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

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

doi:10.1038/s41467-021-26280-1

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

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

Department of Medicine

Research output: Contribution to journal › Article › Research › peer-review

91 Citations (Scopus)

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.

Original language	English
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26280-1
Publication status	Published - 20 Dec 2021

Keywords

Brain
Case-Control Studies
Cohort Studies
Disease Progression
Gene Expression Regulation
Genetic Predisposition to Disease
Genetic Variation
Genome, Human
Humans
Mendelian Randomization Analysis
Parkinson Disease
Quantitative Trait Loci
Risk Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-021-26280-1

https://ddd.uab.cat/record/264453Licence: CC BY

Cite this

Kulisevsky, J., Storm, C. S., Kia, D. A., Almramhi, M. M., Bandres-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., ... Wood, N. W. (2021). Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-26280-1

@article{426a8b4f45a14552a80200b4bd33edfc,

title = "Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome",

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.",

keywords = "Brain, Case-Control Studies, Cohort Studies, Disease Progression, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Mendelian Randomization Analysis, Parkinson Disease, Quantitative Trait Loci, Risk Factors",

author = "Jaime Kulisevsky and Storm, {Catherine S.} and Kia, {Demis A.} and Almramhi, {Mona M.} and Sara Bandres-Ciga and Chris Finan and Noyce, {A. J.} and R. Kaiyrzhanov and B. Middlehurst and M. Tan and Henry Houlden and Morris, {H. R.} and H. Plun-Favreau and Peter Holmans and J. Hardy and D. Trabzuni and J. Quinn and Vivien Bubb and Mok, {K. Y.} and Kinghorn, {K. J.} and P. Lewis and Schreglmann, {S. R.} and R. Lovering and L. R'Bibo and C. Manzoni and M. Rizig and Mina Ryten and S. Guelfi and Valentina Escott-Price and Viorica Chelban and T. Foltynie and N. Williams and Morrison, {K. E.} and C. Clarke and K. Harvey and Jacobs, {B. M.} and Alexis Brice and F. Danjou and S. Lesage and Jean-Christophe Corvol and M. Martinez and C. Schulte and K. Brockmann and J. Sim{\'o}n-S{\'a}nchez and Peter Heutink and P. Rizzu and M. Sharma and T. Gasser and Schneider, {S. A.} and Cookson, {M. R.} and Cornelis Blauwendraat and Craig, {David W} and K. Billingsley and Makarious, {M. B.} and Narendra, {D. P.} and F. Faghri and Gibbs, {J. R.} and Hernandez, {D. G.} and {Van Keuren-Jensen}, K. and Shulman, {J. M.} and H. Iwaki and Leonard, {H. L.} and Nalls, {M. A.} and L. Robak and J. Bras and Rita Guerreiro and S. Lubbe and T. Troycoco and S. Finkbeiner and Mencacci, {N. E.} and C. Lungu and Singleton, {A. B.} and Scholz, {S. W.} and X. Reed and Uitti, {R. J.} and Ross, {O. A.} and Grenn, {F. P.} and A. Moore and Alcalay, {Roy N} and Wszolek, {Z. K.} and Z. Gan-Or and Rouleau, {G. A.} and L. Krohn and K. Mufti and {van Hilten}, {J. J.} and J. Marinus and A.D Adarmes-G{\'o}mez and {Aguilar Barber{\`a}}, Miquel and Ignacio Alvarez and V. Alvarez and Barrero, {F. J.} and Yarza, {J. A. B.} and I. Bernal-Bernal and {Bl{\'a}zquez Estrada}, Marta and Marta Bonilla-Toribio and Bot{\'i}a, {J. A.} and Boungiorno, {M. T.} and Dolores Buiza-Rueda and Ana C{\'a}mara and F. Carrillo and M. Carri{\'o}n-Claro and Debora Cerdan and Jordi Clarim{\'o}n and Yaroslau Compta and M. Diez-Fairen and {Dols Icardo}, Oriol and J. Duarte and Raquel Duran and F. Escamilla-Sevilla and M. Ezquerra and C. Feliz and M. Fern{\'a}ndez and R. Fern{\'a}ndez-Santiago and C.. Garcia and P. Garc{\'i}a-Ruiz and P. G{\'o}mez-Garre and Heredia, {M. J. G.} and Isabel Gonzalez-Aramburu and Pagola, {A. G.} and J. Hoenicka and J. Infante and S. Jes{\'u}s and A. Jimenez-Escrig and Labrador-Espinosa, {Miguel A} and Lopez-Sendon, {J. L.} and {de Munain Arregui}, {A. L.} and Daniel Mac{\'i}as-Garc{\'i}a and Torres, {I. M.} and J. Mar{\'i}n and Marti, {M. J.} and Mart{\'i}nez-Castrillo, {J. C.} and C. M{\'e}ndez-del-Barrio and Gonz{\'a}lez, {M. M.} and M. Mata and A. M{\'i}nguez and P. Mir and Rezola, {E. M.} and E. Mu{\~n}oz and {Pagonabarraga Mora}, Javier and P. Pastor and Errazquin, {F. P.} and T. Peri{\~n}{\'a}n-Tocino and J. Ruiz-Mart{\'i}nez and C. Ruz and Rodriguez, {A. S.} and M. Sierra and E. Suarez-Sanmartin and C. Tabernero and Tartari, {J. P.} and C. Tejera-Parrado and E. Tolosa and F. Valldeoriola and L. Vargas-Gonz{\'a}lez and Lydia Vela and F. Vives and Alexander Zimprich and L. Pihlstrom and M. Toft and P. Taba and S. Koks and S. Hassin-Baer and K. Majamaa and A. Siitonen and P. Tienari and Okubadejo, {N. U.} and Ojo, {O. O.} and C. Shashkin and N. Zharkinbekova and V. Akhmetzhanov and G. Kaishybayeva and A. Karimova and T. Khaibullin and Lynch, {T. L.} and Aroon Hingorani and Wood, {Nicholas W..}",

