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Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease

Molecular Psychiatry volume 12, pages 510–517 (2007)Cite this article

Abstract

In addition to senile plaques, neurofibrillary tangles are characteristic of Alzheimer's disease (AD) pathology, suggesting a clear involvement of the microtubule-associated protein tau (MAPT) in AD. Recent findings, suggesting that the H1c haplotype is associated with increased risk, now also implicate MAPT genetically. In this study, we aim to clarify this association by a fine mapping approach using both a traditional phenotypic association analysis and a quantitative trait (QT) analysis using cerebrospinal fluid (CSF) tau protein levels in the German population. Here, we report that both methodologies identify that the H1c haplotype may play important role in AD (AD risk, P=0.007, uncorrected; CSF tau levels, P=0.027, uncorrected). Further, the use of a sliding window approach in the QT analysis allowed for the narrowing down of the region where a probable causal variant may be located. The data suggest that this may lie at or within close proximity to the rs242557 single nucleotide polymorphism as association with CSF tau levels seems to be primarily driven by rs242557 in a gene dosage-dependent manner (trend model: P=0.002, uncorrected). These findings provide functional evidence to support the genetic association of MAPT with AD.

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Acknowledgements

We thank all individuals who participated in this study for their contribution and would also like to thank both dementia outpatient unit employees for their help in collecting and processing of samples. This work was funded by the German National Genome Network (NGFN) and the German Ministry for Education and Research; Grant no. 01GS0465 (MR).

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Neurochemistry and Neurogenetics Laboratory, Technische Universität München (TU-München), München, Germany

    S M Laws, P Friedrich, J Müller, T Eisele & M Riemenschneider

  2. Sir James McCusker Alzheimer's Disease Research Unit, Alzheimer's and Aging, School of Biomedical and Sports Science, Edith Cowan University, Joondalup, WA, Australia

    S M Laws

  3. Department of Psychiatry and Psychotherapy, Technische Universität München (TU-München), München, Germany

    J Diehl-Schmid, J Bäuml, H Förstl & A Kurz

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  1. S M Laws
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Correspondence to M Riemenschneider.

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Laws, S., Friedrich, P., Diehl-Schmid, J. et al. Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease. Mol Psychiatry 12, 510–517 (2007). https://doi.org/10.1038/sj.mp.4001935

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