Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer's disease

被引:37
作者
Hamshere, Marian L.
Holmans, Peter A.
Avramopoulos, Dimitrios
Bassett, Susan S.
Blacker, Deborah
Bertram, Lars
Wiener, Howard
Rochberg, Nan
Tanzi, Rudolph E.
Myers, Amanda
Vrieze, Fabienne Wavrant-De
Go, Rodney
Fallin, Daniele
Lovestone, Simon
Hardy, John
Goate, Alison
O'Donovan, Michael
Williams, Julie
Owen, Michael J.
机构
[1] Cardiff Univ, Sch Med, Dept Med Psychol, Cardiff CF14 4XN, S Glam, Wales
[2] Cardiff Univ, Biostat & Bioinformat Unit, Sch Med, Cardiff CF14 4XN, S Glam, Wales
[3] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA
[5] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Gerontol Res Unit, Charlestown, MA 02129 USA
[6] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Genet & Aging Res Unit, Charlestown, MA 02129 USA
[7] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA
[8] Univ Alabama, Dept Epidemiol, Birmingham, AL USA
[9] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
[10] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Coral Gables, FL 33124 USA
[11] NIA, Neurogenet Lab, Natl Inst Hlth, Bethesda, MD 20892 USA
[12] Kings Coll London, Inst Psychiat, MRC, Ctr Neurodegenerat Res, London SE5 8AF, England
[13] UCL, Dept Mol Neurosci, Inst Neurol, London WC1N 3BG, England
[14] UCL, Reta Lila Weston Labs, Inst Neurol, London WC1N 3BG, England
基金
英国医学研究理事会;
关键词
D O I
10.1093/hmg/ddm224
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2703 / 2712
页数:10
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