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1. Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Author

Storm, Catherine S., Kia, Demis A., Almramhi, Mona M., Bandres-Ciga, Sara, Finan, Chris, Noyce, A. J., Kaiyrzhanov, R., Middlehurst, B., Tan, M., Houlden, H., Morris, H. R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Quinn, J., Bubb, V., Mok, K. Y., Kinghorn, K. J., Lewis, P., Schreglmann, S. R., Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K. E., Clarke, C., Harvey, K., Jacobs, B. M., Brice, Alexis, Danjou, F., Lesage, S., Corvol, J. C., Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Schneider, S. A., Cookson, M. R., Blauwendraat, C., Craig, D. W., Billingsley, K., Makarious, M. B., Narendra, D. P., Faghri, F., Gibbs, J. R., Hernandez, D. G., Van Keuren-Jensen, K., Shulman, J. M., Iwaki, H., Leonard, H. L., Nalls, M. A., Robak, L., Bras, J., Guerreiro, R., Lubbe, S., Troycoco, T., Finkbeiner, S., Mencacci, N. E., Lungu, C., Singleton, A. B., Scholz, S. W., Reed, X., Uitti, R. J., Ross, O. A., Grenn, F. P., Moore, A., Alcalay, R. N., Wszolek, Z. K., Gan-Or, Z., Rouleau, G. A., Krohn, L., Mufti, K., van Hilten, J. J., Marinus, J., Adarmes-Gómez, A. D., Aguilar Barberà, Miquel, Álvarez Angulo, Iñaki, Alvarez, V., Barrero, F. J., Yarza, J. A. B., Bernal-Bernal, I., Blázquez Estrada, M, Bonilla-Toribio, M., Botía, J. A., Boungiorno, M. T., Buiza-Rueda, Dolores, Cámara, A., Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, Jordi, Compta, Y., Diez-Fairen, M., Dols-Icardo, Oriol, Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernández, M., Fernández-Santiago, R., Garcia, C., García-Ruiz, P., Gómez-Garre, P., Heredia, M. J. G., Gonzalez-Aramburu, I., Pagola, A. G., Hoenicka, J., Infante, J., Jesús, S., Jimenez-Escrig, A., Kulisevsky, Jaime, Labrador-Espinosa, M. A., Lopez-Sendon, J. L., de Munain Arregui, A. L., Macias, D., Torres, I. M., Marín, J., Marti, M. J., Martínez-Castrillo, J. C., Méndez-del-Barrio, C., González, M. M., Mata, M., Mínguez, A., Mir, P., Rezola, E. M., Muñoz, E., Pagonabarraga, J., Pastor, P., Errazquin, F. P., Periñán-Tocino, T., Ruiz-Martínez, J., Ruz, C., Rodriguez, A. S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J. P., Tejera-Parrado, C., Tolosa, E., Valldeoriola, F., Vargas-González, L., Vela, Lydia, Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Taba, P., Koks, S., Hassin-Baer, S., Majamaa, K., Siitonen, A., Tienari, P., Okubadejo, N. U., Ojo, O. O., Shashkin, C., Zharkinbekova, N., Akhmetzhanov, V., Kaishybayeva, G., Karimova, A., Khaibullin, T., Lynch, T. L., Hingorani, Aroon, Wood, Nicholas W.., Universitat Autònoma de Barcelona, Rosetrees Trust, John Black Charitable Foundation, University College London, King Abdulaziz University, National Institute for Health Research (UK), Universidad de Cantabria, HUS Neurocenter, Department of Neurosciences, and Clinicum

Subjects
Aging, Science, Quantitative Trait Loci, General Physics and Astronomy, Neurodegenerative, 3124 Neurology and psychiatry, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, Risk Factors, Genetics research, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Multidisciplinary, Genome, Parkinson's Disease, Genome, Human, Prevention, 3112 Neurosciences, Neurosciences, Brain, Genetic Variation, Parkinson Disease, General Chemistry, Mendelian Randomization Analysis, International Parkinson’s Disease Genomics Consortium, Brain Disorders, Good Health and Well Being, Gene Expression Regulation, Neurology, 5.1 Pharmaceuticals, Case-Control Studies, Neurological, Disease Progression, Development of treatments and therapeutic interventions, Human, Biotechnology
Abstract

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development., There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

