Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer's disease.
Previous attempts to identify genetic loci conferring risk for late-onset Alzheimer's disease (LOAD) through linkage analysis have observed some regions of linkage in common. However, due to the sometimes-considerable overlap between the samples, some of these reports cannot be considered to be independent replications. In order to assess the strength of the evidence for linkage and to obtain the best indication of the location of susceptibility genes, we have amalgamated three large samples to give a total of 723 affected relative pairs (ARPs). Multipoint, model-free ARP linkage analysis was performed. Genome-wide significant evidence for linkage was observed on 10q21.2 (LOD=3.3) and genome-wide suggestive evidence was observed on 9q22.33 (LOD=2.5) and 19q13.32 (LOD=2.0). One further region on 9p21.3 was identified with an LOD score>1. We observe no evidence to suggest that more than one locus is responsible for the linkage to 10q21.2, although this linked region may harbour more than one susceptibility gene. Evidence of allele-sharing heterogeneity between the original collection sites was observed on chromosome 9 but not on chromosome 10 or 19. Evidence for an interaction was observed between loci on chromosomes 10 and 19. Where samples overlapped, the genotyping consistency was high, estimated to average at 97.3%. Our large-scale linkage analysis consolidates clear evidence for a susceptibility locus for LOAD on 10q21.2.
Hamshere
Marian L
ML
Biostatistics and Bioinformatics Unit, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
Holmans
Peter A
PA
Avramopoulos
Dimitrios
D
Bassett
Susan S
SS
Blacker
Deborah
D
Bertram
Lars
L
Wiener
Howard
H
Rochberg
Nan
N
Tanzi
Rudolph E
RE
Myers
Amanda
A
Wavrant-De Vrièze
Fabienne
F
Go
Rodney
R
Fallin
Daniele
D
Lovestone
Simon
S
Hardy
John
J
Goate
Alison
A
O'Donovan
Michael
M
Williams
Julie
J
Owen
Michael J
MJ
D017668:Age of Onset; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D010375:Pedigree; D035781:Siblings
D001057:Apolipoproteins E; D005819:Genetic Markers