The MAPT H1 Haplotype Is a Risk Factor for Alzheimer's Disease in APOE ε4 Non-carriers

被引：29

作者：

Sanchez-Juan, Pascual ^{[1
,2
,3
,4
]}

Moreno, Sonia ^{[1
,3
,4
]}

de Rojaso, Itziar ^{[1
,3
,4
]}

Hernandez, Isabel ^{[1
,3
,4
]}

Valero, Sergi ^{[1
,3
,4
]}

Alegret, Montse ^{[1
,3
,4
]}

Montrreal, Laura ^{[1
,3
,4
]}

Garcia Gonzalez, Pablo ^{[1
,3
,4
]}

Lage, Carmen ^{[1
,2
,3
,4
]}

Lopez-Garcia, Sara ^{[1
,2
,3
,4
]}

Rodriiguez-Rodriguez, Eloy ^{[1
,2
,3
,4
]}

Orellana, Adelina ^{[1
,3
,4
]}

Tarraga, Lluis ^{[1
,3
,4
]}

Boada, Merce ^{[1
,3
,4
]}

Ruiz, Agustin ^{[1
,3
,4
]}

Abdelnour, C. ^{[1
,3
,4
]}

Aguilera, N. ^{[3
,4
]}

Alarcon, E. ^{[3
,4
,5
]}

Alegret, M. ^{[1
,3
,4
]}

Boada, M. ^{[1
,3
,4
]}

Buendia, M. ^{[3
,4
]}

Canabate, P. ^{[1
,3
,4
]}

de Rojas, I ^{[3
,4
]}

Diego, S. ^{[3
,4
]}

Espinosa, A. ^{[1
,3
,4
]}

Gailhajenet, A. ^{[3
,4
]}

Garcia Gonzalez, P. ^{[3
,4
]}

Gil, S. ^{[3
,4
]}

Guitart, M. ^{[3
,4
]}

Hernandez, I ^{[1
,3
,4
,12
]}

Ibarria, M. ^{[3
,4
]}

Lafuente, A. ^{[3
,4
]}

Martin, E. ^{[3
,4
]}

Mauleon, A. ^{[3
,4
]}

Monte-Rubio, G. ^{[3
,4
]}

Montrreal, L. ^{[3
,4
]}

Moreno-Grau, S. ^{[1
,3
,4
,12
]}

Moreno, M. ^{[3
,4
]}

Orellana, A. ^{[3
,4
]}

Ortega, G. ^{[1
,3
,4
]}

Pancho, A. ^{[3
,4
]}

Peleja, E. ^{[3
,4
]}

Perez-Cordon, A. ^{[3
,4
]}

Preckler, S. ^{[3
,4
]}

Rodriguez-Gomez, O. ^{[1
,3
,4
]}

Rosende-Roca, M. ^{[3
,4
]}

Ruiz, A. ^{[1
,3
,4
,12
]}

Ruiz, S. ^{[1
,3
,4
]}

Sanabria, A. ^{[3
,4
]}

Santos-Santos, M. A. ^{[3
,4
]}

机构：

[1] Minist Econ & Competitiveness, Natl Inst Hlth Carlos III, Ctr Networked Biomed Res Neurodegenerat Dis, Madrid, Spain

[2] Univ Cantabria, IDIVAL, Serv Neurol, Univ Hosp Marques de Valdecilla, Santander, Spain

[3] Univ Int Catalunya, Fundacio ACE, Inst Catala Neurociencies Aplicades, Res Ctr, Barcelona, Spain

[4] Univ Int Catalunya, Fundacio ACE, Inst Catala Neurociencies Aplicades, Memory Clin, Barcelona, Spain

[5] Univ Malaga, Sch Med, Dept Surg Biochem & Mol Biol, Malaga, Spain

[6] Univ Santiago de Compostela, Ctr Nacl Genotipado CEGEN PRB3 ISCIII, Grp Med Xenom, Santiago, Spain

[7] IDIS, CIBERER, Fdn Publ Galega Med Xenom, Santiago, Spain

[8] Hosp Clin San Carlos, Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain

[9] Ctr Andaluz Estudios Bioinformat, Seville, Spain

[10] Hosp Univ Valme, Unidad Clin Enfermedades Infecciosas & Microbiol, Seville, Spain

[11] Univ Seville, CSIC, Hosp Univ Virgen del Rocio,Inst Biomed Sevilla, Unidad Trastornos Movimiento,Serv Neurol & Neurof, Seville, Spain

[12] Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, Madrid, Spain

[13] Fundacio Recerca Biomed & Social Mutua Terrassa, Barcelona, Spain

[14] Univ Barcelona, Sch Med, Hosp Univ Mutua de Terrassa, Memory Disorders Unit,Dept Neurol, Barcelona, Spain

