A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping or DNA sequencing. V. Analysis of case/control sampling designs: Alzheimer's disease and the apoprotein E locus.

Present-day associations between haplotypes at a candidate locus and phenotypes exist when phenotypically important mutations occurred at some point during the evolution of the current array of genetic variation. A cladistic statistical design can be defined that focuses power by using the evolutionary history of the candidate DNA region. This paper shows how cladistic methodology is used for the analysis of case/control data, a common sampling design in genetic/disease association studies. A worked example is presented of the associations for sporadic early and late-onset forms of Alzheimer's disease with the 19q13.2 chromosomal region that includes the loci for apoproteins E, CI, and CII. This analysis confirms earlier reports of a strong association of the ApoE epsilon 4 allele with Alzheimer's disease but indicates that it is premature to consider this association causal, particularly for early onset cases. Associations were also found with the epsilon 2 allele, as previously reported, and with the 1 allele at the ApoCI locus. However, this analysis indicates that it is inappropriate both statistically and medically to use single markers as risk predictors when haplotype data are available, even when the mutation leading to the marker is identified as having a strong phenotypic association.

[1]  B. Hyman,et al.  Frequency of the apolipoprotein E ε2 allele is diminished in sporadic Alzheimer disease , 1994, Neuroscience Letters.

[2]  E. Boerwinkle,et al.  A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. I. Basic theory and an analysis of alcohol dehydrogenase activity in Drosophila. , 1987, Genetics.

[3]  A. Hofman,et al.  Apolipoprotein E4 allele in a population–based study of early–onset Alzheimer's disease , 1994, Nature Genetics.

[4]  Margaret A. Pericak-Vance,et al.  Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype , 1994, Experimental Neurology.

[5]  C. Sing,et al.  A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping and DNA sequence data. III. Cladogram estimation. , 1992, Genetics.

[6]  D. Roff,et al.  The statistical analysis of mitochondrial DNA polymorphisms: chi 2 and the problem of small samples. , 1989, Molecular biology and evolution.

[7]  B. Hyman,et al.  Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease. , 1994, Neuroscience letters.

[8]  M. Rossor,et al.  Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. , 1994, Human molecular genetics.

[9]  B. Winblad,et al.  Lack of association between apolipoprotein E allele ɛ4 and sporadic Alzheimer's disease , 1994, Neuroscience Letters.

[10]  C. Sing,et al.  A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. IV. Nested analyses with cladogram uncertainty and recombination. , 1993, Genetics.

[11]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[12]  E. Wijsman,et al.  The apolipoprotein E/CI/CII gene cluster and late-onset Alzheimer disease. , 1994, American journal of human genetics.

[13]  C. Sing,et al.  A cladistic analysis of phenotype associations with haplotypes inferred from restriction endonuclease mapping. II. The analysis of natural populations. , 1988, Genetics.

[14]  A. M. Saunders,et al.  Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease , 1994, Nature Genetics.