Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease

Michael G. Heckman, Koji Kasanuki, Rebecca R. Brennan, Catherine Labbé, Emily R. Vargas, Alexandra I. Soto, Melissa E Murray, Shunsuke Koga, Dennis W Dickson, Owen A Ross

Research output: Contribution to journalArticle

Abstract

Background: Genetic variation at the microtubule-associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule-associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease. Objectives: To evaluate associations of microtubule-associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases. Methods: Five hundred eighty-five autopsy-confirmed Lewy body disease cases were included. Six microtubule-associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule-associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen. Results: The common microtubule-associated protein tau H2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3%) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule-associated protein tau haplotypes (P = 0.0016). Microtubule-associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule-associated protein tau H1 subhaplotypes and neuropathological outcomes were observed. Conclusions: A rare microtubule-associated protein tau H1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule-associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk.

Original languageEnglish (US)
JournalMovement Disorders
DOIs
StatePublished - Jan 1 2019

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Lewy Body Disease
Microtubule-Associated Proteins
Haplotypes
Tyrosine 3-Monooxygenase
Lewy Bodies
Neuropathology
Putamen
Parkinsonian Disorders
Autopsy

Keywords

  • genetics
  • haplotype
  • Lewy body disease
  • MAPT
  • neuropathology

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Heckman, M. G., Kasanuki, K., Brennan, R. R., Labbé, C., Vargas, E. R., Soto, A. I., ... Ross, O. A. (2019). Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease. Movement Disorders. https://doi.org/10.1002/mds.27773

Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease. / Heckman, Michael G.; Kasanuki, Koji; Brennan, Rebecca R.; Labbé, Catherine; Vargas, Emily R.; Soto, Alexandra I.; Murray, Melissa E; Koga, Shunsuke; Dickson, Dennis W; Ross, Owen A.

In: Movement Disorders, 01.01.2019.

Research output: Contribution to journalArticle

Heckman MG, Kasanuki K, Brennan RR, Labbé C, Vargas ER, Soto AI et al. Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease. Movement Disorders. 2019 Jan 1. https://doi.org/10.1002/mds.27773
Heckman, Michael G. ; Kasanuki, Koji ; Brennan, Rebecca R. ; Labbé, Catherine ; Vargas, Emily R. ; Soto, Alexandra I. ; Murray, Melissa E ; Koga, Shunsuke ; Dickson, Dennis W ; Ross, Owen A. / Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease. In: Movement Disorders. 2019.
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abstract = "Background: Genetic variation at the microtubule-associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule-associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease. Objectives: To evaluate associations of microtubule-associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases. Methods: Five hundred eighty-five autopsy-confirmed Lewy body disease cases were included. Six microtubule-associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule-associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen. Results: The common microtubule-associated protein tau H2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3{\%}) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule-associated protein tau haplotypes (P = 0.0016). Microtubule-associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule-associated protein tau H1 subhaplotypes and neuropathological outcomes were observed. Conclusions: A rare microtubule-associated protein tau H1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule-associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk.",
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AU - Brennan, Rebecca R.

AU - Labbé, Catherine

AU - Vargas, Emily R.

AU - Soto, Alexandra I.

AU - Murray, Melissa E

AU - Koga, Shunsuke

AU - Dickson, Dennis W

AU - Ross, Owen A

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N2 - Background: Genetic variation at the microtubule-associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule-associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease. Objectives: To evaluate associations of microtubule-associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases. Methods: Five hundred eighty-five autopsy-confirmed Lewy body disease cases were included. Six microtubule-associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule-associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen. Results: The common microtubule-associated protein tau H2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3%) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule-associated protein tau haplotypes (P = 0.0016). Microtubule-associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule-associated protein tau H1 subhaplotypes and neuropathological outcomes were observed. Conclusions: A rare microtubule-associated protein tau H1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule-associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk.

AB - Background: Genetic variation at the microtubule-associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule-associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease. Objectives: To evaluate associations of microtubule-associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases. Methods: Five hundred eighty-five autopsy-confirmed Lewy body disease cases were included. Six microtubule-associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule-associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen. Results: The common microtubule-associated protein tau H2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3%) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule-associated protein tau haplotypes (P = 0.0016). Microtubule-associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule-associated protein tau H1 subhaplotypes and neuropathological outcomes were observed. Conclusions: A rare microtubule-associated protein tau H1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule-associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk.

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