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15 results on '"Carcel M."'

1. Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Author

Guelfi S., D’Sa K., Botía J.A., Vandrovcova J., Reynolds R.H., Zhang D., Trabzuni D., Collado-Torres L., Thomason A., Quijada Leyton P., Gagliano Taliun S.A., Nalls M.A., Noyce A.J., Nicolas A., Cookson M.R., Bandres-Ciga S., Gibbs J.R., Hernandez D.G., Singleton A.B., Reed X., Leonard H., Blauwendraat C., Faghri F., Bras J., Guerreiro R., Tucci A., Kia D.A., Houlden H., Plun-Favreau H., Mok K.Y., Wood N.W., Lovering R., R’Bibo L., Rizig M., Chelban V., Tan M., Morris H.R., Middlehurst B., Quinn J., Billingsley K., Holmans P., Kinghorn K.J., Lewis P., Escott-Price V., Williams N., Foltynie T., Brice A., Danjou F., Lesage S., Corvol J.-C., Martinez M., Giri A., Schulte C., Brockmann K., Simón-Sánchez J., Heutink P., Gasser T., Rizzu P., Sharma M., Shulman J.M., Robak L., Lubbe S., Mencacci N.E., Finkbeiner S., Lungu C., Scholz S.W., Gan-Or Z., Rouleau G.A., Krohan L., van Hilten J.J., Marinus J., Adarmes-Gómez A.D., Bernal-Bernal I., Bonilla-Toribio M., Buiza-Rueda D., Carrillo F., Carrión-Claro M., Mir P., Gómez-Garre P., Jesús S., Labrador-Espinosa M.A., Macias D., Vargas-González L., Méndez-del-Barrio C., Periñán-Tocino T., Tejera-Parrado C., Diez-Fairen M., Aguilar M., Alvarez I., Boungiorno M.T., Carcel M., Pastor P., Tartari J.P., Alvarez V., González M.M., Blazquez M., Garcia C., Suarez-Sanmartin E., Barrero F.J., Rezola E.M., Yarza J.A.B., Pagola A.G., Arregui A.L.M., Ruiz-Martínez J., Cerdan D., Duarte J., Clarimón J., Dols-Icardo O., Infante J., Marín J., Kulisevsky J., Pagonabarraga J., Gonzalez-Aramburu I., Rodriguez A.S., Sierra M., Duran R., Ruz C., Vives F., Escamilla-Sevilla F., Mínguez A., Cámara A., Compta Y., Ezquerra M., Marti M.J., Fernández M., Muñoz E., Fernández-Santiago R., Tolosa E., Valldeoriola F., García-Ruiz P., Heredia M.J.G., Errazquin F.P., Hoenicka J., Jimenez-Escrig A., Martínez-Castrillo J.C., Lopez-Sendon J.L., Torres I.M., Tabernero C., Vela L., Zimprich A., Pihlstrom L., Koks S., Taba P., Majamaa K., Siitonen A., Okubadejo N.U., Ojo O.O., Forabosco P., Walker R., Small K.S., Smith C., Ramasamy A., Hardy J., Weale M.E., and Ryten M.

Subjects
medicine, RNA splicing, phenotype, brain, genotype, Quantitative Trait Loci, genetic analysis, Polymorphism, Single Nucleotide, Article, genetic regulation, mental disease, transcriptomics, quantitative trait locus, expression quantitative trait locus, single nucleotide polymorphism, Humans, genetics, human, reproducibility, Alleles, Neurons, genome-wide association study, human cell, allele, Putamen, Reproducibility of Results, RNA sequencing, Parkinson Disease, gene expression regulation, cell, cohort analysis, neurologic disease, human tissue, schizophrenia, Substantia Nigra, disease incidence, physiology, gene expression, RNA, physiological response, Nervous System Diseases, nerve cell, Transcriptome, nervous system disorder, basal ganglion
Abstract

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/. © 2020, The Author(s).

Published
2020

2. Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset

Author

Billingsley, Kimberley J, Barbosa, Ines A, Bandres-Ciga, Sara, Quinn, John P, Bubb, Vivien J, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A, Blauwendraat, Cornelis, Gan-Or, Ziv, Gibbs, J Raphael, Nalls, Mike A, Singleton, Andrew, Ryten, Mina, Koks, Sulev, Noyce, A, Tucci, A, Middlehurst, B, Kia, D, Tan, M, Houlden, H, Morris, HR, Plun-Favreau, H, Holmans, P, Hardy, J, Trabzuni, D, Bras, J, Mok, K, Kinghorn, K, Wood, N, Lewis, P, Guerreiro, R, Loverin, R, R'Bibo, L, Rizig, M, Escott-Price, V, Chelban, V, Foltynie, T, Williams, N, Brice, A, Danjou, F, Lesage, S, Martinez, M, Giri, A, Schulte, C, Brockmann, K, Simon-Sanchez, J, Heutink, P, Rizzu, P, Sharma, M, Gasser, T, Nicolas, A, Cookson, M, Faghri, F, Hernandez, D, Shulman, J, Robak, L, Lubbe, S, Finkbeiner, S, Mencacci, N, Lungu, C, Scholz, S, Reed, X, Leonard, H, Rouleau, G, Krohan, L, van Hilten, J, Marinus, J, Adarmes-Gomez, A, Aguilar, M, Alvarez, I, Alvarez, V, Javier Barrero, F, Bergareche Yarza, J, Bernal-Bernal, I, Blazquez, M, Bonilla-Toribio Bernal, M, Boungiorne, M, Buiza-Rueda, Dolores, Camara, A, Carcel, M, Carrillo, F, Carrion-Claro, M, Cerdan, D, Clarimon, J, Compta, Y, Diez-Fairen, M, Dols-Icardo, O, Duarte, J, Duran, RI, Escamilla-Sevilla, F, Ezquerra, M, Fernandez, M, Fernandez-Santiago, R, Garcia, C, Garcia-Ruiz, P, Gomez-Garre, P, Gomez Heredia, M, Gonzalez-Aramburu, I, Gorostidi Pagola, A, Hoenicka, J, Infante, J, Jesus, S, Jimenez-Escrig, A, Kulisevsky, J, Labrador-Espinosa, M, Lopez-Sendon, J, de Munain Arregui, A Lopez, Macias, D, Martinez Torres, I, Marin, J, Jose Marti, M, Martinez-Castrillo, J, Mendez-del-Barrio, C, Menendez Gonzalez, M, Minguez, A, Mir, P, Mondragon Rezola, E, Munoz, E, Pagonabarraga, J, Pastor, P, Perez Errazquin, F, Perinan-Tocino, T, Ruiz-Martinez, J, Ruz, C, Sanchez Rodriguez, A, Sierra, M, Suarez-Sanmartin, E, Tabernero, C, Pablo Tartari, J, Tejera-Parrado, C, Tolosa, E, Valldeoriola, F, Vargas-Gonzalez, L, Vela, L, Vives, F, Zimprich, A, Pihlstrom, L, Taba, P, Majamaa, K, Siitonen, A, Okubadejo, N, Ojo, O, IPDGC, and Universidad de Cantabria