Published
2021

2. Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Author

Storm, C.S., Kia, D.A., Almramhi, M.M., Bandrés-Ciga, S., Finan, C., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Tan, M., Houlden, H., Morris, H.R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Quinn, J., Bubb, V., Mok, K.Y., Kinghorn, K.J., Lewis, P., Schreglmann, S.R., Lovering, R., R’Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K.E., Clarke, C., Harvey, K., Jacobs, B.M., Brice, A., Danjou, F., Lesage, S., Corvol, J-C, Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Schneider, S.A., Cookson, M.R., Blauwendraat, C., Craig, D.W., Billingsley, K., Makarious, M.B., Narendra, D.P., Faghri, F., Gibbs, J.R., Hernandez, D.G., Van Keuren-Jensen, K., Shulman, J.M., Iwaki, H., Leonard, H.L., Nalls, M.A., Robak, L., Bras, J., Guerreiro, R., Lubbe, S., Troycoco, T., Finkbeiner, S., Mencacci, N.E., Lungu, C., Singleton, A.B., Scholz, S.W., Reed, X., Uitti, R.J., Ross, O.A., Grenn, F.P., Moore, A., Alcalay, R.N., Wszolek, Z.K., Gan-Or, Z., Rouleau, G.A., Krohn, L., Mufti, K., van Hilten, J.J., Marinus, J., Adarmes-Gómez, A.D., Aguilar, M., Alvarez, I., Alvarez, V., Barrero, F.J., Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, M., Botía, J.A., Boungiorno, M.T., Buiza-Rueda, D., Cámara, A., Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, J., Compta, Y., Diez-Fairen, M., Dols-Icardo, O., Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernández, M., Fernández-Santiago, R., Garcia, C., García-Ruiz, P., Gómez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesús, S., Jimenez-Escrig, A., Kulisevsky, J., Labrador-Espinosa, M.A., Lopez-Sendon, J.L., de Munain Arregui, A.L., Macias, D., Torres, I.M., Marín, J., Marti, M.J., Martínez-Castrillo, J.C., Méndez-del-Barrio, C., González, M.M., Mata, M., Mínguez, A., Mir, P., Rezola, E.M., Muñoz, E., Pagonabarraga, J., Pastor, P., Errazquin, F.P., Periñán-Tocino, T., Ruiz-Martínez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J.P., Tejera-Parrado, C., Tolosa, E., Valldeoriola, F., Vargas-González, L., Vela, L., Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Taba, P., Kõks, S., Hassin-Baer, S., Majamaa, K., Siitonen, A., Tienari, P., Okubadejo, N.U., Ojo, O.O., Shashkin, C., Zharkinbekova, N., Akhmetzhanov, V., Kaishybayeva, G., Karimova, A., Khaibullin, T., Lynch, T.L., Hingorani, A.D., Wood, N.W., Storm, C.S., Kia, D.A., Almramhi, M.M., Bandrés-Ciga, S., Finan, C., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Tan, M., Houlden, H., Morris, H.R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Quinn, J., Bubb, V., Mok, K.Y., Kinghorn, K.J., Lewis, P., Schreglmann, S.R., Lovering, R., R’Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K.E., Clarke, C., Harvey, K., Jacobs, B.M., Brice, A., Danjou, F., Lesage, S., Corvol, J-C, Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Schneider, S.A., Cookson, M.R., Blauwendraat, C., Craig, D.W., Billingsley, K., Makarious, M.B., Narendra, D.P., Faghri, F., Gibbs, J.R., Hernandez, D.G., Van Keuren-Jensen, K., Shulman, J.M., Iwaki, H., Leonard, H.L., Nalls, M.A., Robak, L., Bras, J., Guerreiro, R., Lubbe, S., Troycoco, T., Finkbeiner, S., Mencacci, N.E., Lungu, C., Singleton, A.B., Scholz, S.W., Reed, X., Uitti, R.J., Ross, O.A., Grenn, F.P., Moore, A., Alcalay, R.N., Wszolek, Z.K., Gan-Or, Z., Rouleau, G.A., Krohn, L., Mufti, K., van Hilten, J.J., Marinus, J., Adarmes-Gómez, A.D., Aguilar, M., Alvarez, I., Alvarez, V., Barrero, F.J., Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, M., Botía, J.A., Boungiorno, M.T., Buiza-Rueda, D., Cámara, A., Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, J., Compta, Y., Diez-Fairen, M., Dols-Icardo, O., Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernández, M., Fernández-Santiago, R., Garcia, C., García-Ruiz, P., Gómez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesús, S., Jimenez-Escrig, A., Kulisevsky, J., Labrador-Espinosa, M.A., Lopez-Sendon, J.L., de Munain Arregui, A.L., Macias, D., Torres, I.M., Marín, J., Marti, M.J., Martínez-Castrillo, J.C., Méndez-del-Barrio, C., González, M.M., Mata, M., Mínguez, A., Mir, P., Rezola, E.M., Muñoz, E., Pagonabarraga, J., Pastor, P., Errazquin, F.P., Periñán-Tocino, T., Ruiz-Martínez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J.P., Tejera-Parrado, C., Tolosa, E., Valldeoriola, F., Vargas-González, L., Vela, L., Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Taba, P., Kõks, S., Hassin-Baer, S., Majamaa, K., Siitonen, A., Tienari, P., Okubadejo, N.U., Ojo, O.O., Shashkin, C., Zharkinbekova, N., Akhmetzhanov, V., Kaishybayeva, G., Karimova, A., Khaibullin, T., Lynch, T.L., Hingorani, A.D., and Wood, N.W.

