Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

Sonia Moreno-Grau; Itziar de Rojas; Isabel Hernández; Inés Quintela; Laura Montrreal; Montserrat Alegret; Begoña Hernández-Olasagarre; Laura Madrid; Antonio González-Perez; Olalla Maroñas; Maitée Rosende-Roca; Ana Mauleón; Liliana Vargas; Asunción Lafuente; Carla Abdelnour; Octavio Rodríguez-Gómez; Silvia Gil; Miguel Ángel Santos-Santos; Ana Espinosa; Gemma Ortega; Ángela Sanabria; Alba Pérez-Cordón; Pilar Cañabate; Mariola Moreno; Silvia Preckler; Susana Ruiz; Nuria Aguilera; Juan Antonio Pineda; Juan Macías; Emilio Alarcón-Martín; Oscar Sotolongo-Grau; C. Abdelnour; E. Alarcon; A. Benaque; M. Boada; M. Buendia; A. Carracedo; A. Corbatón; S. Diego; A. Gailhajenet; P. García González; M. Guitart; M. Ibarria; J. Macias; E. Martín; M. T. Martínez; M. Marquié; G. Monté-Rubio; A. Orellana; A. Pancho; E. Pelejà; L. M. Real; A. Ruiz; S. Ruiz; M. E. Sáez; A. Sanabria; M. Serrano-Rios; L. Tárraga; S. Valero; A. D. Adarmes-Gómez; V. Álvarez; Goo Amer-Ferrer; M. Antequera; Carmen Antúnez; M. Baquero; M. Bernal; R. Blesa; D. Buiza-Rueda; M. J. Bullido; J. A. Burguera; M. Calero; F. Carrillo; M. Carrión-Claro; M. J. Casajeros; J. Clarimón; J. M. Cruz-Gamero; M. M. de Pancorbo; T. del Ser; M. Diez-Fairen; J. Fortea; Emilio Franco; A. Frank-García; J. M. García-Alberca; S. Garcia Madrona; G. Garcia-Ribas; P. Gómez-Garre; S. Hevilla; S. Jesús; Labrador Espinosa; C. Lage; A. Legaz; A. Lleó; A. López de Munáin; S. López-García; D. Macias; S. Manzanares; M. Marín; J. Marín-Muñoz; T. Marín

doi:https://doi.org/10.1016/j.jalz.2019.06.4950

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

Sonia Moreno-Grau, Itziar de Rojas, Isabel Hernández, Inés Quintela, Laura Montrreal, Montserrat Alegret, Begoña Hernández-Olasagarre, Laura Madrid, Antonio González-Perez, Olalla Maroñas, Maitée Rosende-Roca, Ana Mauleón, Liliana Vargas, Asunción Lafuente, Carla Abdelnour, Octavio Rodríguez-Gómez, Silvia Gil, Miguel Ángel Santos-Santos, Ana Espinosa, Gemma OrtegaÁngela Sanabria, Alba Pérez-Cordón, Pilar Cañabate, Mariola Moreno, Silvia Preckler, Susana Ruiz, Nuria Aguilera, Juan Antonio Pineda, Juan Macías, Emilio Alarcón-Martín, Oscar Sotolongo-Grau, C. Abdelnour, E. Alarcon, A. Benaque, M. Boada, M. Buendia, A. Carracedo, A. Corbatón, S. Diego, A. Gailhajenet, P. García González, M. Guitart, M. Ibarria, J. Macias, E. Martín, M. T. Martínez, M. Marquié, G. Monté-Rubio, A. Orellana, A. Pancho, E. Pelejà, L. M. Real, A. Ruiz, S. Ruiz, M. E. Sáez, A. Sanabria, M. Serrano-Rios, L. Tárraga, S. Valero, A. D. Adarmes-Gómez, V. Álvarez, Goo Amer-Ferrer, M. Antequera, Carmen Antúnez, M. Baquero, M. Bernal, R. Blesa, D. Buiza-Rueda, M. J. Bullido, J. A. Burguera, M. Calero, F. Carrillo, M. Carrión-Claro, M. J. Casajeros, J. Clarimón, J. M. Cruz-Gamero, M. M. de Pancorbo, T. del Ser, M. Diez-Fairen, J. Fortea, Emilio Franco, A. Frank-García, J. M. García-Alberca, S. Garcia Madrona, G. Garcia-Ribas, P. Gómez-Garre, S. Hevilla, S. Jesús, Labrador Espinosa, C. Lage, A. Legaz, A. Lleó, A. López de Munáin, S. López-García, D. Macias, S. Manzanares, M. Marín, J. Marín-Muñoz, T. Marín

