TY - JOUR
T1 - Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels
AU - Allen, Mariet
AU - Kachadoorian, Michaela
AU - Quicksall, Zachary
AU - Zou, Fanggeng
AU - Chai, High Seng
AU - Younkin, Curtis
AU - Crook, Julia E.
AU - Pankratz, V. Shane
AU - Carrasquillo, Minerva M.
AU - Krishnan, Siddharth
AU - Nguyen, Thuy
AU - Ma, Li
AU - Malphrus, Kimberly
AU - Lincoln, Sarah
AU - Bisceglio, Gina
AU - Kolbert, Christopher P.
AU - Jen, Jin
AU - Mukherjee, Shubhabrata
AU - Kauwe, John K.
AU - Crane, Paul K.
AU - Haines, Jonathan L.
AU - Mayeux, Richard
AU - Pericak-Vance, Margaret A.
AU - Farrer, Lindsay A.
AU - Schellenberg, Gerard D.
AU - Parisi, Joseph E.
AU - Petersen, Ronald C.
AU - Graff-Radford, Neill R.
AU - Dickson, Dennis W.
AU - Younkin, Steven G.
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
Support for this research was provided by the National Institutes of Health grants: National Institute on Aging (R01 AG032990 to NET and R01 AG018023 to NRG-R and SGY); National Institutes on Neurologic Diseases and Stroke (R01 NS080820 to NET), Mayo Alzheimer’s Disease Research Center: (P50 AG0016574 to RCP, DWD, NRG-R, SGY, and NET); Mayo Alzheimer’s Disease Patient Registry: (U01 AG006576 to RCP); National Institute on Aging (AG025711, AG017216, AG003949 to DWD). This project was also generously supported by the Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program (to RCP, DWD, NRG-R, and SGY), and by the Palumbo Professorship in Alzheimer’s Disease Research (to SGY). MMC and NET are supported partly by GHR Foundation grants. . Combining the ADGC data sets was performed by SM, and was supported by R01 AG 029672 (to PKC), U01 HG 006375 (to Eric Larson), and U01 AG 006781 (to Eric Larson). We thank the patients and their families for their participation, without whom these studies will not have been possible.
Funding Information:
R.C. Petersen, M.D., Ph.D. has been a consultant to GE Healthcare and Elan Pharmaceuticals, has served on a data safety monitoring board in clinical trials sponsored by Pfizer Incorporated and Janssen Alzheimer Immunotherapy and gave a CME lecture at Novartis Incorporated. N. Graff-Radford, M.D. has served as a consultant to Codman and received grant support from Elan Pharmaceutical Research, Pfizer Pharmaceuticals, Medivation, and Forrest.
Publisher Copyright:
© 2014 Allen et al.; licensee BioMed Central Ltd.
PY - 2014/7/1
Y1 - 2014/7/1
N2 - 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.
AB - 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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U2 - 10.1186/alzrt268
DO - 10.1186/alzrt268
M3 - Article
AN - SCOPUS:84906518915
SN - 1758-9193
VL - 6
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 4
M1 - 39
ER -