Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels

Mariet Allen, Michaela Kachadoorian, Zachary Quicksall, Fanggeng Zou, High Seng Chai, Curtis Younkin, Julia E. Crook, V. Shane Pankratz, Minerva M. Carrasquillo, Siddharth Krishnan, Thuy Nguyen, Li Ma, Kimberly Malphrus, Sarah Lincoln, Gina Bisceglio, Christopher P. Kolbert, Jin Jen, Shubhabrata Mukherjee, John K. Kauwe, Paul K. CraneJonathan L. Haines, Richard Mayeux, Margaret A. Pericak-Vance, Lindsay A. Farrer, Gerard D. Schellenberg, Joseph E. Parisi, Ronald C. Petersen, Neill R. Graff-Radford, Dennis W. Dickson, Steven G. Younkin, Nilüfer Ertekin-Taner

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Abstract

Introduction. MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer's disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this. Methods. We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n-controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer's Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated. Results: H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03). Conclusions: These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression.

Original languageEnglish (US)
Article number39
JournalAlzheimer's Research and Therapy
Volume6
Issue number4
DOIs
StatePublished - Jul 1 2014

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

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    Allen, M., Kachadoorian, M., Quicksall, Z., Zou, F., Chai, H. S., Younkin, C., Crook, J. E., Pankratz, V. S., Carrasquillo, M. M., Krishnan, S., Nguyen, T., Ma, L., Malphrus, K., Lincoln, S., Bisceglio, G., Kolbert, C. P., Jen, J., Mukherjee, S., Kauwe, J. K., ... Ertekin-Taner, N. (2014). Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels. Alzheimer's Research and Therapy, 6(4), [39]. https://doi.org/10.1186/alzrt268