[15] Hosp Univ Cent Asturias, Lab Genet, Oviedo, Spain

[16] Inst Invest Biosanit Principado Asturias, Oviedo, Spain

[17] Hosp Univ Son Espases, Dept Neurol, Palma De Mallorca, Spain

[18] Hosp Clin Univ Virgen de la Arrixaca, Unidad Demencias, Murcia, Spain

[19] Hosp Univ & Politecn La Fe, Serv Neurol, Valencia, Spain

[20] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Unidad Demencias,Serv Neurol & Neurofisiol, Seville, Spain

[21] Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Pau Memory Unit,Neurol Dept, Barcelona, Spain

[22] Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, Madrid, Spain

[23] Inst Invest Sanitaria Hosp la Paz, Madrid, Spain

[24] CIEN Fdn, Queen Sofia Fdn, Alzheimer Ctr, Madrid, Spain

[25] Inst Salud Carlos III, Madrid, Spain

[26] Hosp Univ Ramon y Cajal, Madrid, Spain

[27] Univ Basque Country, UPV EHU, Ctr Invest Lascaray, BIOMICs, Leioa, Spain

[28] Hosp Univ La Paz UAM, Neurol Serv, Madrid, Spain

[29] Andalusian Inst Neurosci, Alzheimer Res Ctr, Malaga, Spain

[30] Andalusian Inst Neurosci, Memory Clin, Malaga, Spain

[31] Univ Cantabria, Marques de Valdecilla Univ Hosp, IDIVAL, Neurol Serv, Santander, Spain

[32] Hosp Donostia San Sebastian, Donostia San Sebastian, Spain

[33] Fdn Formac & Invest Sanitarias Reg Murcia, Murcia, Spain

[34] Hosp Cabuenes, Serv Neurol, Gijon, Spain

[35] Fdn CITA Alzheimer, Ctr Invest & Terapias Avanzadas, Donostia San Sebastian, Spain

[36] Navarrabiomed, Pamplona, Spain

[37] Hosp Univ Cent Asturias, Serv Neurol, Oviedo, Spain

[38] Fundacio Pasqua Maragall, Barcelonasseta Brain Res Ctr, Barcelona, Spain

[39] CSIC, Inst Biomed Valencia, Unitat Genet Mol, Valencia, Spain

[40] Inst Invest Sanitaria La Fe, Unidad Mixta Neurol & Genet, Valencia, Spain

[41] Hosp Univ Santa Maria Lleida, Unitat Trastorns Cognitius, Inst Recerca Biomed Lleida, Lleida, Spain

[42] BT CIEN, Madrid, Spain

[43] Hosp Univ La Princesa, Madrid, Spain

[44] Hosp Clin Barcelona, Barcelona, Spain

来源：

FRONTIERS IN AGING NEUROSCIENCE | 2019年 / 11卷

关键词：

Alzheimer's disease; MAPT; APOE; genetic association; PROGRESSIVE SUPRANUCLEAR PALSY; TAU-GENE; CORTICOBASAL DEGENERATION; ASSOCIATION; PROTEIN; LOCUS;

D O I：

10.3389/fnagi.2019.00327

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene, defines two haplotype clades in Caucasians (H1 and H2). The H1 haplotype has been linked inconsistently with AD. In a previous study, we showed that an SNP tagging this haplotype (rs1800547) was associated with AD risk in a large population from the Dementia Genetics Spanish Consortium (DEGESCO) including 4435 cases and 6147 controls. The association was mainly driven by individuals that were non-carriers of the APOE epsilon 4 allele. Our aim was to replicate our previous findings in an independent sample of 4124 AD cases and 3290 controls from Spain (GR@ACE project) and to analyze the effect of the H1 sub-haplotype structure on the risk of AD. The H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0025). Stratification analysis showed that this association was mainly driven by the APOE epsilon 4 non-carriers (OR = 1.15; p = 0.0022). Pooled analysis of both Spanish datasets (n = 17,996) showed that the highest AD risk related to the MAPT H1/H2 haplotype was in those individuals that were the oldest [third tertile (>77 years)] and did not carry APOE epsilon 4 allele (p = 0.001). We did not find a significant association between H1 sub-haplotypes and AD. H1c was nominally associated but lost statistical significance after adjusting by population sub-structure. Our results are consistent with the hypothesis that genetic variants linked to the MAPT H1/H2 are tracking a genuine risk allele for AD. The fact that this association is stronger in APOE epsilon 4 non-carriers partially explains previous controversial results and might be related to a slower alternative causal pathway less dependent on brain amyloid load.

引用

页数：9

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