Human Molecular Genetics Advance Access originally published online on August 27, 2007
Human Molecular Genetics 2007 16(22):2703-2712; doi:10.1093/hmg/ddm224
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Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer's disease
1 Biostatistics and Bioinformatics Unit and 2 Department of Psychological Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK, 3 Department of Psychiatry, and 4 McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 5 Gerontology Research Unit, Department of Psychiatry and 6 Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA, 7 Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA, 8 Department of Epidemiology, University of Alabama at Birmingham, USA, 9 Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA, 10 Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, USA, 11 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892-3707, USA, 12 MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK and 13 Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK
* To whom correspondence should be addressed. Tel: +44 2920743058; Fax: +44 2920746554; Email: owenmj{at}cardiff.ac.uk
Received August 11, 2007; Revised August 12, 2007; Accepted August 12, 2007
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.
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