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A full genome scan for late onset Alzheimer's disease
Authors:Kehoe, P   Wavrant-De Vrieze, F   Crook, R   Wu, WS   Holmans, P   Fenton, I   Spurlock, G   Norton, N   Williams, H   Williams, N   Lovestone, S   Perez-Tur, J   Hutton, M   Chartier-Harlin, MC   Shears, S   Roehl, K   Booth, J   Van Voorst, W   Ramic, D   Williams, J   Goate, A   Hardy, J   Owen, MJ
Affiliation:Neuropsychiatric Genetics Unit, Tenovus Building, University of Wales College of Medicine, Heath Park,Cardiff CF4 4XN, UK.
Abstract:We have genotyped 292 affected sibling pairs (ASPs) with Alzheimer'sdisease (AD) according to NINCDS-ADRDA diagnostic criteria and with onsetages of >/=65 years using 237 microsatellite markers separated by anaverage distance of 16.3 cM. Data were analysed by SPLINK and MAPMAKER/SIBSon the whole sample of 292 ASPs and subsets of 162 ASPs where both memberspossessed an apolipoprotein E (APOE)straightepsilon4 allele and 63 pairswhere neither possessed anstraightepsilon4 allele. Sixteen peaks with amultipoint lod score (MLS) >1 either in the whole sample, thestraightepsilon4-positive or -negative subgroups were observed onchromosomes 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 thesefindings exceeded those expected by chance, although many are likely to befalse positives. The highest lod scores on chromosomes 1 (MLS 2.67), 9 (MLS2.38), 10 (MLS 2.27) and 19 (MLS 1.79) fulfilLander and Kruglyak'sdefinition of 'suggestive' in that they would be expected to occur bychance once or less per genome scan. Several other peaks were onlymarginally less significant than this, in particular those on chromosomes14 (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 largestgenome scan to date in AD and shows for the first time that this is agenetically complex disorder involving several, perhaps many, genes inaddition to APOE. Moreover, our data will be of interest to those hoping toidentify positional candidate genes using information emerging fromneurobiological studies of AD.
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