Department of Genetics and Microbiology

Research output: Contribution to journal › Article › Research

31 Citations (Scopus)

Abstract

© 2019 The Authors Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

Original language	English
Pages (from-to)	1333-1347
Number of pages	15
Journal	Alzheimer's and Dementia
Volume	15
Issue number	10
DOIs	https://doi.org/10.1016/j.jalz.2019.06.4950
Publication status	Published - 1 Oct 2019

Keywords

Alzheimer's disease
Biological pathway
Cerebral amyloid angiopathy
GWAS
Vascular pathology
IMMUNITY
CEREBRAL AMYLOID ANGIOPATHY
METAANALYSIS
RARE
COGNITIVE FUNCTION
GENE
VASCULAR RISK
MUTATIONS
ONSET

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Moreno-Grau, S., de Rojas, I., Hernández, I., Quintela, I., Montrreal, L., Alegret, M., Hernández-Olasagarre, B., Madrid, L., González-Perez, A., Maroñas, O., Rosende-Roca, M., Mauleón, A., Vargas, L., Lafuente, A., Abdelnour, C., Rodríguez-Gómez, O., Gil, S., Santos-Santos, M. Á., Espinosa, A., ... Marín, T. (2019). Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project. Alzheimer's and Dementia, 15(10), 1333-1347. https://doi.org/10.1016/j.jalz.2019.06.4950

Moreno-Grau, Sonia ; de Rojas, Itziar ; Hernández, Isabel ; Quintela, Inés ; Montrreal, Laura ; Alegret, Montserrat ; Hernández-Olasagarre, Begoña ; Madrid, Laura ; González-Perez, Antonio ; Maroñas, Olalla ; Rosende-Roca, Maitée ; Mauleón, Ana ; Vargas, Liliana ; Lafuente, Asunción ; Abdelnour, Carla ; Rodríguez-Gómez, Octavio ; Gil, Silvia ; Santos-Santos, Miguel Ángel ; Espinosa, Ana ; Ortega, Gemma ; Sanabria, Ángela ; Pérez-Cordón, Alba ; Cañabate, Pilar ; Moreno, Mariola ; Preckler, Silvia ; Ruiz, Susana ; Aguilera, Nuria ; Pineda, Juan Antonio ; Macías, Juan ; Alarcón-Martín, Emilio ; Sotolongo-Grau, Oscar ; Abdelnour, C. ; Alarcon, E. ; Benaque, A. ; Boada, M. ; Buendia, M. ; Carracedo, A. ; Corbatón, A. ; Diego, S. ; Gailhajenet, A. ; García González, P. ; Guitart, M. ; Ibarria, M. ; Macias, J. ; Martín, E. ; Martínez, M. T. ; Marquié, M. ; Monté-Rubio, G. ; Orellana, A. ; Pancho, A. ; Pelejà, E. ; Real, L. M. ; Ruiz, A. ; Ruiz, S. ; Sáez, M. E. ; Sanabria, A. ; Serrano-Rios, M. ; Tárraga, L. ; Valero, S. ; Adarmes-Gómez, A. D. ; Álvarez, V. ; Amer-Ferrer, Goo ; Antequera, M. ; Antúnez, Carmen ; Baquero, M. ; Bernal, M. ; Blesa, R. ; Buiza-Rueda, D. ; Bullido, M. J. ; Burguera, J. A. ; Calero, M. ; Carrillo, F. ; Carrión-Claro, M. ; Casajeros, M. J. ; Clarimón, J. ; Cruz-Gamero, J. M. ; de Pancorbo, M. M. ; del Ser, T. ; Diez-Fairen, M. ; Fortea, J. ; Franco, Emilio ; Frank-García, A. ; García-Alberca, J. M. ; Garcia Madrona, S. ; Garcia-Ribas, G. ; Gómez-Garre, P. ; Hevilla, S. ; Jesús, S. ; Espinosa, Labrador ; Lage, C. ; Legaz, A. ; Lleó, A. ; López de Munáin, A. ; López-García, S. ; Macias, D. ; Manzanares, S. ; Marín, M. ; Marín-Muñoz, J. ; Marín, T. / Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project. In: Alzheimer's and Dementia. 2019 ; Vol. 15, No. 10. pp. 1333-1347.

