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

TitleAssociation of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels.
Publication TypeJournal Article
Year of Publication2014
AuthorsAllen, M, Kachadoorian, M, Quicksall, Z, Zou, F, Chai, HSeng, Younkin, C, Crook, JE, V Pankratz, S, Carrasquillo, MM, Krishnan, S, Nguyen, T, Ma, L, Malphrus, K, Lincoln, S, Bisceglio, G, Kolbert, CP, Jen, J, Mukherjee, S, Kauwe, JK, Crane, PK, Haines, JL, Mayeux, R, Pericak-Vance, MA, Farrer, LA, Schellenberg, GD, Parisi, JE, Petersen, RC, Graff-Radford, NR, Dickson, DW, Younkin, SG, Ertekin-Taner, N
JournalAlzheimers Res Ther
Volume6
Issue4
Pagination39
Date Published2014
ISSN1758-9193
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.

DOI10.1186/alzrt268
Alternate JournalAlzheimers Res Ther
PubMed ID25324900
PubMed Central IDPMC4198935
Grant ListU01 AG032984 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States