Subjects
0301 basic medicine, Mitochondrial DNA, medicine.medical_specialty, Aging, Parkinson's disease, Mitochondrial disease, Mitochondrion, Biology, Neurodegenerative, Bioinformatics, lcsh:RC346-429, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Mendelian randomization, Mitophagy, medicine, Genetics, 2.1 Biological and endogenous factors, Aetiology, lcsh:Neurology. Diseases of the nervous system, Parkinson's Disease, Medical genetics, Neurosciences, medicine.disease, Brain Disorders, International Parkinson’s Disease Genomics Consortium, 030104 developmental biology, Proteostasis, Neurology, Risk factors, Neurological, Neurology (clinical), Medical genetic, 030217 neurology & neurosurgery
Abstract

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD., This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949

Published
2019

3. Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability

Author

Reynolds, R.H., Botia, J., Nalls, M.A., Hardy, J., Taliun, S.A.G., Ryten, M., Noyce, A.J., Nicolas, A., Cookson, M.R., Bandres-Ciga, S., Gibbs, J.R., Hernandez, D.G., Singleton, A.B., Reed, X., Leonard, H., Blauwendraat, C., Faghri, F., Bras, J., Guerreiro, R., Tucci, A., Kia, D.A., Houlden, H., Plun-Favreau, H., Mok, K.Y., Wood, N.W., Lovering, R., R'Bibo, L., Rizig, M., Chelban, V., Trabzuni, D., Tan, M., Morris, H.R., Middlehurst, B., Quinn, J., Billingsley, K., Holmans, P., Kinghorn, K.J., Lewis, P., Escott-Price, V., Williams, N., Foltynie, T., Brice, A., Danjou, F., Lesage, S., Corvol, J.C., Martinez, M., Giri, A., Schulte, C., Brockmann, K., Simon-Sanchez, J., Heutink, P., Gasser, T., Rizzu, P., Sharma, M., Shulman, J.M., Robak, L., Lubbe, S., Mencacci, N.E., Finkbeiner, S., Lungu, C., Scholz, S.W., Gan-Or, Z., Rouleau, G.A., Krohan, L., Hilten, J.J. van, Marinus, J., Adarmes-Gomez, A.D., Bernal-Bernal, I., Bonilla-Toribio, M., Buiza-Rueda, D., Carrillo, F., Carrion-Claro, M., Mir, P., Gomez-Garre, P., Jesus, S., Labrador-Espinosa, M.A., Macias, D., Vargas-Gonzalez, L., Mendez-del-Barrio, C., Perinan-Tocino, T., Tejera-Parrado, C., Diez-Fairen, M., Aguilar, M., Alvarez, I., Boungiorno, M.T., Carcel, M., Pastor, P., Tartari, J.P., Alvarez, V., Gonzalez, M.M., Blazquez, M., Garcia, C., Suarez-Sanmartin, E., Barrero, F.J., Rezola, E.M., Yarza, J.A.B., Pagola, A.G., Arregui, A.L.D., Ruiz-Martinez, J., Cerdan, D., Duarte, J., Clarimon, J., Dols-Icardo, O., Infante, J., Marin, J., Kulisevsky, J., Pagonabarraga, J., Gonzalez-Aramburu, I., Rodriguez, A.S., Sierra, M., Duran, R., Ruz, C., Vives, F., Escamilla-Sevilla, F., Minguez, A., Camara, A., Compta, Y., Ezquerra, M., Marti, M.J., Fernandez, M., Munoz, E., Fernandez-Santiago, R., Tolosa, E., Valldeoriola, F., Garcia-Ruiz, P., Heredia, M.J.G., Errazquin, F.P., Hoenicka, J., Jimenez-Escrig, A., Martinez-Castrillo, J.C., Lopez-Sendon, J.L., Torres, I.M., Tabernero, C., Vela, L., Zimprich, A., Pihlstrom, L., Koks, S., Taba, P., Majamaa, K., Siitonen, A., Okubadejo, N.U., Ojo, O.O., Pitcher, T., Anderson, T., Bentley, S., Fowdar, J., Mellick, G., Dalrymple-Alford, J., Henders, A.K., Kassam, I., Montgomery, G., Sidorenko, J., Zhang, F.T., Xue, A.L., Vallerga, C.L., Wallace, L., Wray, N.R., Yang, J., Visscher, P.M., Gratten, J., Silburn, P.A., Halliday, G., Hickie, I., Kwok, J., Lewis, S., Kennedy, M., Pearson, J., Int Parkinsons Dis Genomics, and Syst Genomics Parkinsons Dis