Abstract

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.

Published
2021

3. 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

4. The ANKK1 Protein Associated with Addictions has Nuclear and Cytoplasmic Localization and Shows a Differential Response of Ala239Thr to Apomorphine.

Author

Garrido, E., Palomo, T., Ponce, G., García-Consuegra, I., Jiménez-Arriero, M., and Hoenicka, J.

Subjects
APOMORPHINE, PHARMACODYNAMICS, DRUG addiction, GENETIC polymorphisms, DOPAMINE receptors, LINKAGE disequilibrium, PHENOTYPES, ALANINE
Abstract

The TaqIA single-nucleotide polymorphism (SNP), which is the most widely studied genetic polymorphism in addictions, is located at the gene that encodes the RIP kinase ANKK1 near the gene for dopamine receptor D2. The TaqIA SNP is in strong linkage disequilibrium with the SNP rs7118900, which changes the alanine at position 239 to threonine in the ANKK1 protein (Ala239/A2; Thr239/A1). In silico analysis has predicted that this polymorphic substitution creates an additional phosphorylation site in the kinase domain of ANKK1. To investigate the contribution of ANKK1 to the pathophysiology of TaqIA-associated phenotypes, we analyzed transfected HEK293T cells with the human ANKK1-kinase and ANKK1-kinase variants tagged with GFP. We observed that the ANKK1-kinase is located in both the nucleus and the cytoplasm, suggesting that there is nucleocytoplasmic shuttling of this putative signal transducer. In addition, we found that the Ala239Thr ANKK1-kinase polymorphism exhibited strong expression differences in both the nucleus and the cytoplasm at basal level and when stimulated with the dopamine agonist apomorphine. Specifically, the ANKK1-kinase variant showed the highest level of basal protein expression, while ANKK1-kinase was 0.64-fold lower. After treatment with apomorphine, ANKK1-kinase showed a 2.4-fold increment in protein levels, whereas a 0.67-fold reduction was observed in ANKK1-kinase. Thus, here we provide the first evidence of functional ANKK1 differences that are marked by TaqIA and could be associated with vulnerability to addiction. [ABSTRACT FROM AUTHOR]

Published
2011
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5. Impulsivity and sustained attention in pathological gamblers: influence of childhood ADHD history.

Author

Rodriguez-Jimenez, R., Avila, C., Jimenez-Arriero, M. A., Ponce, G., Monasor, R., Jimenez, M., Aragües, M., Hoenicka, J., Rubio, G., Palomo, T., and Aragües, M

Subjects
GAMBLING, COMPULSIVE gambling, IMPULSIVE personality, ATTENTION-deficit hyperactivity disorder, FRONTAL lobe, PREFRONTAL cortex, HUMAN behavior, GAMBLING & psychology, ANALYSIS of variance, BEHAVIOR, COMPARATIVE studies, LOCUS of control, NEUROPSYCHOLOGICAL tests, RESEARCH methodology, MEDICAL cooperation, PERSONALITY assessment, PSYCHOLOGICAL tests, PSYCHOMETRICS, RESEARCH, SELF-evaluation, EVALUATION research
Abstract

Pathological gambling (PG) has been associated to both impulsiveness and attention deficit/hyperactivity disorder (ADHD) in different studies. Our objective was to compare different impulsivity and sustained attention variables, using both behavioural tasks and self-administered questionnaires, in a group of pathological gamblers with a history of childhood ADHD (PG-ADHD; n = 16), a group of pathological gamblers without this history (PG-non-ADHD; n = 39), and a control group (n = 40). As instruments of measure, we used the stop signal task (to evaluate inhibitory control/impulsivity), the differential reinforcement of Low Rate Responding Task (delay of gratification/impulsivity) and the Continuous Performance Test (sustained attention). The Barratt Impulsivity Scale (BIS-11) was used as a self-administered questionnaire to measure impulsiveness. Our results show that patients in the PG-ADHD group exhibit a significantly lower capacity to delay gratification than those in the PG-non-ADHD and control groups, and less inhibitory control than patients in the PG-non-ADHD group. On self-administered questionnaires such as the BIS-11 the PG-ADHD group obtained higher scores than the PG-non-ADHD and control groups. However, no differences were found with respect to sustained attention using the CPT. Our results suggest a possible selective implication of the prefrontal cortex in PG, which would be especially evident in those with a childhood history of ADHD. [ABSTRACT FROM AUTHOR]

Published
2006
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6. Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1).

