Association of MAPT Subhaplotypes with Risk of Progressive Supranuclear Palsy and Severity of Tau Pathology

Michael G. Heckman, Rebecca R. Brennan, Catherine Labbé, Alexandra I. Soto, Shunsuke Koga, Michael Deture, Melissa E Murray, Ronald Carl Petersen, Bradley F Boeve, Jay A Van Gerpen, Ryan J. Uitti, Zbigniew K Wszolek, Rosa V Rademakers, Dennis W Dickson, Owen A Ross

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Abstract

Importance: The association between the microtubule-associated protein tau (MAPT) H1 haplotype and the risk of progressive supranuclear palsy (PSP) has been well documented. However, the specific H1 subhaplotypes that drive the association have not been evaluated in large studies, nor have they been studied in relation to neuropathologic severity of disease. Objective: To comprehensively evaluate the associations of MAPT haplotypes with the risk of PSP and the severity of tau pathology using a large series of neuropathologically confirmed PSP cases. Design, Setting, and Participants: A case-control study was used to investigate the associations between MAPT haplotypes and the risk of PSP, and a case series was conducted for examination of associations of MAPT haplotypes with the severity of tau pathology. All 802 neuropathologically confirmed PSP cases were obtained from a neurodegenerative disorders brain bank between January 1, 1998, and December 31, 2013, and 1312 clinical controls were obtained from the neurology department of the Mayo Clinic. Statistical analysis was performed from February 17 to December 12, 2018. Main Outcomes and Measures: Presence of PSP in case-control analysis and semiquantitative tau pathology scores for neurofibrillary tangles, neuropil threads, tufted astrocytes, and oligodendroglial coiled bodies in PSP cases. Results: For 802 patients with PSP (376 women and 426 men), the median age at death was 75 years (range, 52-98 years). For 1312 controls (701 women and 611 men), the median age at blood collection was 69 years (range, 45-92 years). After adjustment for multiple testing, known associations with risk of PSP were observed for the H2 and H1c haplotypes. Novel associations with PSP were observed for 3 H1 subhaplotypes, including H1d (odds ratio, 1.86; 95% CI, 1.43-2.42; P = 2 × 10 -6 ), H1g (odds ratio, 3.64; 95% CI, 2.04-6.50; P = 2 × 10 -6 ), and H1o (odds ratio, 2.60; 95% CI, 1.63-4.16; P = 2 × 10 -5 ). Although not significant after multiple testing adjustment, 3 of these PSP risk haplotypes (H2, H1c, and H1d) were also nominally associated with measures of severity of tau pathology in PSP cases. Nominally significant associations with severity of tau pathology were also noted for the H1e and H1q haplotypes. Conclusions and Relevance: This study has identified novel associations with risk of PSP for 3 MAPT H1 subhaplotypes. In addition, potential weaker associations between several haplotypes (including several PSP risk haplotypes) and severity of tau pathology were observed. These findings expand the current understanding of the role of MAPT haplotypic variation in susceptibility to and neuropathologic severity of PSP..

Original languageEnglish (US)
JournalJAMA neurology
DOIs
StatePublished - Jan 1 2019

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Progressive Supranuclear Palsy
Microtubule-Associated Proteins
Pathology
Haplotypes
Odds Ratio
Neuropil Threads
Coiled Bodies
Neurofibrillary Tangles
Neurology
Astrocytes
Neurodegenerative Diseases
Case-Control Studies

ASJC Scopus subject areas

  • Clinical Neurology

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Association of MAPT Subhaplotypes with Risk of Progressive Supranuclear Palsy and Severity of Tau Pathology. / Heckman, Michael G.; Brennan, Rebecca R.; Labbé, Catherine; Soto, Alexandra I.; Koga, Shunsuke; Deture, Michael; Murray, Melissa E; Petersen, Ronald Carl; Boeve, Bradley F; Van Gerpen, Jay A; Uitti, Ryan J.; Wszolek, Zbigniew K; Rademakers, Rosa V; Dickson, Dennis W; Ross, Owen A.

In: JAMA neurology, 01.01.2019.