year = "2021",

month = dec,

day = "20",

doi = "10.1038/s41467-021-26280-1",

language = "English",

volume = "12",

number = "1",

}

Kulisevsky, J, Storm, CS, Kia, DA, Almramhi, MM, Bandres-Ciga, S, Finan, C, Noyce, AJ, Kaiyrzhanov, R, Middlehurst, B, Tan, M, Houlden, H, Morris, HR, Plun-Favreau, H, Holmans, P, Hardy, J, Trabzuni, D, Quinn, J, Bubb, V, Mok, KY, Kinghorn, KJ, Lewis, P, Schreglmann, SR, Lovering, R, R'Bibo, L, Manzoni, C, Rizig, M, Ryten, M, Guelfi, S, Escott-Price, V, Chelban, V, Foltynie, T, Williams, N, Morrison, KE, Clarke, C, Harvey, K, Jacobs, BM, 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, SA, Cookson, MR, Blauwendraat, C, Craig, DW, Billingsley, K, Makarious, MB, Narendra, DP, Faghri, F, Gibbs, JR, Hernandez, DG, Van Keuren-Jensen, K, Shulman, JM, Iwaki, H, Leonard, HL, Nalls, MA, Robak, L, Bras, J, Guerreiro, R, Lubbe, S, Troycoco, T, Finkbeiner, S, Mencacci, NE, Lungu, C, Singleton, AB, Scholz, SW, Reed, X, Uitti, RJ, Ross, OA, Grenn, FP, Moore, A, Alcalay, RN, Wszolek, ZK, Gan-Or, Z, Rouleau, GA, Krohn, L, Mufti, K, van Hilten, JJ, Marinus, J, Adarmes-Gómez, AD, Aguilar Barberà, M, Alvarez, I, Alvarez, V, Barrero, FJ, Yarza, JAB, Bernal-Bernal, I, Blázquez Estrada, M, Bonilla-Toribio, M, Botía, JA, Boungiorno, MT, 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, MJG, Gonzalez-Aramburu, I, Pagola, AG, Hoenicka, J, Infante, J, Jesús, S, Jimenez-Escrig, A, Labrador-Espinosa, MA, Lopez-Sendon, JL, de Munain Arregui, AL, Macías-García, D, Torres, IM, Marín, J, Marti, MJ, Martínez-Castrillo, JC, Méndez-del-Barrio, C, González, MM, Mata, M, Mínguez, A, Mir, P, Rezola, EM, Muñoz, E, Pagonabarraga Mora, J, Pastor, P, Errazquin, FP, Periñán-Tocino, T, Ruiz-Martínez, J, Ruz, C, Rodriguez, AS, Sierra, M, Suarez-Sanmartin, E, Tabernero, C, Tartari, JP, Tejera-Parrado, C, Tolosa, E, Valldeoriola, F, Vargas-González, L, Vela, L, Vives, F, Zimprich, A, Pihlstrom, L, Toft, M, Taba, P, Koks, S, Hassin-Baer, S, Majamaa, K, Siitonen, A, Tienari, P, Okubadejo, NU, Ojo, OO, Shashkin, C, Zharkinbekova, N, Akhmetzhanov, V, Kaishybayeva, G, Karimova, A, Khaibullin, T, Lynch, TL, Hingorani, A & Wood, NW 2021, 'Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome', Nature Communications, vol. 12, no. 1. https://doi.org/10.1038/s41467-021-26280-1

