Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease

Abstract

We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

“…We did not find evidence for linkage for GSTO1 at 10q26.12 for the age-at-onset phenotype, but found weak evidence for linkage with the AD phenotype [21]. Holmans et al [13] performed an affected sib-pair linkage analysis with ageat-onset, and observed the strongest support for linkage at chromosome 21q21, which was previously reported by Olson and colleagues [16]. In our dataset, locus 21q22 yielded a modest LOD score of 1.08.…”

“…With few exceptions [13,16], reports of genome-wide scans of familial AD have relied on the clinical diagnosis as the trait of interest [5]. However, Li et al [14,40] argued that the age-atonset of disease is equally important because the "regulation of onset could make it possible to delay onset beyond an individual's normal life span."…”

“…Indeed, analyses using age-at-onset of disease as a quantitative trait have yielded multiple putative loci on chromosomes 2, 7, 9, 14, 15, 20 and 21, and some of these loci were also found to be significant in the analyses of AD phenotype [13][14][15][16][17][18][19]. However, most of these analyses lack independent confirmation, with the exception of the locus at 14q32 [16] which is of interest because of its location near PSEN 1.…”

Enhanced linkage of a locus on chromosome 2 to premature coronary artery disease in the absence of hypercholesterolemia

“…An alternative approach is to include suspected sources of heterogeneity as covariates in the statistical model. The use of covariates in linkage analysis has contributed to mapping or confirming the position of genes for prostate cancer, 8,9 late-onset Alzheimer disease 10,11 and recurrent early-onset depression. 12 In this study, we report the results of a sibling pair linkage analysis of CAD on chromosome 2 using the British Heart Foundation (BHF) Family Heart Study including hypercholesterolemia as a covariate.…”

Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia

“…Previous genome-wide family-based linkage analyses have identified several loci linked to AD [9][10][11][12][13][14][15][16][17][18][19] and confirmed linkage by several groups has been reported to chromosome (chr.) 9p, 9q, 10q, 12p and 19q.…”