Research output: Contribution to journalArticle

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title = "Association of MAPT Subhaplotypes with Risk of Progressive Supranuclear Palsy and Severity of Tau Pathology",
abstract = "Importance: The association between the microtubule-associated protein tau (MAPT) H1 haplotype and the risk of progressive supranuclear palsy (PSP) has been well documented. However, the specific H1 subhaplotypes that drive the association have not been evaluated in large studies, nor have they been studied in relation to neuropathologic severity of disease. Objective: To comprehensively evaluate the associations of MAPT haplotypes with the risk of PSP and the severity of tau pathology using a large series of neuropathologically confirmed PSP cases. Design, Setting, and Participants: A case-control study was used to investigate the associations between MAPT haplotypes and the risk of PSP, and a case series was conducted for examination of associations of MAPT haplotypes with the severity of tau pathology. All 802 neuropathologically confirmed PSP cases were obtained from a neurodegenerative disorders brain bank between January 1, 1998, and December 31, 2013, and 1312 clinical controls were obtained from the neurology department of the Mayo Clinic. Statistical analysis was performed from February 17 to December 12, 2018. Main Outcomes and Measures: Presence of PSP in case-control analysis and semiquantitative tau pathology scores for neurofibrillary tangles, neuropil threads, tufted astrocytes, and oligodendroglial coiled bodies in PSP cases. Results: For 802 patients with PSP (376 women and 426 men), the median age at death was 75 years (range, 52-98 years). For 1312 controls (701 women and 611 men), the median age at blood collection was 69 years (range, 45-92 years). After adjustment for multiple testing, known associations with risk of PSP were observed for the H2 and H1c haplotypes. Novel associations with PSP were observed for 3 H1 subhaplotypes, including H1d (odds ratio, 1.86; 95{\%} CI, 1.43-2.42; P = 2 × 10 -6 ), H1g (odds ratio, 3.64; 95{\%} CI, 2.04-6.50; P = 2 × 10 -6 ), and H1o (odds ratio, 2.60; 95{\%} CI, 1.63-4.16; P = 2 × 10 -5 ). Although not significant after multiple testing adjustment, 3 of these PSP risk haplotypes (H2, H1c, and H1d) were also nominally associated with measures of severity of tau pathology in PSP cases. Nominally significant associations with severity of tau pathology were also noted for the H1e and H1q haplotypes. Conclusions and Relevance: This study has identified novel associations with risk of PSP for 3 MAPT H1 subhaplotypes. In addition, potential weaker associations between several haplotypes (including several PSP risk haplotypes) and severity of tau pathology were observed. These findings expand the current understanding of the role of MAPT haplotypic variation in susceptibility to and neuropathologic severity of PSP..",
author = "Heckman, {Michael G.} and Brennan, {Rebecca R.} and Catherine Labb{\'e} and Soto, {Alexandra I.} and Shunsuke Koga and Michael Deture and Murray, {Melissa E} and Petersen, {Ronald Carl} and Boeve, {Bradley F} and {Van Gerpen}, {Jay A} and Uitti, {Ryan J.} and Wszolek, {Zbigniew K} and Rademakers, {Rosa V} and Dickson, {Dennis W} and Ross, {Owen A}",
year = "2019",
month = "1",
day = "1",
doi = "10.1001/jamaneurol.2019.0250",
language = "English (US)",
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T1 - Association of MAPT Subhaplotypes with Risk of Progressive Supranuclear Palsy and Severity of Tau Pathology

AU - Heckman, Michael G.

AU - Brennan, Rebecca R.

AU - Labbé, Catherine

AU - Soto, Alexandra I.

AU - Koga, Shunsuke

AU - Deture, Michael

AU - Murray, Melissa E

AU - Petersen, Ronald Carl

AU - Boeve, Bradley F

AU - Van Gerpen, Jay A

AU - Uitti, Ryan J.

