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Myers AJ, Kaleem M, Marlowe L, Pittman AM, Lees AJ, Fung HC, Duckworth J, Leung D, Gibson A, Morris CM, de Silva R, Hardy J. The H1c haplotype at the MAPT locus is associated with Alzheimer's disease. Hum Mol Genet. 2005 Aug 15;14(16):2399-404. Epub 2005 Jul 6 PubMed.
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University of Antwerp (UA), Flanders Interuniversity Institute for Biotechnology (VIB)
Myers et al. demonstrated association of a specific MAPT H1 haplotype (H1c) with late-onset AD using a 6-htSNP mapping panel that was developed based on HapMap data.
We have recently studied MAPT association in a well-characterized early onset AD sample and found no significant association. We used a highly informative 15 htSNP panel that we developed based on complete resequencing of the MAPT gene in 23 individuals (Cruts et al. Hum Mol Genet 14: 1753-62 2005). We validated this htSNP set by finemapping MAPT association of progressive supranuclear palsy to a variant in a conserved regulatory region upstream of exon 1 (Rademakers et al. Hum Mol Genet In Press) and by identifying association with Parkinson’s disease in a sample not associated with the extended H1-H2 inversion haplotypes. Our highly informative htSNP panel captures more than 99 percent of the genetic diversity at MAPT, including the H1c haplotype (9 percent), which is one of the two ancestral H1 haplotypes (Rademakers et al. Hum Mol Genet In Press).
Together, our data strongly suggest that the association of MAPT with late-onset AD reported by Myers et al. is not implicated in early onset AD and has a relatively small effect on AD susceptibility. We are currently analyzing the SNP panel which we extended to include 42 SNPs covering the 138 kb of MAPT in a large late-onset AD sample (N = 552) to test possible associations and if so, finemap the associated region harboring the underlying genetic susceptibility variant(s).
Marc Cruts (marc.cruts@ua.ac.be), Rosa Rademakers (roos.rademakers@ua.ac.be), Kristel Sleegers (kristel.sleegers@ua.ac.be), Christine Van Broeckhoven (christine.vanbroeckhoven@ua.ac.be)
References:
Cruts M, Rademakers R, Gijselinck I, van der Zee J, Dermaut B, De Pooter T, de Rijk P, Del-Favero J, Van Broeckhoven C. Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum Mol Genet. 2005 Jul 1;14(13):1753-62. PubMed.
Rademakers R, Melquist S, Cruts M, Theuns J, Del-Favero J, Poorkaj P, Baker M, Sleegers K, Crook R, De Pooter T, Bel Kacem S, Adamson J, Van den Bossche D, Van den Broeck M, Gass J, Corsmit E, De Rijk P, Thomas N, Engelborghs S, Heckman M, Litvan I, Crook J, De Deyn PP, Dickson D, Schellenberg GD, Van Broeckhoven C, Hutton ML. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet. 2005 Nov 1;14(21):3281-92. Epub 2005 Sep 29 PubMed.
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