@article{90bb406a43c14011a57638f1f6da7f74,

title = "Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project",

abstract = "{\textcopyright} 2019 The Authors Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.",

keywords = "Alzheimer's disease, Biological pathway, Cerebral amyloid angiopathy, GWAS, Vascular pathology, IMMUNITY, CEREBRAL AMYLOID ANGIOPATHY, METAANALYSIS, RARE, COGNITIVE FUNCTION, GENE, VASCULAR RISK, MUTATIONS, ONSET",

author = "Sonia Moreno-Grau and {de Rojas}, Itziar and Isabel Hern{\'a}ndez and In{\'e}s Quintela and Laura Montrreal and Montserrat Alegret and Bego{\~n}a Hern{\'a}ndez-Olasagarre and Laura Madrid and Antonio Gonz{\'a}lez-Perez and Olalla Maro{\~n}as and Mait{\'e}e Rosende-Roca and Ana Maule{\'o}n and Liliana Vargas and Asunci{\'o}n Lafuente and Carla Abdelnour and Octavio Rodr{\'i}guez-G{\'o}mez and Silvia Gil and Santos-Santos, {Miguel {\'A}ngel} and Ana Espinosa and Gemma Ortega and {\'A}ngela Sanabria and Alba P{\'e}rez-Cord{\'o}n and Pilar Ca{\~n}abate and Mariola Moreno and Silvia Preckler and Susana Ruiz and Nuria Aguilera and Pineda, {Juan Antonio} and Juan Mac{\'i}as and Emilio Alarc{\'o}n-Mart{\'i}n and Oscar Sotolongo-Grau and C. Abdelnour and E. Alarcon and A. Benaque and M. Boada and M. Buendia and A. Carracedo and A. Corbat{\'o}n and S. Diego and A. Gailhajenet and {Garc{\'i}a Gonz{\'a}lez}, P. and M. Guitart and M. Ibarria and J. Macias and E. Mart{\'i}n and Mart{\'i}nez, {M. T.} and M. Marqui{\'e} and G. Mont{\'e}-Rubio and A. Orellana and A. Pancho and E. Pelej{\`a} and Real, {L. M.} and A. Ruiz and S. Ruiz and S{\'a}ez, {M. E.} and A. Sanabria and M. Serrano-Rios and L. T{\'a}rraga and S. Valero and Adarmes-G{\'o}mez, {A. D.} and V. {\'A}lvarez and Goo Amer-Ferrer and M. Antequera and Carmen Ant{\'u}nez and M. Baquero and M. Bernal and R. Blesa and D. Buiza-Rueda and Bullido, {M. J.} and Burguera, {J. A.} and M. Calero and F. Carrillo and M. Carri{\'o}n-Claro and Casajeros, {M. J.} and J. Clarim{\'o}n and Cruz-Gamero, {J. M.} and {de Pancorbo}, {M. M.} and {del Ser}, T. and M. Diez-Fairen and J. Fortea and Emilio Franco and A. Frank-Garc{\'i}a and Garc{\'i}a-Alberca, {J. M.} and {Garcia Madrona}, S. and G. Garcia-Ribas and P. G{\'o}mez-Garre and S. Hevilla and S. Jes{\'u}s and Labrador Espinosa and C. Lage and A. Legaz and A. Lle{\'o} and {L{\'o}pez de Mun{\'a}in}, A. and S. L{\'o}pez-Garc{\'i}a and D. Macias and S. Manzanares and M. Mar{\'i}n and J. Mar{\'i}n-Mu{\~n}oz and T. Mar{\'i}n",