Published
2019

4. Moving beyond neurons : the role of cell type-specific gene regulation in Parkinson's disease heritability

Author

Reynolds, R. H., Botía, J., Nalls, M. A., Noyce, A. J., Nicolas, A., Cookson, M. R., Bandres-Ciga, S., Gibbs, J. R., Hernandez, D. G., Singleton, A. B., Reed, X., Leonard, H., Blauwendraat, Cornelis, Faghri, F., Bras, J., Guerreiro, Rita, Tucci, A., Kia, Demis A, Houlden, Henry, Plun-Favreau, H., Mok, K. Y., Wood, N. W., Lovering, R., R'Bibo, L., Rizig, M., Chelban, Viorica, Trabzuni, D., Tan, M., Morris, H. R., Middlehurst, B., Quinn, J., Billingsley, K., Holmans, Peter, Kinghorn, K. J., Lewis, P., Escott-Price, Valentina, Williams, N., Foltynie, T., Brice, Alexis, Danjou, F., Lesage, S., Corvol, Jean-Christophe, Martinez, M., Giri, A., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, Peter, Gasser, Thomas, Rizzu, P., Sharma, M., Shulman, J. M., Robak, L., Lubbe, S., Mencacci, N. E., Finkbeiner, S., Lungu, C., Scholz, S. W., Gan-Or, Z., Rouleau, G. A., Krohan, L., van Hilten, J. J., Marinus, J., Adarmes-Gómez, A.D, Bernal-Bernal, I., Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Carrillo, F., Carrión-Claro, M., Mir, P., Gómez-Garre, P., Jesús, S., Labrador-Espinosa, Miguel A, Macías-García, Daniel, Vargas-González, L., Méndez-del-Barrio, C., Periñán-Tocino, T., Tejera-Parrado, C., Diez-Fairen, Monica., Aguilar Barberà, Miquel, Alvarez, Ignacio, Boungiorno, M. T., Carcel, M., Pastor, Pau, Tartari, J. P., Alvarez, V., González, M. M., Blázquez Estrada, Marta, Garcia, C.., Suarez-Sanmartin, E., Barrero, F. J., Rezola, E. M., Yarza, J. A. B., Pagola, A. G., de Munain Arregui, A. L., Ruiz-Martínez, J., Cerdan, Debora, Duarte, J., Clarimón, Jordi, Dols Icardo, Oriol, Infante, J., Marín, J., Kulisevsky, Jaime, Pagonabarraga Mora, Javier, Gonzalez-Aramburu, Isabel, Rodriguez, A. S., Sierra, M., Duran, Raquel, Ruz, C., Vives, F., Escamilla-Sevilla, F., Mínguez, A., Cámara, Ana, Compta, Yaroslau, Ezquerra, M., Marti, M. J., Fernández, M., Muñoz García, José Esteban, Fernández Santiago, Rubén, Tolosa, E., Valldeoriola, F., García-Ruiz, P., Heredia, M. J. G., Errazquin, F. P., Hoenicka, J., Jimenez-Escrig, A., Martínez-Castrillo, J. C., Lopez-Sendon, J. L., Torres, I. M., Tabernero, C., Vela, Lydia, Zimprich, Alexander, Pihlstrom, L., Koks, S., Taba, P., Majamaa, K., Siitonen, A., Okubadejo, N. U., Ojo, O. O., Pitcher, T., Anderson, T., Bentley, S., Fowdar, J., Mellick, G., Dalrymple-Alford, J., Henders, Anjali K, Kassam, I., Montgomery, G., Sidorenko, J., Zhang, F., Xue, A., Vallerga, C. L., Wallace, Leanne, Wray, N. R., Yang, J., Visscher, P. M., Gratten, J., Silburn, P. A., Halliday, G., Hickie, Ian B, Kwok, J., Lewis, S., Kennedy, M., Pearson, J., Hardy, J., Gagliano Taliun, S. A., Ryten, Mina, and Universitat Autònoma de Barcelona

