Human Molecular Genetics, Vol 8, 237-245, Copyright © 1999 by Oxford University Press
P Kehoe, F Wavrant-De Vrieze, R Crook, WS Wu, P Holmans, I Fenton, G Spurlock, N Norton, H Williams, N Williams, S Lovestone, J Perez-Tur, M Hutton, MC Chartier-Harlin, S Shears, K Roehl, J Booth, W Van Voorst, D Ramic, J Williams, A Goate, J Hardy and MJ Owen
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.
ARTICLES
A full genome scan for late onset Alzheimer's disease
Neuropsychiatric Genetics Unit, Tenovus Building, University of Wales College of Medicine, Heath Park,Cardiff CF4 4XN, UK.
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