year = "2019",

month = oct,

day = "1",

doi = "https://doi.org/10.1016/j.jalz.2019.06.4950",

language = "English",

volume = "15",

pages = "1333--1347",

number = "10",

}

Moreno-Grau, S, de Rojas, I, Hernández, I, Quintela, I, Montrreal, L, Alegret, M, Hernández-Olasagarre, B, Madrid, L, González-Perez, A, Maroñas, O, Rosende-Roca, M, Mauleón, A, Vargas, L, Lafuente, A, Abdelnour, C, Rodríguez-Gómez, O, Gil, S, Santos-Santos, MÁ, Espinosa, A, Ortega, G, Sanabria, Á, Pérez-Cordón, A, Cañabate, P, Moreno, M, Preckler, S, Ruiz, S, Aguilera, N, Pineda, JA, Macías, J, Alarcón-Martín, E, Sotolongo-Grau, O, Abdelnour, C, Alarcon, E, Benaque, A, Boada, M, Buendia, M, Carracedo, A, Corbatón, A, Diego, S, Gailhajenet, A, García González, P, Guitart, M, Ibarria, M, Macias, J, Martín, E, Martínez, MT, Marquié, M, Monté-Rubio, G, Orellana, A, Pancho, A, Pelejà, E, Real, LM, Ruiz, A, Ruiz, S, Sáez, ME, Sanabria, A, Serrano-Rios, M, Tárraga, L, Valero, S, Adarmes-Gómez, AD, Álvarez, V, Amer-Ferrer, G, Antequera, M, Antúnez, C, Baquero, M, Bernal, M, Blesa, R, Buiza-Rueda, D, Bullido, MJ, Burguera, JA, Calero, M, Carrillo, F, Carrión-Claro, M, Casajeros, MJ, Clarimón, J, Cruz-Gamero, JM, de Pancorbo, MM, del Ser, T, Diez-Fairen, M, Fortea, J, Franco, E, Frank-García, A, García-Alberca, JM, Garcia Madrona, S, Garcia-Ribas, G, Gómez-Garre, P, Hevilla, S, Jesús, S, Espinosa, L, Lage, C, Legaz, A, Lleó, A, López de Munáin, A, López-García, S, Macias, D, Manzanares, S, Marín, M, Marín-Muñoz, J & Marín, T 2019, 'Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project', Alzheimer's and Dementia, vol. 15, no. 10, pp. 1333-1347. https://doi.org/10.1016/j.jalz.2019.06.4950

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project. / Moreno-Grau, Sonia; de Rojas, Itziar; Hernández, Isabel; Quintela, Inés; Montrreal, Laura; Alegret, Montserrat; Hernández-Olasagarre, Begoña; Madrid, Laura; González-Perez, Antonio; Maroñas, Olalla; Rosende-Roca, Maitée; Mauleón, Ana; Vargas, Liliana; Lafuente, Asunción; Abdelnour, Carla; Rodríguez-Gómez, Octavio; Gil, Silvia; Santos-Santos, Miguel Ángel; Espinosa, Ana; Ortega, Gemma; Sanabria, Ángela; Pérez-Cordón, Alba; Cañabate, Pilar; Moreno, Mariola; Preckler, Silvia; Ruiz, Susana; Aguilera, Nuria; Pineda, Juan Antonio; Macías, Juan; Alarcón-Martín, Emilio; Sotolongo-Grau, Oscar; Abdelnour, C.; Alarcon, E.; Benaque, A.; Boada, M.; Buendia, M.; Carracedo, A.; Corbatón, A.; Diego, S.; Gailhajenet, A.; García González, P.; Guitart, M.; Ibarria, M.; Macias, J.; Martín, E.; Martínez, M. T.; Marquié, M.; Monté-Rubio, G.; Orellana, A.; Pancho, A.; Pelejà, E.; Real, L. M.; Ruiz, A.; Ruiz, S.; Sáez, M. E.; Sanabria, A.; Serrano-Rios, M.; Tárraga, L.; Valero, S.; Adarmes-Gómez, A. D.; Álvarez, V.; Amer-Ferrer, Goo; Antequera, M.; Antúnez, Carmen; Baquero, M.; Bernal, M.; Blesa, R.; Buiza-Rueda, D.; Bullido, M. J.; Burguera, J. A.; Calero, M.; Carrillo, F.; Carrión-Claro, M.; Casajeros, M. J.; Clarimón, J.; Cruz-Gamero, J. M.; de Pancorbo, M. M.; del Ser, T.; Diez-Fairen, M.; Fortea, J.; Franco, Emilio; Frank-García, A.; García-Alberca, J. M.; Garcia Madrona, S.; Garcia-Ribas, G.; Gómez-Garre, P.; Hevilla, S.; Jesús, S.; Espinosa, Labrador; Lage, C.; Legaz, A.; Lleó, A.; López de Munáin, A.; López-García, S.; Macias, D.; Manzanares, S.; Marín, M.; Marín-Muñoz, J.; Marín, T.