Abstract

Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

Published
2019

5. Moving beyond neurons:the role of cell type-specific gene regulation in Parkinson’s disease heritability

Author

Reynolds, R. H. (Regina H.), Botia, J. (Juan), Nalls, M. A. (Mike A.), Hardy, J. (John), Taliun, S. A. (Sarah A. Gagliano), Ryten, M. (Mina), Noyce, A. J. (Alastair J.), Nicolas, A. (Aude), Cookson, M. R. (Mark R.), Bandres-Ciga, S. (Sara), Gibbs, J. R. (J. Raphael), Hernandez, D. G. (Dena G.), Singleton, A. B. (Andrew B.), Reed, X. (Xylena), Leonard, H. (Hampton), Blauwendraat, C. (Cornelis), Faghri, F. (Faraz), Bras, J. (Jose), Guerreiro, R. (Rita), Tucci, A. (Arianna), Kia, D. A. (Demis A.), Houlden, H. (Henry), Plun-Favreau, H. (Helene), Mok, K. Y. (Kin Y.), Wood, N. W. (Nicholas W.), Lovering, R. (Ruth), R'Bibo, L. (Lea), Rizig, M. (Mie), Chelban, V. (Viorica), Trabzuni, D. (Daniah), Tan, M. (Manuela), Morris, H. R. (Huw R.), Middlehurst, B. (Ben), Quinn, J. (John), Billingsley, K. (Kimberley), Holmans, P. (Peter), Kinghorn, K. J. (Kerri J.), Lewis, P. (Patrick), Escott-Price, V. (Valentina), Williams, N. (Nigel), Foltynie, T. (Thomas), Brice, A. (Alexis), Danjou, F. (Fabrice), Lesage, S. (Suzanne), Corvol, J.-C. (Jean-Christophe), Martinez, M. (Maria), Giri, A. (Anamika), Schulte, C. (Claudia), Brockmann, K. (Kathrin), Simon-Sanchez, J. (Javier), Heutink, P. (Peter), Gasser, T. (Thomas), Rizzu, P. (Patrizia), Sharma, M. (Manu), Shulman, J. M. (Joshua M.), Robak, L. (Laurie), Lubbe, S. (Steven), Mencacci, N. E. (Niccolo E.), Finkbeiner, S. (Steven), Lungu, C. (Codrin), Scholz, S. W. (Sonja W.), Gan-Or, Z. (Ziv), Rouleau, G. A. (Guy A.), Krohan, L. (Lynne), van Hilten, J. J. (Jacobus J.), Marinus, J. (Johan), Adarmes-Gomez, A. D. (Astrid D.), Bernal-Bernal, I. (Inmaculada), Bonilla-Toribio, M. (Marta), Buiza-Rueda, D. (Dolores), Carrillo, F. (Fatima), Carrion-Claro, M. (Mario), Mir, P. (Pablo), Gomez-Garre, P. (Pilar), Jesus, S. (Silvia), Labrador-Espinosa, M. A. (Miguel A.), Macias, D. (Daniel), Vargas-Gonzalez, L. (Laura), Mendez-del-Barrio, C. (Carlota), Perinan-Tocino, T. (Teresa), Tejera-Parrado, C. (Cristina), Diez-Fairen, M. (Monica), Aguilar, M. (Miquel), Alvarez, I. (Ignacio), Teresa Boungiorno, M. (Mara), Carcel, M. (Maria), Pastor, P. (Pau), Pablo Tartari, J. (Juan), Alvarez, V. (Victoria), Menendez Gonzalez, M. (Manuel), Blazquez, M. (Marta), Garcia, C. (Ciara), Suarez-Sanmartin, E. (Esther), Javier Barrero, F. (Francisco), Mondragon Rezola, E. (Elisabet), Bergareche Yarza, J. A. (Jesus Alberto), Gorostidi Pagola, A. (Ana), de Munain Arregui, A. L. (Adolfo Lopez), Ruiz-Martinez, J. (Javier), Cerdan, D. (Debora), Duarte, J. (Jacinto), Clarimon, J. (Jordi), Dols-Icardo, O. (Oriol), Infante, J. (Jon), Marin, J. (Juan), Kulisevsky, J. (Jaime), Pagonabarraga, J. (Javier), Gonzalez-Aramburu, I. (Isabel), Sanchez Rodriguez, A. (Antonio), Sierra, M. (Mara), Duran, R. (Raquel), Ruz, C. (Clara), Vives, F. (Francisco), Escamilla-Sevilla, F. (Francisco), Minguez, A. (Adolfo), Camara, A. (Ana), Compta, Y. (Yaroslau), Ezquerra, M. (Mario), Jose Marti, M. (Maria), Fernandez, M. (Manel), Munoz, E. (Esteban), Fernandez-Santiago, R. (Ruben), Tolosa, E. (Eduard), Valldeoriola, F. (Francesc), Garcia-Ruiz, P. (Pedro), Gomez Heredia, M. J. (Maria Jose), Perez Errazquin, F. (Francisco), Hoenicka, J. (Janet), Jimenez-Escrig, A. (Adriano), Carlos Martinez-Castrillo, J. (Juan), Luis Lopez-Sendon, J. (Jose), Martinez Torres, I. (Irene), Tabernero, C. (Cesar), Vela, L. (Lydia), Zimprich, A. (Alexander), Pihlstrom, L. (Lasse), Koks, S. (Sulev), Taba, P. (Pille), Majamaa, K. (Kari), Siitonen, A. (Ari), Okubadejo, N. U. (Njideka U.), Ojo, O. O. (Oluwadamilola O.), Pitcher, T. (Toni), Anderson, T. (Tim), Bentley, S. (Steven), Fowdar, J. (Javed), Mellick, G. (George), Dalrymple-Alford, J. (John), Henders, A. K. (Anjali K.), Kassam, I. (Irfahan), Montgomery, G. (Grant), Sidorenko, J. (Julia), Zhang, F. (Futao), Xue, A. (Angli), Vallerga, C. L. (Costanza L.), Wallace, L. (Leanne), Wray, N. R. (Naomi R.), Yang, J. (Jian), Visscher, P. M. (Peter M.), Gratten, J. (Jacob), Silburn, P. A. (Peter A.), Halliday, G. (Glenda), Hickie, I. (Ian), Kwok, J. (John), Lewis, S. (Simon), Kennedy, M. (Martin), Pearson, J. (John), Reynolds, R. H. (Regina H.), Botia, J. (Juan), Nalls, M. A. (Mike A.), Hardy, J. (John), Taliun, S. A. (Sarah A. Gagliano), Ryten, M. (Mina), Noyce, A. J. (Alastair J.), Nicolas, A. (Aude), Cookson, M. R. (Mark R.), Bandres-Ciga, S. (Sara), Gibbs, J. R. (J. Raphael), Hernandez, D. G. (Dena G.), Singleton, A. B. (Andrew B.), Reed, X. (Xylena), Leonard, H. (Hampton), Blauwendraat, C. (Cornelis), Faghri, F. (Faraz), Bras, J. (Jose), Guerreiro, R. (Rita), Tucci, A. (Arianna), Kia, D. A. (Demis A.), Houlden, H. (Henry), Plun-Favreau, H. (Helene), Mok, K. Y. (Kin Y.), Wood, N. W. (Nicholas W.), Lovering, R. (Ruth), R'Bibo, L. (Lea), Rizig, M. (Mie), Chelban, V. (Viorica), Trabzuni, D. (Daniah), Tan, M. (Manuela), Morris, H. R. (Huw R.), Middlehurst, B. (Ben), Quinn, J. (John), Billingsley, K. (Kimberley), Holmans, P. (Peter), Kinghorn, K. J. (Kerri J.), Lewis, P. (Patrick), Escott-Price, V. (Valentina), Williams, N. (Nigel), Foltynie, T. (Thomas), Brice, A. (Alexis), Danjou, F. (Fabrice), Lesage, S. (Suzanne), Corvol, J.-C. (Jean-Christophe), Martinez, M. (Maria), Giri, A. (Anamika), Schulte, C. (Claudia), Brockmann, K. (Kathrin), Simon-Sanchez, J. (Javier), Heutink, P. (Peter), Gasser, T. (Thomas), Rizzu, P. (Patrizia), Sharma, M. (Manu), Shulman, J. M. (Joshua M.), Robak, L. (Laurie), Lubbe, S. (Steven), Mencacci, N. E. (Niccolo E.), Finkbeiner, S. (Steven), Lungu, C. (Codrin), Scholz, S. W. (Sonja W.), Gan-Or, Z. (Ziv), Rouleau, G. A. (Guy A.), Krohan, L. (Lynne), van Hilten, J. J. (Jacobus J.), Marinus, J. (Johan), Adarmes-Gomez, A. D. (Astrid D.), Bernal-Bernal, I. (Inmaculada), Bonilla-Toribio, M. (Marta), Buiza-Rueda, D. (Dolores), Carrillo, F. (Fatima), Carrion-Claro, M. (Mario), Mir, P. (Pablo), Gomez-Garre, P. (Pilar), Jesus, S. (Silvia), Labrador-Espinosa, M. A. (Miguel A.), Macias, D. (Daniel), Vargas-Gonzalez, L. (Laura), Mendez-del-Barrio, C. (Carlota), Perinan-Tocino, T. (Teresa), Tejera-Parrado, C. (Cristina), Diez-Fairen, M. (Monica), Aguilar, M. (Miquel), Alvarez, I. (Ignacio), Teresa Boungiorno, M. (Mara), Carcel, M. (Maria), Pastor, P. (Pau), Pablo Tartari, J. (Juan), Alvarez, V. (Victoria), Menendez Gonzalez, M. (Manuel), Blazquez, M. (Marta), Garcia, C. (Ciara), Suarez-Sanmartin, E. (Esther), Javier Barrero, F. (Francisco), Mondragon Rezola, E. (Elisabet), Bergareche Yarza, J. A. (Jesus Alberto), Gorostidi Pagola, A. (Ana), de Munain Arregui, A. L. (Adolfo Lopez), Ruiz-Martinez, J. (Javier), Cerdan, D. (Debora), Duarte, J. (Jacinto), Clarimon, J. (Jordi), Dols-Icardo, O. (Oriol), Infante, J. (Jon), Marin, J. (Juan), Kulisevsky, J. (Jaime), Pagonabarraga, J. (Javier), Gonzalez-Aramburu, I. (Isabel), Sanchez Rodriguez, A. (Antonio), Sierra, M. (Mara), Duran, R. (Raquel), Ruz, C. (Clara), Vives, F. (Francisco), Escamilla-Sevilla, F. (Francisco), Minguez, A. (Adolfo), Camara, A. (Ana), Compta, Y. (Yaroslau), Ezquerra, M. (Mario), Jose Marti, M. (Maria), Fernandez, M. (Manel), Munoz, E. (Esteban), Fernandez-Santiago, R. (Ruben), Tolosa, E. (Eduard), Valldeoriola, F. (Francesc), Garcia-Ruiz, P. (Pedro), Gomez Heredia, M. J. (Maria Jose), Perez Errazquin, F. (Francisco), Hoenicka, J. (Janet), Jimenez-Escrig, A. (Adriano), Carlos Martinez-Castrillo, J. (Juan), Luis Lopez-Sendon, J. (Jose), Martinez Torres, I. (Irene), Tabernero, C. (Cesar), Vela, L. (Lydia), Zimprich, A. (Alexander), Pihlstrom, L. (Lasse), Koks, S. (Sulev), Taba, P. (Pille), Majamaa, K. (Kari), Siitonen, A. (Ari), Okubadejo, N. U. (Njideka U.), Ojo, O. O. (Oluwadamilola O.), Pitcher, T. (Toni), Anderson, T. (Tim), Bentley, S. (Steven), Fowdar, J. (Javed), Mellick, G. (George), Dalrymple-Alford, J. (John), Henders, A. K. (Anjali K.), Kassam, I. (Irfahan), Montgomery, G. (Grant), Sidorenko, J. (Julia), Zhang, F. (Futao), Xue, A. (Angli), Vallerga, C. L. (Costanza L.), Wallace, L. (Leanne), Wray, N. R. (Naomi R.), Yang, J. (Jian), Visscher, P. M. (Peter M.), Gratten, J. (Jacob), Silburn, P. A. (Peter A.), Halliday, G. (Glenda), Hickie, I. (Ian), Kwok, J. (John), Lewis, S. (Simon), Kennedy, M. (Martin), and Pearson, J. (John)

