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Chromosome 10

Increasing evidence from genome wide scans has suggested that there is a disease risk locus for late-onset Alzheimer's disease (LOAD) on chromosome 10. In the follow up study to their genome scan (Kehoe et al 1999 Myers et al (Myers et al 2000 obtained a maximum lod score (MLS) of 3.83 between markers D10S1225 and D10S1227, at ~ 65Mb This result was independent of APOE genotype. Furthermore, the same data set produced a smaller MLS around the APOE locus suggesting that the relative risk of the chromosome 10 locus is similar to APOE. In addition, the same region (between markers D10S1227 and D10S1211) was found to contain a quantitative trait locus for plasma Aβ42 levels (Ertekin-Taner et al 2000 However, a third study did not identify linkage in this region, instead observing linkage around the IDE locus (~100Mb), which was more pronounced in late-onset samples and in families with no APOE ε4 allele (D10S583, D10S1671 and D10S1710) (Bertram et al 2000 However, the studies by Myers et al 2000 and Bertram et al 2000 used overlapping samples from the National Institutes of Mental Health (NIMH) and would not be expected to generate different results. Furthermore, although Bertram et al 2000 re-analysed their data using only the overlapping samples the linkage signal at the proximal marker did not increase. Cited reasons for this replication failure were differences in sample design; for example use of families or sib pairs, stratification and analytical methods (Bertram et al 2000 Additionally, linkage can be observed over large regions making it difficult to identify the precise variant responsible for the positive results, and equally, computer simulations have shown that chance variation in location estimates can be substantial depending on the strength of the underlying linkage signal (Roberts et al 1999 This suggests that the chromosome 10 locus may have a weak effect, consistent with a susceptibility locus for a complex disorder, and may explain the inconsistent location reports. However, since these original linkage reports, additional reports have lent support to the existence of two separate linkage peaks on chromosome 10. These reports suggest the existence of a locus affecting plasma Aβ levels (Myers et al 2000 Ertekin-Taner et al 2000 Wijsman et al 2004 and a more distal region affecting AAO (Li et al 2002

Our collaborators have generated the positive linkage results on 10q21-22 (Kehoe et al 1999; Myers et al 2000, 2002) and a recent paper by Bertram and Tanzi (2004) has reviewed the results obtained from the AD genome screens. Two sided p values were compared between studies using a cut-off of p<0.01. The strongest results were obtained from chromosomes 6, 9, 10, 12, 19 and 21, and the most consistent result on chromosome 10 was located at 10q21-22 with p values <0.01 in four studies (Curtis et al 2001; Olson et al 2002 Myers et al 2002 Blacker et al 2003

Since the original linkage reports were published in 1999, numerous studies have identified positive associations with candidate genes on chromosome 10. The three genes studied the most extensively are alpha-T catenin CTNNA3 (VR22), the urokinase plasminogen activator, PLAU, and insulin degrading enzyme (IDE).

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Chromosome 10