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.
| Original language | English |
|---|---|
| Pages (from-to) | 383-394 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 67 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 23 2000 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
Cite this
SNPing away at complex diseases : Analysis of single-nucleotide polymorphisms around APOE in alzheimer disease. / Martin, Eden R; Lai, E. H.; Gilbert, John; Rogala, A. R.; Afshari, A. J.; Riley, J.; Finch, K. L.; Stevens, J. E.; Livak, K. J.; Slotterbeck, B. D.; Slifer, S. H.; Warren, L. L.; Conneally, R. M.; Schmechel, D. E.; Purvis, I.; Pericak-Vance, Margaret A; Roses, A. D.; Vance, Jeffery M.
In: American Journal of Human Genetics, Vol. 67, No. 2, 23.08.2000, p. 383-394.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - SNPing away at complex diseases
T2 - Analysis of single-nucleotide polymorphisms around APOE in alzheimer disease
AU - Martin, Eden R
AU - Lai, E. H.
AU - Gilbert, John
AU - Rogala, A. R.
AU - Afshari, A. J.
AU - Riley, J.
AU - Finch, K. L.
AU - Stevens, J. E.
AU - Livak, K. J.
AU - Slotterbeck, B. D.
AU - Slifer, S. H.
AU - Warren, L. L.
AU - Conneally, R. M.
AU - Schmechel, D. E.
AU - Purvis, I.
AU - Pericak-Vance, Margaret A
AU - Roses, A. D.
AU - Vance, Jeffery M
PY - 2000/8/23
Y1 - 2000/8/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033863391&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033863391&partnerID=8YFLogxK
U2 - 10.1086/303003
DO - 10.1086/303003
M3 - Article
C2 - 10869235
AN - SCOPUS:0033863391
VL - 67
SP - 383
EP - 394
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -