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, Juliana 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. CraneJonathan L. Haines, Richard Mayeux, Margaret A. Pericak-Vance, Lindsay A. Farrer, Gerard D. Schellenberg, Joseph E Parisi, Ronald Carl Petersen, Neill R Graff Radford, Dennis W Dickson, Steven G Younkin, Nilufer Taner

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number39
JournalAlzheimer's Research and Therapy
Volume6
Issue number4
DOIs
StatePublished - Jul 1 2014

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Haplotypes
Alzheimer Disease
Gene Expression
Brain
Temporal Lobe
Cerebellum
Single Nucleotide Polymorphism
Alleles
Neurofibrillary Tangles
Nucleic Acid Regulatory Sequences
Odds Ratio
Confidence Intervals

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Cognitive Neuroscience

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Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels. / Allen, Mariet; Kachadoorian, Michaela; Quicksall, Zachary; Zou, Fanggeng; Chai, High Seng; Younkin, Curtis; Crook, Juliana; Pankratz, V. Shane; Carrasquillo, Minerva M; Krishnan, Siddharth; Nguyen, Thuy; Ma, Li; Malphrus, Kimberly; Lincoln, Sarah; Bisceglio, Gina; Kolbert, Christopher P.; Jen, Jin; Mukherjee, Shubhabrata; Kauwe, John K.; Crane, Paul K.; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Parisi, Joseph E; Petersen, Ronald Carl; Graff Radford, Neill R; Dickson, Dennis W; Younkin, Steven G; Taner, Nilufer.

In: Alzheimer's Research and Therapy, Vol. 6, No. 4, 39, 01.07.2014.

Research output: Contribution to journalArticle

Allen, M, Kachadoorian, M, Quicksall, Z, Zou, F, Chai, HS, Younkin, C, Crook, J, Pankratz, VS, Carrasquillo, MM, Krishnan, S, Nguyen, T, Ma, L, Malphrus, K, Lincoln, S, Bisceglio, G, Kolbert, CP, Jen, J, Mukherjee, S, Kauwe, JK, Crane, PK, Haines, JL, Mayeux, R, Pericak-Vance, MA, Farrer, LA, Schellenberg, GD, Parisi, JE, Petersen, RC, Graff Radford, NR, Dickson, DW, Younkin, SG & Taner, N 2014, 'Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels', Alzheimer's Research and Therapy, vol. 6, no. 4, 39. https://doi.org/10.1186/alzrt268
Allen, Mariet ; Kachadoorian, Michaela ; Quicksall, Zachary ; Zou, Fanggeng ; Chai, High Seng ; Younkin, Curtis ; Crook, Juliana ; Pankratz, V. Shane ; Carrasquillo, Minerva M ; Krishnan, Siddharth ; Nguyen, Thuy ; Ma, Li ; Malphrus, Kimberly ; Lincoln, Sarah ; Bisceglio, Gina ; Kolbert, Christopher P. ; Jen, Jin ; Mukherjee, Shubhabrata ; Kauwe, John K. ; Crane, Paul K. ; Haines, Jonathan L. ; Mayeux, Richard ; Pericak-Vance, Margaret A. ; Farrer, Lindsay A. ; Schellenberg, Gerard D. ; Parisi, Joseph E ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Dickson, Dennis W ; Younkin, Steven G ; Taner, Nilufer. / Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels. In: Alzheimer's Research and Therapy. 2014 ; Vol. 6, No. 4.
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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.",
author = "Mariet Allen and Michaela Kachadoorian and Zachary Quicksall and Fanggeng Zou and Chai, {High Seng} and Curtis Younkin and Juliana Crook and Pankratz, {V. Shane} and Carrasquillo, {Minerva M} and Siddharth Krishnan and Thuy Nguyen and Li Ma and Kimberly Malphrus and Sarah Lincoln and Gina Bisceglio and Kolbert, {Christopher P.} and Jin Jen and Shubhabrata Mukherjee and Kauwe, {John K.} and Crane, {Paul K.} and Haines, {Jonathan L.} and Richard Mayeux and Pericak-Vance, {Margaret A.} and Farrer, {Lindsay A.} and Schellenberg, {Gerard D.} and Parisi, {Joseph E} and Petersen, {Ronald Carl} and {Graff Radford}, {Neill R} and Dickson, {Dennis W} and Younkin, {Steven G} and Nilufer Taner",
year = "2014",
month = "7",
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doi = "10.1186/alzrt268",
language = "English (US)",
volume = "6",
journal = "Alzheimer's Research and Therapy",
issn = "1758-9193",
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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, Juliana

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 Carl

AU - Graff Radford, Neill R

AU - Dickson, Dennis W

AU - Younkin, Steven G

AU - Taner, Nilufer

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

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