Abstract

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

Published
2019

6. Stable GDP-tubulin islands rescue dynamic microtubules.

Author

Bagdadi N, Wu J, Delaroche J, Serre L, Delphin C, De Andrade M, Carcel M, Nawabi H, Pinson B, Vérin C, Couté Y, Gory-Fauré S, Andrieux A, Stoppin-Mellet V, and Arnal I

Subjects
Animals, Guanosine Triphosphate metabolism, Humans, Microtubules metabolism, Tubulin metabolism, Tubulin genetics, Guanosine Diphosphate metabolism
Abstract

Microtubules are dynamic polymers that interconvert between phases of growth and shrinkage, yet they provide structural stability to cells. Growth involves hydrolysis of GTP-tubulin to GDP-tubulin, which releases energy that is stored within the microtubule lattice and destabilizes it; a GTP cap at microtubule ends is thought to prevent GDP subunits from rapidly dissociating and causing catastrophe. Here, using in vitro reconstitution assays, we show that GDP-tubulin, usually considered inactive, can itself assemble into microtubules, preferentially at the minus end, and promote persistent growth. GDP-tubulin-assembled microtubules are highly stable, displaying no detectable spontaneous shrinkage. Strikingly, islands of GDP-tubulin within dynamic microtubules stop shrinkage events and promote rescues. Microtubules thus possess an intrinsic capacity for stability, independent of accessory proteins. This finding provides novel mechanisms to explain microtubule dynamics., (© 2024 Bagdadi et al.)

Published
2024
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7. ABO Blood Groups and Incidence of COVID-19 in the Mass Gathering Events in Borriana (Spain), March 2020: A Retrospective Cohort Study.

Author

Domènech-Montoliu S, Puig-Barberà J, Guerra-Murcia O, Pac-Sa MR, Orrico-Sanchéz A, Gómez-Lanas L, Sala-Trull D, Domènech-Leon C, Del Rio-González A, Sánchez-Urbano M, Satorres-Martinez P, Latorre-Poveda M, Ferrando-Rubert S, Aparisi-Esteve L, Badenes-Marques G, Blasco-Gari R, Casanova-Suarez J, Fontal-Carcel M, Gil-Fortuño M, Hernández-Pérez N, Jovani-Sales D, López-Diago L, Notari-Rodríguez C, Pérez-Olaso O, Romeu-Garcia MA, Ruíz-Puig R, and Arnedo-Pena A

Abstract

Our objective was to estimate the incidence of COVID-19 and the ABO blood Groups in the mass-gathering events (MGEs) during the Falles Festival in Borriana (Spain) from 6-10 March 2020. We conducted a population-based retrospective cohort study and measured anti-SARS-CoV-2 antibodies and the ABO of participants. We performed laboratory COVID-19 tests and obtained the ABO in 775 subjects (72.8% of the original exposed cohort): O-group (45.2%), A-group (43.1%), B-group (8.5%) and AB-group (3.4%). Adjusted for confounding factors, including COVID-19 exposure during the MGEs, attack rates of COVID-19 for each ABO group were 55.4%, 59.6%, 60.2%, and 63.7%. The adjusted relative risks were for O-group 0.93 (95% Confidence Interval [CI] 0.83-1.04), for A-group 1.06 (95% CI 0.94-1.18), for B-group 1.04 (95%CI 0.88-1.24), and for AB-group 1.11 (95% CI 0.81-1.51) with no significant differences. Conclusions: Our results suggest no effect of ABO on COVID-19 incidence. We observed weak but not significant protection of the O-group and not a significantly greater infection risk for the remaining groups compared with the O-group. More studies are needed to resolve the controversies regarding the association between ABO and COVID-19.

Published
2023
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8. Complications Post-COVID-19 and Risk Factors among Patients after Six Months of a SARS-CoV-2 Infection: A Population-Based Prospective Cohort Study.

Author

Domènech-Montoliu S, Puig-Barberà J, Pac-Sa MR, Vidal-Utrillas P, Latorre-Poveda M, Del Rio-González A, Ferrando-Rubert S, Ferrer-Abad G, Sánchez-Urbano M, Aparisi-Esteve L, Badenes-Marques G, Cervera-Ferrer B, Clerig-Arnau U, Dols-Bernad C, Fontal-Carcel M, Gomez-Lanas L, Jovani-Sales D, León-Domingo MC, Llopico-Vilanova MD, Moros-Blasco M, Notari-Rodríguez C, Ruíz-Puig R, Valls-López S, and Arnedo-Pena A

Abstract

In October 2020, we conducted a population-based prospective cohort study to determine post-COVID-19 complications, recovery, return to usual health, and associated risk factors in 536 cases of COVID-19 outbreak in Borriana (Spain) by administering an epidemiological questionnaire via phone interviews. A total of 484 patients participated (90.3%), age mean 37.2 ± 17.1 years, and 301 females (62.2%). Mild illness was the most common COVID-19 manifestation. After six months, 160 patients (33.1%) suffered at least one complication post-COVID-19, and 47 (29.4%) of them sought medical assistance. The most frequent persistent symptoms were hair loss, fatigue, loss of smell or taste, and headache. Risk factors associated with a complication were female sex (adjusted relative risk, [aRR] = 1.93 95% confidence interval [CI] 1.41-2.65), age 35 years and above (aRR = 1.50 95% CI 1.14-1.99), B blood group (aRR = 1.51 95% CI 1.04-2.16), current smoker (RR = 1.61 95% CI 1.02-2.54), and at least a COVID-19 exposure (aRR = 2.13 95% CI 1.11-4.09). Male sex, age younger than 35 years, and low COVID-19 exposures were associated with better recovery and return to usual health. A third of patients presented persistent symptoms compatible with the long-COVID-19 syndrome. In conclusion, an active medical follow-up of post-COVID-19 patients must be implemented.

Published
2022
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9. ABO Blood Groups and the Incidence of Complications in COVID-19 Patients: A Population-Based Prospective Cohort Study.

Author

Domènech-Montoliu S, Puig-Barberà J, Pac-Sa MR, Vidal-Utrillas P, Latorre-Poveda M, Rio-González AD, Ferrando-Rubert S, Ferrer-Abad G, Sánchez-Urbano M, Aparisi-Esteve L, Badenes-Marques G, Cervera-Ferrer B, Clerig-Arnau U, Dols-Bernad C, Fontal-Carcel M, Gomez-Lanas L, Jovani-Sales D, León-Domingo MC, Llopico-Vilanova MD, Moros-Blasco M, Notari-Rodríguez C, Ruíz-Puig R, Valls-López S, and Arnedo-Pena A

Subjects
Adult, Cohort Studies, Female, Humans, Incidence, Middle Aged, Prospective Studies, SARS-CoV-2, Young Adult, ABO Blood-Group System, COVID-19
Abstract

After a COVID-19 outbreak in the Falles festival of Borriana (Spain) during March 2020, a cohort of patients were followed until October 2020 to estimate complications post-COVID-19, considering ABO blood groups (ABO). From 536 laboratory-confirmed cases, 483 completed the study (90.1%) carried by the Public Health Center of Castelló and the Emergency and Microbiology and Clinical Analysis of Hospital de la Plana Vila-real. The study included ABO determination and telephone interviews of patients. The participants had a mean age of 37.2 ± 17.1 years, 300 females (62.1%). ABO were O (41.4%), A (45.5%), B (9.1%), and AB (3.9%). We found no difference in the incidence of COVID-19 infections. A total of 159 (32.9%) patients reported one or more post-COVID-19 complications with divergent incidences after adjustment: O (32.3%), A (32.6%), B (54.1%), and AB (27.6%); B groups had more complications post-COVID-19 when compared with O group (adjusted relative risk [aRR] 95% confidence interval [CI] 1.68, 95% CI 1.24-2.27), and symptoms of fatigue (1.79, 95% CI 1.08-2.95), myalgia (2.06, 95% CI 1.10-3.84), headache (2.61, 95% CI 1.58-4.31), and disorder of vision (4.26 95% CI 1.33-13.60). In conclusion, we observed significant differences in post-COVID-19 complications by ABO, with a higher incidence in B group. Additional research is justified to confirm our results.

Published
2021
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10. "Mass gathering events and COVID-19 transmission in Borriana (Spain): A retrospective cohort study".

Author

Domènech-Montoliu S, Pac-Sa MR, Vidal-Utrillas P, Latorre-Poveda M, Del Rio-González A, Ferrando-Rubert S, Ferrer-Abad G, Sánchez-Urbano M, Aparisi-Esteve L, Badenes-Marques G, Cervera-Ferrer B, Clerig-Arnau U, Dols-Bernad C, Fontal-Carcel M, Gomez-Lanas L, Jovani-Sales D, León-Domingo MC, Llopico-Vilanova MD, Moros-Blasco M, Notari-Rodríguez C, Ruíz-Puig R, Valls-López S, and Arnedo-Pena A

Subjects
Adolescent, Adult, Aged, COVID-19 diagnosis, COVID-19 transmission, COVID-19 virology, COVID-19 Testing, Child, Child, Preschool, Female, Holidays, Humans, Infant, Male, Middle Aged, Retrospective Studies, Risk Factors, SARS-CoV-2 isolation & purification, Spain epidemiology, Surveys and Questionnaires, Young Adult, COVID-19 epidemiology
Abstract

Objective: Mass gathering events (MGEs) are associated with the transmission of COVID-19. Between 6 and 10 March 2020, several MGEs related to the Falles festival took place in Borriana, a municipality in the province of Castellon (Spain). The aim of this study was to estimate the incidence of COVID-19 and its association with these MGEs, and to quantify the potential risk factors of its occurrence., Methods: During May and June 2020, a population-based retrospective cohort study was carried out by the Public Health Center of Castelló and the Hospital de la Plana in Vila-real. Participants were obtained from a representative sample of 1663 people with potential exposure at six MGEs. A questionnaire survey was carried out to obtain information about attendance at MGEs and COVID-19 disease. In addition, a serologic survey of antibodies against SARS-Cov-2 was implemented. Inverse probability weighted regression was used in the statistical analysis., Results: A total of 1338 subjects participated in the questionnaire survey (80.5%), 997 of whom undertook the serologic survey. Five hundred and seventy cases were observed with an attack rate (AR) of 42.6%; average age was 36 years, 62.3% were female, 536 cases were confirmed by laboratory tests, and 514 cases were found with SARS-CoV-2 total antibodies. Considering MGE exposure, AR was 39.2% (496/1264). A dose-response relationship was found between MGE attendance and the disease, (adjusted relative risk [aRR] = 4.11 95% confidence interval [CI]3.25-5.19). Two MGEs with a dinner and dance in the same building had higher risks. Associated risk factors with the incidence were older age, obesity, and upper and middle class versus lower class; current smoking was protective., Conclusions: The study suggests the significance of MGEs in the COVID-19 transmission that could explain the subsequent outbreak in Borriana., Competing Interests: The authors have declared that no competing interest exist.

Published
2021
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11. Added value of cerebrospinal fluid multimarker analysis in diagnosis and progression of dementia.

Author

Álvarez I, Diez-Fairen M, Aguilar M, González JM, Ysamat M, Tartari JP, Carcel M, Alonso A, Brix B, Arendt P, and Pastor P

Subjects
Amyloid beta-Peptides, Biomarkers, Humans, Peptide Fragments, Positron-Emission Tomography, tau Proteins, Alzheimer Disease diagnostic imaging, Cognitive Dysfunction diagnostic imaging, Frontotemporal Dementia diagnostic imaging
Abstract

Background and Purpose: Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as diagnostic tools for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain amyloid positron emission tomography (PET). We also investigated whether they help in differentiating AD from other dementias and examined their influence in tracing the progression to dementia., Methods: Amyloid-β (Aβ) 1-42, total tau (t-tau), phosphorylated tau, Aβ 40 , Aβ 38 , beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), neurogranin (ng), phosphorylated neurofilament heavy-chain, and α-synuclein (α-syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an amyloid PET scan. We also analyzed longitudinal clinical data from 239 subjects., Results: Emerging CSF markers, especially ng/BACE-1 ratio (area under the curve = 0.77) and their combinations with core AD CSF markers (all AUCs >0.85), showed high accuracy to discriminate amyloid PET positivity. Subjects with AD had higher CSF BACE-1, ng, and α-syn levels than those with non-AD dementia. CSF t-tau/α-syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core AD ratios predicted a faster conversion from mild cognitive impairment (MCI) stage to AD and appeared to be helpful when core AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core AD markers, several emerging/core AD two-marker ratios, and CSF ng levels., Conclusions: These results suggest that emerging biomarkers in conjunction with core AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD, and predict a faster progression of dementia., (© 2020 European Academy of Neurology.)

Published
2021
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12. Exome-wide rare variant analysis in familial essential tremor.

Author

Diez-Fairen M, Houle G, Ortega-Cubero S, Bandres-Ciga S, Alvarez I, Carcel M, Ibañez L, Fernandez MV, Budde JP, Trotta JR, Tonda R, Chong JX, Bamshad MJ, Nickerson DA, Aguilar M, Tartari JP, Gironell A, García-Martín E, Agundez JA, Alonso-Navarro H, Jimenez-Jimenez FJ, Fernandez M, Valldeoriola F, Marti MJ, Tolosa E, Coria F, Pastor MA, Vilariño-Güell C, Rajput A, Dion PA, Cruchaga C, Rouleau GA, and Pastor P

Subjects
Adult, Age of Onset, Aged, Aged, 80 and over, Female, Humans, Male, Matrix Metalloproteinase 10 genetics, Middle Aged, Pedigree, Exome Sequencing, Young Adult, Essential Tremor genetics, Genetic Predisposition to Disease
Abstract

Introduction: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing., Methods: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes., Results: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders., Conclusions: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2021
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13. Pooled-DNA target sequencing of Parkinson genes reveals novel phenotypic associations in Spanish population.

