title: No association of a non-synonymous PLAU polymorphism with Alzheimer's disease and disease-related traits.
abstract: A 30 cM broad genomic region on the long arm of chromosome 10 at 80 cM shows significant and consistent linkage with AD and with plasma concentration of the beta-amyloid peptide 1-42 (Abeta42). The PLAU gene, which is involved in the production and degradation of Abeta42, maps to that region and is therefore a strong positional candidate for association with sporadic AD. We analyzed the non-synonymous single nucleotide polymorphism (SNP) rs2227564 in two independent case-control series from Switzerland and Greece and investigated the influence of this SNP on cognition in elderly individuals. Because PLAU modulates the cleavage of the amyloid precursor protein (APP) and the degradation of Abeta, we also determined the levels of Abeta in the brain, plasma and in the cerebrospinal fluid (CSF). We found no evidence for association of this SNP with AD or with AD-related traits such as beta-amyloid load in the medial temporal lobe or Abeta42 concentration in the CSF and in plasma. Our findings do not support a major role of PLAU polymorphisms as susceptibility factors for AD and suggest that large-scale association studies which combine genetic information from populations with similar genetic background might prevent the generation of spurious associations. Although PLAU may be pathophysiologially related to AD, the contribution of common genetic variants of this gene to the risk for developing AD is likely to be low.
authors.affiliation: Division of Psychiatry Research, University of Zürich, Lengstrasse 31, 8029 Zürich, Switzerland. papas@bli.unizh.ch
authors.forename: Andreas
authors.initials: A
authors.lastname: Papassotiropoulos
authors.forename: Magdalini
authors.initials: M
authors.lastname: Tsolaki
authors.forename: M Axel
authors.initials: MA
authors.lastname: Wollmer
authors.forename: Dimitra
authors.initials: D
authors.lastname: Molyva
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Kim-Dung
authors.initials: KD
authors.lastname: Huynh
authors.forename: Jay
authors.initials: J
authors.lastname: Tracy
authors.forename: Hannes B
authors.initials: HB
authors.lastname: Staehelin
authors.forename: Andreas U
authors.initials: AU
authors.lastname: Monsch
authors.forename: Roger M
authors.initials: RM
authors.lastname: Nitsch
authors.forename: Christoph
authors.initials: C
authors.lastname: Hock
mesh_terms: D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D016022:Case-Control Studies; D005787:Gene Frequency; D005838:Genotype; D006115:Greece; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D013557:Switzerland; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D014568:Urokinase-Type Plasminogen Activator