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

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

doi:10.1186/alzrt268

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.

Highlights

Microtubule-associated protein tau (MAPT) encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer’s disease (AD)
Rare missense and exon 10 splicing mutations, which lead to increased levels of tau isoforms with four microtubule binding domains lead to familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [2,3], whereas the common MAPT H1 haplotype strongly associates with increased risk of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) [4,5,6,7,8]
Association of MAPT single Single nucleotide polymorphism (SNP) with late-onset AD (LOAD) risk Six MAPT htSNPs were tested for association with LOAD risk in the Mayo Clinic and Alzheimer’s Disease Genetics Consortium (ADGC) cohorts both individually and combined (Table 1)

Summary

Introduction

MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer’s disease (AD). Alzheimer’s disease (AD), the most prevalent cause of dementia, is defined by two neuropathological hallmarks: senile plaques primarily composed of extracellular amyloidbeta (Aβ) deposits and intracellular neurofibrillary tangles (NFTs) comprised of hyper-phosphorylated tau protein. Variants have evolved that occur on only the H1 haplotype resulting in multiple sub-haplotypes. Both common and rare genetic variation in MAPT have been strongly implicated in primary tauopathies. A recent genome-wide association study (GWAS) of PSP risk identified MAPT as the strongest locus, with risk alleles at rs8070723 which tags the H1 haplotype and for rs242557, which partially tags the H1c subhaplotype [8]

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Discussion

Conclusion