleotide polymorphisms (SNPs) to identify disease genes with association analysis has been extensive. However, there is little empiric evidence to support this strategy. To begin to examine the practical issues surrounding this methodology, we identified 10 SNPs in the region immediately surrounding the apolipoprotein E locus (APOE), an established susceptibility gene for Alzheimer disease. Our goal was to examine patterns of allelic association to begin to investigate the question of whether APOE could have been identified using SNPs. Our strongest evidence of association was at the 2 SNPs immediately flanking APOE.
Genomics 02/2000; 63(1):7-12. · 3.02 Impact Factor
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ABSTRACT: Whole-genome association studies using single-nucleotide polymorphisms (SNPs) are the proposed method of choice for the identification of loci associated with complex diseases. In this report, we address the feasibility of generating high-density SNP maps (with <100-kb spacing). As a pilot study, we concentrated on a 4-Mb region around the human APOE locus on chromosome 19. We compared the efficiency of SNP detection using YAC-based versus BAC/PAC-based maps, sequencing individual DNAs versus a pooled DNA sample, and we evaluated three different software applications for polymorphism detection. A total of 121 SNPs (25 in coding regions) were identified. The frequency of SNP detection was 1 SNP/1.1 kb of genomic sequence. From APOE to CALM3 (approximately 2 Mb), the average marker spacing was approximately 30 kb. Fifty-one SNPs were genotyped in five populations, and 10 SNPs showed an allele frequency differential greater than 0.5 between populations. Our results demonstrated that high-density SNP maps can be efficiently generated using existing technologies and that a genome-wide map with 60,000-100,000 SNPs is achievable in a reasonable time frame.
Genomics 11/1998; 54(1):31-8. · 3.02 Impact Factor
