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@ARTICLE{Valentino:269189,
author = {Valentino, Rebecca R and Scotton, William J and Roemer,
Shanu F and Lashley, Tammaryn and Heckman, Michael G and
Shoai, Maryam and Martinez-Carrasco, Alejandro and Tamvaka,
Nicole and Walton, Ronald L and Baker, Matthew C and
Macpherson, Hannah L and Real, Raquel and Soto-Beasley,
Alexandra I and Mok, Kin and Revesz, Tamas and Christopher,
Elizabeth A and DeTure, Michael and Seeley, William W and
Lee, Edward B and Frosch, Matthew P and Molina-Porcel, Laura
and Gefen, Tamar and Redding-Ochoa, Javier and Ghetti,
Bernardino and Robinson, Andrew C and Kobylecki, Christopher
and Rowe, James B and Beach, Thomas G and Teich, Andrew F
and Keith, Julia L and Bodi, Istvan and Halliday, Glenda M
and Gearing, Marla and Arzberger, Thomas and Morris,
Christopher M and White, Charles L and Mechawar, Naguib and
Boluda, Susana and MacKenzie, Ian R and McLean, Catriona and
Cykowski, Matthew D and Wang, Shih-Hsiu J and Graff,
Caroline and Nagra, Rashed M and Kovacs, Gabor G and
Giaccone, Giorgio and Neumann, Manuela and Ang, Lee-Cyn and
Carvalho, Agostinho and Morris, Huw R and Rademakers, Rosa
and Hardy, John A and Dickson, Dennis W and Rohrer, Jonathan
D and Ross, Owen A},
collaboration = {Consortium, Pick's disease International},
othercontributors = {Warner, Thomas T and Jaunmuktane, Zane and Boeve, Bradley F
and Duara, Ranjan and Graff-Radford, Neill R and Josephs,
Keith A and Knopman, David S and Koga, Shunsuke and Murray,
Melissa E and Lyons, Kelly E and Pahwa, Rajesh and Petersen,
Ronald C and Whitwell, Jennifer L and Grinberg, Lea T and
Miller, Bruce and Schlereth, Athena and Spina, Salvatore and
Grossman, Murray and Irwin, David J and Suh, EunRan and
Trojanowski, John Q and Van Deerlin, Vivianna M and Wolk,
David A and Connors, Theresa R and Dooley, Patrick M and
Oakley, Derek H and Aldecoa, Iban and Balasa, Mircea and
Gelpi, Ellen and Borrego-Écija, Sergi and Gascon-Bayarri,
Jordi and Sánchez-Valle, Raquel and Sanz-Cartagena, Pilar
and Piñol-Ripoll, Gerard and Bigio, Eileen H and Flanagan,
Margaret E and Rogalski, Emily J and Weintraub, Sandra and
Schneider, Julie A and Peng, Lihua and Zhu, Xiongwei and
Chang, Koping and Troncoso, Juan C and Prokop, Stefan and
Newell, Kathy L and Jones, Matthew and Richardson, Anna and
Roncaroli, Federico and Snowden, Julie and Allinson, Kieren
and Singh, Poonam and Serrano, Geidy E and Flowers, Xena E
and Goldman, James E and Heaps, Allison C and Leskinen,
Sandra P and Black, Sandra E and Masellis, Mario and King,
Andrew and Al-Sarraj, Safa and Troakes, Claire and Hodges,
John R and Kril, Jillian J and Kwok, John B and Piguet,
Olivier and Roeber, Sigrun and Attems, Johannes and Thomas,
Alan J and Evers, Bret M and Bieniek, Kevin F and Sieben,
Anne A and Cras, Patrick P and De Vil, Bart B and Bird,
Thomas and Castellani, Rudolph J and Chaffee, Ann and
Franklin, Erin and Haroutunian, Vahram and Jacobsen, Max and
Keene, Dirk and Latimer, Caitlin S and Metcalf, Jeff and
Perrin, Richard J and Purohit, Dushyant P and Rissman,
Robert A and Schantz, Aimee and Walker, Jamie and De Deyn,
Peter P and Duyckaerts, Charles and Le Ber, Isabelle and
Seilhean, Danielle and Turbant-Leclere, Sabrina and Ervin,
John F and Nennesmo, Inger and Riehl, James and Nacmias,
Benedetta and Finger, Elizabeth C and Blauwendraat, Cornelis
and Nalls, Mike A and Singleton, Andrew B and Vitale, Dan
and Cunha, Cristina and Wszolek, Zbigniew K},
title = {{MAPT} {H}2 haplotype and risk of {P}ick's disease in the
{P}ick's disease {I}nternational {C}onsortium: a genetic
association study.},
journal = {The lancet},
volume = {23},
number = {5},
issn = {1474-4422},
address = {London},
publisher = {Lancet Publ. Group},
reportid = {DZNE-2024-00488},
pages = {487 - 499},
year = {2024},
abstract = {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.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.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).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.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.},
keywords = {Female / Humans / Male / Genetic Association Studies /
Haplotypes / Pick Disease of the Brain: genetics / tau
Proteins: genetics / Tauopathies / MAPT protein, human (NLM
Chemicals)},
cin = {AG Neumann},
ddc = {610},
cid = {I:(DE-2719)1210003},
pnm = {352 - Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38631765},
doi = {10.1016/S1474-4422(24)00083-8},
url = {https://pub.dzne.de/record/269189},
}