Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity - PubMed (original) (raw)

Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity

W K Scott et al. Am J Hum Genet. 2000 Mar.

Abstract

Apolipoprotein E (APOE) is the only confirmed susceptibility gene for late-onset Alzheimer disease (AD). In a recent genomic screen of 54 families with late-onset AD, we detected significant evidence for a second late-onset AD locus located on chromosome 12 between D12S373 and D12S390. Linkage to this region was strongest in 27 large families with at least one affected individual without an APOE-4 allele, suggesting that APOE and the chromosome 12 locus might have independent effects. We have since genotyped several additional markers across the region, to refine the linkage results. In analyzing these additional data, we have addressed the issue of heterogeneity in the data set by weighting results by clinical and neuropathologic features, sibship size, and APOE genotype. When considering all possible affected sib pairs (ASPs) per nuclear family, we obtained a peak maximum LOD score between D12S1057 and D12S1042. The magnitude and location of the maximum LOD score changed when different weighting schemes were used to control for the number of ASPs contributed by each nuclear family. Using the affected-relative-pair method implemented in GENEHUNTER-PLUS, we obtained a maximum LOD score between D12S398 and D12S1632, 25 cM from the original maximum LOD score. These results indicate that family size influences the location estimate for the chromosome 12 AD gene. The results of conditional linkage analysis by use of GENEHUNTER-PLUS indicated that evidence for linkage to chromosome 12 was stronger in families with affected individuals lacking an APOE-4 allele; much of this evidence came from families with affected individuals with neuropathologic diagnosis of dementia with Lewy bodies (DLB). Taken together, these results indicate that the chromosome 12 locus acts independently of APOE to increase the risk of late-onset familial AD and that it may be associated with the DLB variant of AD.

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Figures

Figure 1

Figure 1

Multipoint ASP analysis, by use of all possible ASPs, all independent ASPs, and one ASP per nuclear family, with the use of ASPEX, and by the average across all ASPs, with the use of GENEHUNTER-PLUS.

Figure 2

Figure 2

Multipoint affected-relative-pair (LOD*) analysis that is either unweighted, APOE-4− weighted, or APOE-4+ weighted.

Figure 3

Figure 3

Multipoint affected-relative-pair (LOD*) analysis, unweighted and stratified on the basis of presence or absence of DLB.

Figure 4

Figure 4

Multipoint affected relative pair (LOD*) analysis overall and stratified on the basis of presence or absence of DLB, with APOE-4− weighting.

Figure 5

Figure 5

Regions of chromosome 12 implicated by the present study and by other studies (Rogaeva et al. ; Wu et al. ; Kehoe et al. 1999).

References

Electronic-Database Information

    1. Genome Database, The, http://www.gdb.org/ (for follow-up markers)
    1. Marshfield Medical Research Foundation, Center for Medical Genetics, http://www.marshmed.org/genetics/ (for follow-up markers)
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for AD [MIM 104300]) -PubMed

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