AU - Wszolek, Zbigniew K

AU - Rademakers, Rosa V

AU - Dickson, Dennis W

AU - Ross, Owen A

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Importance: The association between the microtubule-associated protein tau (MAPT) H1 haplotype and the risk of progressive supranuclear palsy (PSP) has been well documented. However, the specific H1 subhaplotypes that drive the association have not been evaluated in large studies, nor have they been studied in relation to neuropathologic severity of disease. Objective: To comprehensively evaluate the associations of MAPT haplotypes with the risk of PSP and the severity of tau pathology using a large series of neuropathologically confirmed PSP cases. Design, Setting, and Participants: A case-control study was used to investigate the associations between MAPT haplotypes and the risk of PSP, and a case series was conducted for examination of associations of MAPT haplotypes with the severity of tau pathology. All 802 neuropathologically confirmed PSP cases were obtained from a neurodegenerative disorders brain bank between January 1, 1998, and December 31, 2013, and 1312 clinical controls were obtained from the neurology department of the Mayo Clinic. Statistical analysis was performed from February 17 to December 12, 2018. Main Outcomes and Measures: Presence of PSP in case-control analysis and semiquantitative tau pathology scores for neurofibrillary tangles, neuropil threads, tufted astrocytes, and oligodendroglial coiled bodies in PSP cases. Results: For 802 patients with PSP (376 women and 426 men), the median age at death was 75 years (range, 52-98 years). For 1312 controls (701 women and 611 men), the median age at blood collection was 69 years (range, 45-92 years). After adjustment for multiple testing, known associations with risk of PSP were observed for the H2 and H1c haplotypes. Novel associations with PSP were observed for 3 H1 subhaplotypes, including H1d (odds ratio, 1.86; 95% CI, 1.43-2.42; P = 2 × 10 -6 ), H1g (odds ratio, 3.64; 95% CI, 2.04-6.50; P = 2 × 10 -6 ), and H1o (odds ratio, 2.60; 95% CI, 1.63-4.16; P = 2 × 10 -5 ). Although not significant after multiple testing adjustment, 3 of these PSP risk haplotypes (H2, H1c, and H1d) were also nominally associated with measures of severity of tau pathology in PSP cases. Nominally significant associations with severity of tau pathology were also noted for the H1e and H1q haplotypes. Conclusions and Relevance: This study has identified novel associations with risk of PSP for 3 MAPT H1 subhaplotypes. In addition, potential weaker associations between several haplotypes (including several PSP risk haplotypes) and severity of tau pathology were observed. These findings expand the current understanding of the role of MAPT haplotypic variation in susceptibility to and neuropathologic severity of PSP..

AB - Importance: The association between the microtubule-associated protein tau (MAPT) H1 haplotype and the risk of progressive supranuclear palsy (PSP) has been well documented. However, the specific H1 subhaplotypes that drive the association have not been evaluated in large studies, nor have they been studied in relation to neuropathologic severity of disease. Objective: To comprehensively evaluate the associations of MAPT haplotypes with the risk of PSP and the severity of tau pathology using a large series of neuropathologically confirmed PSP cases. Design, Setting, and Participants: A case-control study was used to investigate the associations between MAPT haplotypes and the risk of PSP, and a case series was conducted for examination of associations of MAPT haplotypes with the severity of tau pathology. All 802 neuropathologically confirmed PSP cases were obtained from a neurodegenerative disorders brain bank between January 1, 1998, and December 31, 2013, and 1312 clinical controls were obtained from the neurology department of the Mayo Clinic. Statistical analysis was performed from February 17 to December 12, 2018. Main Outcomes and Measures: Presence of PSP in case-control analysis and semiquantitative tau pathology scores for neurofibrillary tangles, neuropil threads, tufted astrocytes, and oligodendroglial coiled bodies in PSP cases. Results: For 802 patients with PSP (376 women and 426 men), the median age at death was 75 years (range, 52-98 years). For 1312 controls (701 women and 611 men), the median age at blood collection was 69 years (range, 45-92 years). After adjustment for multiple testing, known associations with risk of PSP were observed for the H2 and H1c haplotypes. Novel associations with PSP were observed for 3 H1 subhaplotypes, including H1d (odds ratio, 1.86; 95% CI, 1.43-2.42; P = 2 × 10 -6 ), H1g (odds ratio, 3.64; 95% CI, 2.04-6.50; P = 2 × 10 -6 ), and H1o (odds ratio, 2.60; 95% CI, 1.63-4.16; P = 2 × 10 -5 ). Although not significant after multiple testing adjustment, 3 of these PSP risk haplotypes (H2, H1c, and H1d) were also nominally associated with measures of severity of tau pathology in PSP cases. Nominally significant associations with severity of tau pathology were also noted for the H1e and H1q haplotypes. Conclusions and Relevance: This study has identified novel associations with risk of PSP for 3 MAPT H1 subhaplotypes. In addition, potential weaker associations between several haplotypes (including several PSP risk haplotypes) and severity of tau pathology were observed. These findings expand the current understanding of the role of MAPT haplotypic variation in susceptibility to and neuropathologic severity of PSP..

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