Author

Diez-Fairen M, Benitez BA, Ortega-Cubero S, Lorenzo-Betancor O, Cruchaga C, Lorenzo E, Samaranch L, Carcel M, Obeso JA, Rodriguez-Oroz MC, Aguilar M, Coria F, Pastor MA, and Pastor P

Subjects
Adult, Aged, Aged, 80 and over, Female, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics, Male, Middle Aged, Mutation, Phenotype, Protein Kinases genetics, Sequence Analysis, DNA, Spain, Ubiquitin-Protein Ligases genetics, White People genetics, Young Adult, Genetic Predisposition to Disease, Parkinson Disease genetics
Abstract

Eighteen loci and several susceptibility genes have been related to Parkinson's disease (PD). However, most studies focus on single genes in small PD series. Our aim was to establish the genetic background of a large Spanish PD sample. Pooled-DNA target sequencing of 7 major PD genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, GBA, and MAPT) was performed in 562 PD cases. Forty-four variants were found among 114 individuals (20.28%, p<0.05). Among these variants, 30 were found in Mendelian genes (68.18%) and 14 in PD susceptibility genes (31.82%). Seven novel variants were identified. Interestingly, most variants were found in PARK2 and PINK1 genes, whereas SNCA and DJ-1 variants were rare. Validated variants were also genotyped in Spanish healthy controls (n = 597). Carriers of heterozygous PARK2 variants presented earlier disease onset and showed dementia more frequently. PD subjects carrying 2 variants at different genes (1.42%) had an earlier age of onset and a predominantly akinetic-rigid PD phenotype (55.6%, p < 0.05), suggesting that the accumulation of genetic risk variants could modify PD phenotype., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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14. Target-enriched sequencing of chromosome 17q21.31 in sporadic tauopathies reveals no candidate variants.

Author

Razquin C, Ortega-Cubero S, Rojo-Bustamante E, Diez-Fairen M, Lorenzo E, Alonso E, Ezquerra M, Ross OA, Carcel M, Lorenzo-Betancor O, Soto AI, Burgess JD, Ertekin-Taner N, Dickson DW, Pastor MA, Tolosa E, and Pastor P

Subjects
Basal Ganglia, Cerebral Cortex, Haplotypes, Heterozygote, Humans, Neurodegenerative Diseases genetics, Receptors, Corticotropin-Releasing Hormone genetics, Receptors, Corticotropin-Releasing Hormone metabolism, Risk, Supranuclear Palsy, Progressive genetics, tau Proteins genetics, tau Proteins metabolism, Chromosomes, Human, Pair 17 genetics, Genetic Association Studies, Genetic Variation genetics, Tauopathies genetics
Abstract

The main genetic risk factors for progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are located at chromosome 17q21.31. The identification of risk H1 subhaplotypes suggests that disease-specific variants can be identified by resequencing the 17q21.31 region (1.4 Mb) in carriers of risk H1 subhaplotypes. We hypothesized that PSP/CBD H1 subhaplotype carriers could have undergone a mutational event absent among unaffected carriers leading to the disease risk. We performed this strategy in definite PSP subjects, definite CBD subjects, and healthy controls and tried to replicate the findings in a larger PSP/CBD case-control series. In the resequencing process, 40 candidate variants were identified, but an association between PSP and rs76970862 was replicated only using an unadjusted model. Gene expression association analysis of this variant suggested no potential functional effect. Although our results failed to identify disease-associated variants, it is still possible that the risk of PSP/CBD at chromosome 17 is driven by rare variants, even in PSP/CBD H1 cases or variants located outside the capture regions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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15. Clinic-Based Validation of Cerebrospinal Fluid Biomarkers with Florbetapir PET for Diagnosis of Dementia.

Author

Álvarez I, Aguilar M, González JM, Ysamat M, Lorenzo-Bosquet C, Alonso A, Tartari JP, Romero S, Diez-Fairen M, Carcel M, Pujalte F, and Pastor P

Subjects
Aged, Amyloid beta-Peptides cerebrospinal fluid, Analysis of Variance, Apolipoproteins E genetics, Cognition Disorders etiology, Dementia complications, Dementia genetics, Female, Humans, Male, Middle Aged, Peptide Fragments cerebrospinal fluid, Positron-Emission Tomography, tau Proteins cerebrospinal fluid, Aniline Compounds metabolism, Biomarkers cerebrospinal fluid, Dementia cerebrospinal fluid, Dementia diagnostic imaging, Ethylene Glycols metabolism
Abstract

Background: Cerebrospinal fluid (CSF) biomarker studies have shown variable accuracy for diagnosis of Alzheimer's disease (AD); therefore, internal validation is recommended., Objective: To investigate the correlation between CSF biomarkers and cerebral 18-Florbetapir positron emission tomography (Amyloid-PET) and calculate their sensitivity and specificity to obtain the optimal clinical cut-off points to diagnose the etiology of cognitive impairment., Methods: We performed Amyloid-PET scans and CSF biomarker levels analyses in 68 subjects (50 with mild cognitive impairment, 11 with AD dementia, and 7 with non-AD dementia). Visual examination of Amyloid-PET scans was performed. CSF analyses were performed using standard sandwich ELISA., Results: Amyloid-PET was positive in 36 subjects, negative in 26, and inconclusive in 6. Optimal clinical cut-off points for CSF markers were the following: amyloid-β 1-42 (Aβ42) = 629 pg/ml, total tau (t-tau) = 532 pg/ml, phosphorylated tau (p-tau) = 88 pg/ml, and t-tau/Aβ42 ratio = 0.58. T-tau/Aβ42 ratio showed the best sensitivity and specificity (92 and 84%, respectively). T-tau and p-tau CSF levels (r2 = 0.867) followed by the t-tau and t-tau/Aβ42 CSF ratio (r2 = 0.666) showed the strongest inter-marker correlation. Interestingly, subjects with inconclusive Amyloid-PET showed intermediate values for all CSF markers between negative and positive Amyloid-PET groups., Conclusions: CSF t-tau/Aβ42 ratio appears to be the most accurate AD CSF marker. The presence of intermediate values for CSF markers among the subjects with inconclusive Amyloid-PET suggests the presence of other dementias associated with AD pathology or intermediate phenotypes.

Published
2018
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