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 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

doi:10.1186/alzrt268

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

Alzheimers Res Ther. 2014 Jul 1;6(4):39. doi: 10.1186/alzrt268. eCollection 2014.

Authors

Mariet Allen¹, Michaela Kachadoorian¹, Zachary Quicksall¹, Fanggeng Zou¹, High Seng Chai², Curtis Younkin¹, Julia E Crook³, V Shane Pankratz², Minerva M Carrasquillo¹, Siddharth Krishnan¹, Thuy Nguyen¹, Li Ma¹, Kimberly Malphrus¹, Sarah Lincoln¹, Gina Bisceglio¹, Christopher P Kolbert⁴, Jin Jen⁴, Shubhabrata Mukherjee⁵, John K Kauwe⁶, Paul K Crane⁵, Jonathan L Haines⁷, Richard Mayeux⁸, Margaret A Pericak-Vance⁹, Lindsay A Farrer¹⁰, Gerard D Schellenberg¹¹, Joseph E Parisi¹², Ronald C Petersen¹³, Neill R Graff-Radford¹⁴, Dennis W Dickson¹, Steven G Younkin¹, Nilüfer Ertekin-Taner¹⁵

Affiliations

¹ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
² Department of Health Sciences Research, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
³ Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
⁴ Medical Genome Facility, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
⁵ Department of Medicine, University of Washington, Seattle 98104, WA, USA.
⁶ Departments of Biology, Neuroscience, Brigham Young University, Provo, UT 84602, USA.
⁷ Department of Molecular Physiology and Biophysics, and the Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA ; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
⁸ Gertrude H. Sergievsky Center, Department of Neurology, and Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
⁹ The John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
¹⁰ Departments of Biostatistics, Medicine (Genetics Program), Ophthalmology, Neurology, and Epidemiology, Boston University, Boston, MA, USA.
¹¹ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
¹³ Department of Neurology, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
¹⁴ Department of Neurology, Mayo Clinic Florida, 4500 San Pablo Road, Birdsall 3, Jacksonville, FL 32224, USA.
¹⁵ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA ; Department of Neurology, Mayo Clinic Florida, 4500 San Pablo Road, Birdsall 3, Jacksonville, FL 32224, USA.

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.

Abstract

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