A full genome scan for late onset Alzheimer's disease

Abstract

We have genotyped 292 affected sibling pairs (ASPs) with Alzheimer's disease (AD) according to NINCDS-ADRDA diagnostic criteria and with onset ages of >/=65 years using 237 microsatellite markers separated by an average distance of 16.3 cM. Data were analysed by SPLINK and MAPMAKER/SIBS on the whole sample of 292 ASPs and subsets of 162 ASPs where both members possessed an apolipoprotein E (APOE)straightepsilon4 allele and 63 pairs where neither possessed anstraightepsilon4 allele. Sixteen peaks with a multipoint lod score (MLS) >1 either in the whole sample, the straightepsilon4-positive or -negative subgroups were observed on chromosomes 1 (two peaks), 2, 5, 6, 9 (two peaks), 10 (two peaks), 12, 13, 14, 19, 21 and X (two peaks). Simulation studies revealed that these findings exceeded those expected by chance, although many are likely to be false positives. The highest lod scores on chromosomes 1 (MLS 2.67), 9 (MLS 2.38), 10 (MLS 2.27) and 19 (MLS 1.79) fulfilLander and Kruglyak's definition of 'suggestive' in that they would be expected to occur by chance once or less per genome scan. Several other peaks were only marginally less significant than this, in particular those on chromosomes 14 (MLS 2.16), 5 (MLS 2.00), 12, close to alpha2-macroglobulin (MLS 1.91), and 21, close to amyloid precursor protein (MLS 1.77). This is the largest genome scan to date in AD and shows for the first time that this is a genetically complex disorder involving several, perhaps many, genes in addition to APOE. Moreover, our data will be of interest to those hoping to identify positional candidate genes using information emerging from neurobiological studies of AD.

The ups and downs of Wnt signaling in prevalent neurological disorders

“…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.…”

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

“…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.…”

Relevance and limitations of public databases for microarray design: a critical approach to gene predictions

“…Loci likely to contain any gene of interest for AD have been defined using bibliographic study, [6][7][8][9] based on the analysis of previously published genome scan results obtained from late-onset familial forms of AD (Table 1).…”

“…We planned to make home-made microarrays to screen all ORFs contained in the risk-associated loci (over nine different chromosomes) previously identified in genome scan studies. [6][7][8][9] Two approaches were defined: (i) the first one is based on the development of specific PCR probes from a bank of 12 000 unique cDNAs; (ii) the second one consists in developing specific oligonucleotides. The aim of this report was to show the relevance and limitations of the bio-informatics analysis work, which we developed from NCBI database, to select ORFs of interest for this project.…”