In: Alzheimer's and Dementia, Vol. 15, No. 10, 01.10.2019, p. 1333-1347.

Research output: Contribution to journal › Article › Research

TY - JOUR

T1 - Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

AU - Moreno-Grau, Sonia

AU - de Rojas, Itziar

AU - Hernández, Isabel

AU - Quintela, Inés

AU - Montrreal, Laura

AU - Alegret, Montserrat

AU - Hernández-Olasagarre, Begoña

AU - Madrid, Laura

AU - González-Perez, Antonio

AU - Maroñas, Olalla

AU - Rosende-Roca, Maitée

AU - Mauleón, Ana

AU - Vargas, Liliana

AU - Lafuente, Asunción

AU - Abdelnour, Carla

AU - Rodríguez-Gómez, Octavio

AU - Gil, Silvia

AU - Santos-Santos, Miguel Ángel

AU - Espinosa, Ana

AU - Ortega, Gemma

AU - Sanabria, Ángela

AU - Pérez-Cordón, Alba

AU - Cañabate, Pilar

AU - Moreno, Mariola

AU - Preckler, Silvia

AU - Ruiz, Susana

AU - Aguilera, Nuria

AU - Pineda, Juan Antonio

AU - Macías, Juan

AU - Alarcón-Martín, Emilio

AU - Sotolongo-Grau, Oscar

AU - Abdelnour, C.

AU - Alarcon, E.

AU - Benaque, A.

AU - Boada, M.

AU - Buendia, M.

AU - Carracedo, A.

AU - Corbatón, A.

AU - Diego, S.

AU - Gailhajenet, A.

AU - García González, P.

AU - Guitart, M.

AU - Ibarria, M.

AU - Macias, J.

AU - Martín, E.

AU - Martínez, M. T.

AU - Marquié, M.

AU - Monté-Rubio, G.

AU - Orellana, A.

AU - Pancho, A.

AU - Pelejà, E.

AU - Real, L. M.

AU - Ruiz, A.

AU - Ruiz, S.

AU - Sáez, M. E.

AU - Sanabria, A.

AU - Serrano-Rios, M.

AU - Tárraga, L.

AU - Valero, S.

AU - Adarmes-Gómez, A. D.

AU - Álvarez, V.

AU - Amer-Ferrer, Goo

AU - Antequera, M.

AU - Antúnez, Carmen

AU - Baquero, M.

AU - Bernal, M.

AU - Blesa, R.

AU - Buiza-Rueda, D.

AU - Bullido, M. J.

AU - Burguera, J. A.

AU - Calero, M.

AU - Carrillo, F.

AU - Carrión-Claro, M.

AU - Casajeros, M. J.

AU - Clarimón, J.

AU - Cruz-Gamero, J. M.

AU - de Pancorbo, M. M.

AU - del Ser, T.

AU - Diez-Fairen, M.

AU - Fortea, J.

AU - Franco, Emilio

AU - Frank-García, A.

AU - García-Alberca, J. M.

AU - Garcia Madrona, S.

AU - Garcia-Ribas, G.

AU - Gómez-Garre, P.

AU - Hevilla, S.

AU - Jesús, S.

AU - Espinosa, Labrador

AU - Lage, C.

AU - Legaz, A.

AU - Lleó, A.

AU - López de Munáin, A.

AU - López-García, S.

AU - Macias, D.

AU - Manzanares, S.

AU - Marín, M.

AU - Marín-Muñoz, J.

AU - Marín, T.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - © 2019 The Authors Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

AB - © 2019 The Authors Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

KW - Alzheimer's disease

KW - Biological pathway

KW - Cerebral amyloid angiopathy

KW - GWAS

KW - Vascular pathology

KW - IMMUNITY

KW - CEREBRAL AMYLOID ANGIOPATHY

KW - METAANALYSIS

KW - RARE

KW - COGNITIVE FUNCTION

KW - GENE

KW - VASCULAR RISK

KW - MUTATIONS

KW - ONSET

UR - http://www.mendeley.com/research/genomewide-association-analysis-dementia-clinical-endophenotypes-reveal-novel-loci-associated-alzhei

U2 - https://doi.org/10.1016/j.jalz.2019.06.4950

DO - https://doi.org/10.1016/j.jalz.2019.06.4950

M3 - Article

C2 - 31473137

VL - 15

SP - 1333

EP - 1347

IS - 10

ER -

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

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