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

Abstract

IntroductionMAPT 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.MethodsWe 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.ResultsH2-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).ConclusionsThese 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.

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

“…Five upstream elements were identified as regulators of the changes that were observed: MAPT (microtubule-associated protein tau), PSEN1 (presenilin 1), AβPP (amyloid-β precursor protein), HTT (huntingtin), and D-glucose. MAPT, PSEN1, AβPP, and HTT are known to play a role in AD pathogenesis ([11, 45, 46]; reviewed by [47–49]). Multiple studies with 18 F-fluorodeoxyglucose demonstrate that in AD there is a progressive reduction of glucose metabolism which correlates with severity of the disease (reviewed by [50]).…”

Tau: From research to clinical development

“…The H1 haplotype shows a strong association with an increased risk of PSP, CBD, and AGD, likely caused by the presence of certain singlenucleotide polymorphisms that may cause subtle changes in splicing or gene expression [14]. The H1 haplotype is also associated with an increased risk of Parkinson's disease [15] and multiple system atrophy [16], as well as a significant but small increased likelihood of late-onset AD (LOAD), whereas the H2 haplotype leads to a reduced risk of LOAD [17].…”

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

“…174 However, the association between MAPT variations and the most common tauopathy, Alzheimer disease, is still not clear, although several studies suggest such an association. [175][176][177] MAPT haplotypes, such as the H1 haplotype, were identified in various studies as important risk factors for PD, 4,[7][8][9]12,13 in which tau does not accumulate. Furthermore, MAPT-associated SNP is the second strongest risk factor in PD GWAS, with an OR of 0.77 and p D 2 £ 10 ¡48 .…”