Initial results of a genome survey for novel alzheimer's disease risk genes: association with a locus on the X chromosome

Abstract

As the initial step in a systematic genome survey, 16 simple sequence tandem repeat polymorphisms that span the X chromosome at an average spacing of 10 cM were examined for allelic associations with typical-onset Alzheimer's disease (AD). The efficiency of this survey was substantially enhanced by genotyping pools of genomic DNA from 50 autopsy-confirmed AD cases and 50 autopsied controls who were similar in sex ratio, race, and age at death. The frequency of the DXS1047 202-bp allele was twice as common among AD cases (0.45+/-S.E. 0.06) than controls (0.22+/-S.E. 0.05), a finding that was reproduced in an independent and geographically disparate sample. Consistent with Hardy-Weinberg equilibrium, the proportion of women with AD who carried the 202-bp allele, 73% was nearly double that observed for men with AD, 38%. However, the frequency of the 202-bp allele was similar for men and women and the presence of this allele did not affect the age at onset of dementia in either sex. Furthermore, the frequency of the DXS1047 202-bp allele in AD cases and controls was unaffected by the APOE genotype, indicating that these two loci modulate AD risk independently. Finally, the frequency of the 202-bp allele among 50 autopsy-confirmed cases of Parkinson's disease (0.29+/-S.E. 0.06) was indistinguishable from the control value, reflecting relative specificity for this allelic association with AD.

Effects of ApoE4 and maternal history of dementia on hippocampal atrophy

“…This unique predisposition may be mediated by X chromosome [Kehoe, et al, 1999; Zubenko, et al, 1998] or mitochondrial DNA susceptability genes [Mancuso, et al, 2008; Onyango, et al, 2006; Schapira, 2006]. The theory of causative mitochondrial DNA alterations is especially compelling as a decline in mitochondrial respiratory function invariably leads to metabolic disruption, increased generation of reactive oxygen species, enhanced apopotosis [Lin and Beal, 2006], cell loss and brain atrophy all of which occur in AD [Markesbery, 1997].…”

Genome survey for susceptibility loci for recurrent, early‐onset major depression: Results at 10cM resolution

“…We have previously completed systematic surveys of the human genome at an average resolution of 10 cM for simple sequence tandem repeat polymorphisms (SSTRPs) that target susceptibility genes for Alzheimers disease and other complex human phenotypes by virtue of linkage disequilibrium [Zubenko et al, 1998a, 1998b]. The efficiency of this approach was enhanced by genotyping pools of DNA from affected individuals and otherwise matched controls.…”

The X-chromosome instability phenotype in Alzheimer’s disease: A clinical sign of accelerating aging?

“…For instance, repeated non-disjunction of chromosome X, and 18, and 21 by PCS in who are women clinically normal and who have offspring with Down's syndrome have twice the chance to develop AD [3, 30, 31]. Interestingly, there is a preferential susceptibility of chromosomes X, 18, and 21 in aged and AD subjects, especially the X chromosome in women [32]. Also, a recent genome-wide association study provided substantial evidence for an association between genetic variation in the protocadherin 11 gene (PCDH 11) on the X chromosome and increased late-onset Alzheimer's disease in females [33].…”