SNPing away at complex diseases: Analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease

There has been great interest in the prospects of using single-nucleotide p olymorphisms (SNPs) in the search for complex disease genes, and several in itiatives 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 beg in 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). Six ty SNPs in a 1.5-Mb region surrounding APOE were genotyped in samples of un related cases of AD, in controls, and in families with AD. Standard tests w ere conducted to look for association of SNP alleles with AD, in cases and controls. We also used family-based association analyses, including recentl y developed methods to look for haplotype association. Evidence of associat ion (P less than or equal to .05) was identified for 7 of 13 SNPs, includin g the APOE-4 polymorphism, spanning 40 kb on either side of APOE. As expect ed, very strong evidence for association with AD was seen for the APOE-4 po lymorphism, as well as for two other SNPs that lie <16 kb from APOE. Haplot ype analysis using family data increased significance over that seen in sin gle-locus tests for some of the markers, and, for these data, improved loca lization of the gene. Our results demonstrate that associations can be dete cted at SNPs near a complex disease gene. We found that a high density of m arkers will be necessary in order to have a good chance of including SNPs w ith detectable levels of allelic association with the disease mutation, and statistical analysis based on haplotypes can provide additional informatio n with respect to tests of significance and fine localization of complex di sease genes.