TY - JOUR

T1 - Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome

AU - Kulisevsky, Jaime

AU - Storm, Catherine S.

AU - Kia, Demis A.

AU - Almramhi, Mona M.

AU - Bandres-Ciga, Sara

AU - Finan, Chris

AU - Noyce, A. J.

AU - Kaiyrzhanov, R.

AU - Middlehurst, B.

AU - Tan, M.

AU - Houlden, Henry

AU - Morris, H. R.

AU - Plun-Favreau, H.

AU - Holmans, Peter

AU - Hardy, J.

AU - Trabzuni, D.

AU - Quinn, J.

AU - Bubb, Vivien

AU - Mok, K. Y.

AU - Kinghorn, K. J.

AU - Lewis, P.

AU - Schreglmann, S. R.

AU - Lovering, R.

AU - R'Bibo, L.

AU - Manzoni, C.

AU - Rizig, M.

AU - Ryten, Mina

AU - Guelfi, S.

AU - Escott-Price, Valentina

AU - Chelban, Viorica

AU - Foltynie, T.

AU - Williams, N.

AU - Morrison, K. E.

AU - Clarke, C.

AU - Harvey, K.

AU - Jacobs, B. M.

AU - Brice, Alexis

AU - Danjou, F.

AU - Lesage, S.

AU - Corvol, Jean-Christophe

AU - Martinez, M.

AU - Schulte, C.

AU - Brockmann, K.

AU - Simón-Sánchez, J.

AU - Heutink, Peter

AU - Rizzu, P.

AU - Sharma, M.

AU - Gasser, T.

AU - Schneider, S. A.

AU - Cookson, M. R.

AU - Blauwendraat, Cornelis

AU - Craig, David W

AU - Billingsley, K.

AU - Makarious, M. B.

AU - Narendra, D. P.

AU - Faghri, F.

AU - Gibbs, J. R.

AU - Hernandez, D. G.

AU - Van Keuren-Jensen, K.

AU - Shulman, J. M.

AU - Iwaki, H.

AU - Leonard, H. L.

AU - Nalls, M. A.

AU - Robak, L.

AU - Bras, J.

AU - Guerreiro, Rita

AU - Lubbe, S.

AU - Troycoco, T.

AU - Finkbeiner, S.

AU - Mencacci, N. E.

AU - Lungu, C.

AU - Singleton, A. B.

AU - Scholz, S. W.

AU - Reed, X.

AU - Uitti, R. J.

AU - Ross, O. A.

