Results of a high-resolution genome screen of 437 Alzheimer's Disease families

Blacker, Deborah; Bertram, Lars; Saunders, Aleister J.; Moscarillo, T J; Albert, Marilyn; Wiener, Howard W.; Perry, Rodney T.; Collins, Julianne S.; Harrell, Lindy E.; Go, Rodney C.P.; Mahoney, Amy; Beaty, Terri H.; Fallin, M. Danielle; Avramopoulos, Dimitrios; Chase, Gary A.; Folstein, Marshal F.; McInnis, Melvin G.; Bassett, Susan Spear; Doheny, Kimberly J.; Pugh, Elizabeth; Tanzi, Rudolph E.

doi:10.1093/hmg/ddg007

Cited by 312 publications

(223 citation statements)

References 45 publications

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“…A fact consistent with this observation is that genome-wide screens have identified several regions that show significant linkage to AD, of which the most likely to harbor new risk factors are chromosomes 1, 9, 10, 12, 19 and 21 (Pericak-Vance et al, 1997;Rogaeva et al, 1998;Wu et al, 1998;Kehoe et al, 1999;Scott et al, 2000;Mayeux et al, 2002;Myers et al, 2002;Blacker et al, 2003;Saunders et al, 2003). Several candidate gene association studies have recently focused in examining common genetic variation among Wnt signaling components in AD.…”

Section: Alzheimer's Disease Apolipoprotein E and Wnt Signalingmentioning

confidence: 76%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

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In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/b-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/b-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

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Section: Alzheimer's Disease Apolipoprotein E and Wnt Signalingmentioning

confidence: 76%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

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“…Case-control studies of genetic association, while offering enhanced power, may be prone to false positive associations due to population stratification. While a number of genome scans of AD have been reported, [45][46][47][48] including one small study of AD þ P, 4 significant or suggestive linkage to chromosome 22q, where COMT is located, has not been reported. The absence of prior evidence of linkage to chromosome 22q does not exclude the possibility of association of COMT with AD þ P. We are aware of one other casecontrol study that has also found a significant association of RS4680 G alleles with psychosis risk in AD, although other SNPs were not studied.…”

Section: Discussionmentioning

confidence: 99%

Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease

Devlin

et al. 2005

Mol Psychiatry

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Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD þ P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case-control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G-A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both single locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD þ P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD þ P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD þ P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/ RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD þ P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.

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“…Furthermore, the Expanded genetic study of 109 Swedish AD families A Sillén et al 6p24 region has not been reported earlier to be linked to AD, although findings of several smaller linkage peaks (LODs between 1.5 and 1.9) in the adjacent chromosomal regions 6p21 and 6q21 have been described. 14,15,17,18 In addition to the already discussed highly significant linkage to 19q13.33, the 4q25 region appeared as a suggestive peak both in the original (spt LOD ¼ 2.35, P ¼ 0.35 in the e4-positive subgroup) and this extended (spt LOD ¼ 2.31, P ¼ 0.28 in the e4-positive subgroup, and LOD ¼ 2.31, P ¼ 0.31 in 109 families) genome-wide scan for AD susceptibility genes. Although simulation analyses and the spt LOD scores of flanking markers (Supplementary Table 2) suggest that these LOD scores are not significant, one may be cautious to rule out the possibility of a susceptibility gene in this part of the genome as at least one candidate gene, COL25A1, is located in this region.…”

Section: Discussionmentioning

confidence: 99%

Expanded high-resolution genetic study of 109 Swedish families with Alzheimer's disease

et al. 2007

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Alzheimer's disease (AD) is a neurodegenerative disease that affects approximately 20 million persons all over the world. There are both sporadic and familial forms of AD. We have previously reported a genomewide linkage analysis on 71 Swedish AD families using 365 genotyped microsatellite markers. In this study, we increased the number of individuals included in the original 71 analysed families besides adding 38 new families. These 109 families were genotyped for 1100 novel microsatellite markers. The present study reports on the linkage data generated from the non-overlapping genotypes from the first genome scan and the genotypes of the present scan, which results in a total of 1289 successfully genotyped markers at an average density of 2.85 cM on 468 individuals from 109 AD families. Non-parametric linkage analysis yielded a significant multipoint LOD score in chromosome 19q13, the region harbouring the major susceptibility gene APOE, both for the whole set of families (LOD ¼ 5.0) and the APOE e4-positive subgroup made up of 63 families (LOD ¼ 5.3). Other suggestive linkage peaks that were observed in the original genome scan of 71 Swedish AD families were not detected in this extended analysis, and the previously reported linkage signals in chromosomes 9, 10 and 12 were not replicated.

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Results of a high-resolution genome screen of 437 Alzheimer's Disease families

Cited by 312 publications

References 45 publications

The ups and downs of Wnt signaling in prevalent neurological disorders

The ups and downs of Wnt signaling in prevalent neurological disorders

Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease

Expanded high-resolution genetic study of 109 Swedish families with Alzheimer's disease

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