Author

Barrero, F. J., Ampuero, I., Morales, B., Vives, F., De Dios Luna del Castillo, J., Hoenicka, J., and Garcí Yébenes, J.

Subjects
MENTAL depression, PARKINSON'S disease, GENETIC polymorphisms, POPULATION genetics, CANNABINOIDS, GENES
Abstract

Depression is a common symptom in Parkinson's disease (PD) and it is present in up to 40%of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher's exact test: P=0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.The Pharmacogenomics Journal (2005) 5, 135-141. doi:10.1038/sj.tpj.6500301 Published online 25 January 2005 [ABSTRACT FROM AUTHOR]

Published
2005
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7. DRD2 TaqIA polymorphism is associated with urinary homovanillic acid levels in a sample of spanish male alcoholic patients.

Author

Ponce, G., Hoenicka, J., Rodríguez-jiménez, R., Gozalo, A., Jimenéz, M., Monasor, R., Aragüés, M., Rubio, G., Jiménez-arriero, M., Ramos, J., and Palomo, T.

Abstract

The TaqIA1 allele of the dopamine receptor gene D ( DRD2) has been associated with alcoholism, as well as with other addictive behaviours. The exact nature of how the presence of this allele can be a vulnerability factor in the development of alcoholism remains unclear. In this study we found that the presence in the DRD2 genotype of the TaqIA1 allele in Spanish alcoholics is associated with higher levels of urine homovanillic acid (HVA) when compared to patients homozygous for the TaqIA2 allele. A sample of 142 Spanish male alcoholic patients was split into 2 groups on the basis of the presence or absence of the A1 allele in their genotype. The urine sample was analyzed by high performance liquid cromatography (HPLC), and the concentration of homovanillic acid (HVA), 5-hydroxyin-doleacetic acid (5-HIAA) and vanilylmandelic acid (VMA) was determined. We found a statistical difference in the concentration of HVA between the groups, that suggests this polymorphism could be related to the variance of urine HVA levels. [ABSTRACT FROM AUTHOR]

Published
2004
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8. An unusual late-onset case of propionic acidaemia: biochemical investigations, neuroradiological findings and mutation analysis.

Author

Pérez-Cerdá, C., Merinero, B., Martí, M., Cabrera, J. C., Peña, L., García, M. J., Gangoiti, J., Sanz, P., Rodríguez-Pombo, P., Hoenicka, J., Richard, E., Muro, S., and Ugarte, M.

Subjects
JUVENILE diseases, NEUROLOGICAL disorders
Abstract

Unlabelled: We report a 5-year-old boy with propionic acidaemia who developed a rapidly fatal necrosis of the basal ganglia after an episode of clinical deterioration. Neither metabolic acidosis nor hyperammonaemia were present. Organic acid analysis in both urine and CSF showed increased levels of methylcitric and 3-hydroxypropionic acids. Propionic acidaemia was confirmed by demonstrating a propionyl-CoA carboxylase deficiency (11% of control value) in skin fibroblasts. DNA analysis revealed that the patient was a compound heterozygote for two mutations in the PCCB gene.Conclusion: Propionic acidaemia can present as a sudden and fatal neurological disease and not only as an organic aciduria with severe biochemical dis-turbances and progressive neurological deterioration. [ABSTRACT FROM AUTHOR]

Published
1998

9. Association between cannabinoid receptor gene (CNR1) and childhood attention deficit/hyperactivity disorder in Spanish male alcoholic patients.

Author

Ponce, G, Hoenicka, J, Rubio, G, Ampuero, I, Jimenez-Arriero, M A, Rodriguez-Jimenez, R, Palomo, T, and Ramos, J A

Subjects
*CANNABINOIDS, *DOPAMINERGIC mechanisms, *PRESYNAPTIC receptors, *ATTENTION-deficit hyperactivity disorder, *GENETIC polymorphisms
Abstract

The endocannabinoid system is known to regulate the dopaminergic system through CB1 presynaptic receptors. The CB1 receptor is further encoded by CNR1 gene, which is known to carry a nine-allele microsatellite polymorphism. There is a quantitative relationship between largest-sized alleles of CNR1 gene and the presence of attention deficit- hyperactivity disorder (ADHD), during childhood in Spanish male alcoholic patients. In comparison with non-ADHD patients and control individuals, those alcoholic patients who suffered from ADHD during childhood were found to carry the longer forms of alleles. Therefore, the cannabinoid system is known to affect dopaminergic transmission and is regarded as a potential physiopathological cause of ADHD.

Published
2003
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