TY - JOUR
T1 - MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium
T2 - a genetic association study
AU - Pick's disease International Consortium
AU - Valentino, Rebecca R.
AU - Scotton, William J.
AU - Roemer, Shanu F.
AU - Lashley, Tammaryn
AU - Heckman, Michael G.
AU - Shoai, Maryam
AU - Martinez-Carrasco, Alejandro
AU - Tamvaka, Nicole
AU - Walton, Ronald L.
AU - Baker, Matthew C.
AU - Macpherson, Hannah L.
AU - Real, Raquel
AU - Soto-Beasley, Alexandra I.
AU - Mok, Kin
AU - Revesz, Tamas
AU - Christopher, Elizabeth A.
AU - DeTure, Michael
AU - Seeley, William W.
AU - Lee, Edward B.
AU - Frosch, Matthew P.
AU - Molina-Porcel, Laura
AU - Gefen, Tamar
AU - Redding-Ochoa, Javier
AU - Ghetti, Bernardino
AU - Robinson, Andrew C.
AU - Kobylecki, Christopher
AU - Rowe, James B.
AU - Beach, Thomas G.
AU - Teich, Andrew F.
AU - Keith, Julia L.
AU - Bodi, Istvan
AU - Halliday, Glenda M.
AU - Gearing, Marla
AU - Arzberger, Thomas
AU - Morris, Christopher M.
AU - White, Charles L.
AU - Mechawar, Naguib
AU - Boluda, Susana
AU - MacKenzie, Ian R.
AU - McLean, Catriona
AU - Cykowski, Matthew D.
AU - Wang, Shih Hsiu J.
AU - Graff, Caroline
AU - Nagra, Rashed M.
AU - Kovacs, Gabor G.
AU - Giaccone, Giorgio
AU - Neumann, Manuela
AU - Ang, Lee Cyn
AU - Carvalho, Agostinho
AU - Morris, Huw R.
N1 - Publisher Copyright:
© 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2024/5
Y1 - 2024/5
N2 - Background: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. Methods: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. Findings: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (β –0·54 [95% CI –1·94 to 0·87], p=0·45) or disease duration (β 0·05 [–0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (β 2·66 [0·63 to 4·70], p=0·011), H1i (β –3·66 [–6·83 to –0·48], p=0·025), and H1u (β –5·25 [–10·42 to –0·07], p=0·048); and with disease duration for H1x (β –0·57 [–1·07 to –0·07], p=0·026). Interpretation: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. Funding: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.
AB - Background: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. Methods: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. Findings: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (β –0·54 [95% CI –1·94 to 0·87], p=0·45) or disease duration (β 0·05 [–0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (β 2·66 [0·63 to 4·70], p=0·011), H1i (β –3·66 [–6·83 to –0·48], p=0·025), and H1u (β –5·25 [–10·42 to –0·07], p=0·048); and with disease duration for H1x (β –0·57 [–1·07 to –0·07], p=0·026). Interpretation: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. Funding: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.
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U2 - 10.1016/S1474-4422(24)00083-8
DO - 10.1016/S1474-4422(24)00083-8
M3 - Article
C2 - 38631765
AN - SCOPUS:85190172282
SN - 1474-4422
VL - 23
SP - 487
EP - 499
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 5
ER -