Department of Medicine, Center for Human Genetics, and Bryan Alzheimer Disease Research Center, Duke University Medical Center, Durham, Duke University Medical Center, Durham, NC; Glaxo Wellcome, Inc., Research Triangle Park, NC; Glaxo Wellcome, Inc., London; PE Biosystems, Foster City, CA; and Department of Medicine and Molecular Genetics, Indiana University School of Medicine, IndianapolisAddress for correspondence and reprints: Dr. Eden R. Martin, Duke University Medical Center, Box 3468, Durham, NC 27710. E-mail: ude.ekud.cm.ghc@nitrameAddress for correspondence and reprints: Dr. Eden R. Martin, Duke University Medical Center, Box 3468, Durham, NC 27710. E-mail: ude.ekud.cm.ghc@nitrameReceived 2000 Mar 20; Accepted 2000 May 26.Copyright © 2000 by The American Society of Human Genetics. All rights reserved.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.
Acknowledgments
We thank all of the families whose participation made this project possible. This research was supported in part by National Institutes of Health (NIH) Program Project grant 2 P01 NS26630-11A1, NIH/National Institute of Neurological Disorders and Stroke grant 5 R01 NS31153-07, National Institute on Aging grant 5 P50 AG05128-16, and funding from Glaxo Wellcome, Inc. Support also was provided by grants from the Alzheimer’s Association. We also thank the personnel at the Center for Human Genetics of Duke University Medical Center, and special thanks are due to Drs. Beth Hauser, Bill Scott, Dmitri Zaykin, and Norman Kaplan, for the many discussions regarding this work.
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