AU - Grenn, F. P.

AU - Moore, A.

AU - Alcalay, Roy N

AU - Wszolek, Z. K.

AU - Gan-Or, Z.

AU - Rouleau, G. A.

AU - Krohn, L.

AU - Mufti, K.

AU - van Hilten, J. J.

AU - Marinus, J.

AU - Adarmes-Gómez, A.D

AU - Aguilar Barberà, Miquel

AU - Alvarez, Ignacio

AU - Alvarez, V.

AU - Barrero, F. J.

AU - Yarza, J. A. B.

AU - Bernal-Bernal, I.

AU - Blázquez Estrada, Marta

AU - Bonilla-Toribio, Marta

AU - Botía, J. A.

AU - Boungiorno, M. T.

AU - Buiza-Rueda, Dolores

AU - Cámara, Ana

AU - Carrillo, F.

AU - Carrión-Claro, M.

AU - Cerdan, Debora

AU - Clarimón, Jordi

AU - Compta, Yaroslau

AU - Diez-Fairen, M.

AU - Dols Icardo, Oriol

AU - Duarte, J.

AU - Duran, Raquel

AU - Escamilla-Sevilla, F.

AU - Ezquerra, M.

AU - Feliz, C.

AU - Fernández, M.

AU - Fernández-Santiago, R.

AU - Garcia, C..

AU - García-Ruiz, P.

AU - Gómez-Garre, P.

AU - Heredia, M. J. G.

AU - Gonzalez-Aramburu, Isabel

AU - Pagola, A. G.

AU - Hoenicka, J.

AU - Infante, J.

AU - Jesús, S.

AU - Jimenez-Escrig, A.

AU - Labrador-Espinosa, Miguel A

AU - Lopez-Sendon, J. L.

AU - de Munain Arregui, A. L.

AU - Macías-García, Daniel

AU - Torres, I. M.

AU - Marín, J.

AU - Marti, M. J.

AU - Martínez-Castrillo, J. C.

AU - Méndez-del-Barrio, C.

AU - González, M. M.

AU - Mata, M.

AU - Mínguez, A.

AU - Mir, P.

AU - Rezola, E. M.

AU - Muñoz, E.

AU - Pagonabarraga Mora, Javier

AU - Pastor, P.

AU - Errazquin, F. P.

AU - Periñán-Tocino, T.

AU - Ruiz-Martínez, J.

AU - Ruz, C.

AU - Rodriguez, A. S.

AU - Sierra, M.

AU - Suarez-Sanmartin, E.

AU - Tabernero, C.

AU - Tartari, J. P.

AU - Tejera-Parrado, C.

AU - Tolosa, E.

AU - Valldeoriola, F.

AU - Vargas-González, L.

AU - Vela, Lydia

AU - Vives, F.

AU - Zimprich, Alexander

AU - Pihlstrom, L.

AU - Toft, M.

AU - Taba, P.

AU - Koks, S.

AU - Hassin-Baer, S.

AU - Majamaa, K.

AU - Siitonen, A.

AU - Tienari, P.

AU - Okubadejo, N. U.

AU - Ojo, O. O.

AU - Shashkin, C.

AU - Zharkinbekova, N.

AU - Akhmetzhanov, V.

AU - Kaishybayeva, G.

AU - Karimova, A.

AU - Khaibullin, T.

AU - Lynch, T. L.

AU - Hingorani, Aroon

AU - Wood, Nicholas W..

PY - 2021/12/20

Y1 - 2021/12/20

N2 - 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.

AB - 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.

KW - Brain

KW - Case-Control Studies

KW - Cohort Studies

KW - Disease Progression

KW - Gene Expression Regulation

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome, Human

KW - Humans

KW - Mendelian Randomization Analysis

KW - Parkinson Disease

KW - Quantitative Trait Loci

KW - Risk Factors

U2 - 10.1038/s41467-021-26280-1

DO - 10.1038/s41467-021-26280-1

M3 - Article

C2 - 34930919

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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