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Open Access 01-08-2014 | Research

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

Authors: 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 Crane, Jonathan 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, Alzheimer’s Disease Genetics Consortium (ADGC)

Published in: Alzheimer's Research & Therapy | Issue 4/2014

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.

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Title: Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels
Authors: 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 Crane
Jonathan 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
Alzheimer’s Disease Genetics Consortium (ADGC)
Publication date: 01-08-2014
Publisher: BioMed Central
Published in: Alzheimer's Research & Therapy / Issue 4/2014
Electronic ISSN: 1758-9193
DOI: https://doi.org/10.1186/alzrt268

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Introduction

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

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