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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. Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

Author

Chen, Z., Zhang, D., Reynolds, R.H., Gustavsson, E.K., García-Ruiz, S., D'Sa, K., Fairbrother-Browne, A., Vandrovcova, J., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Kia, D.A., Tan, M., Morris, H.R., Plun-Favreau, H., Holmans, P., Trabzuni, D., Bras, J., Quinn, J., Mok, K.Y., Kinghorn, K.J., Billingsley, K., Wood, N.W., Lewis, P., Schreglmann, S., Guerreiro, Rita, Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Brice, A., Danjou, F., Lesage, S., Corvol, Jean-Christophe, Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Nicolas, A., Cookson, M. R, Bandres-Ciga, S., Blauwendraat, Cornelis, Craig, David W, Faghri, F., Gibbs, J.R., Hernandez, D.G., Van Keuren-Jensen, K., Shulman, J.M., Leonard, H.L., Nalls, M.A., Robak, L., Lubbe, S., Finkbeiner, S., Mencacci, N.E., Lungu, C., Singleton, A. B., Scholz, S.W., Reed, X., Alcalay, Roy N, Gan-Or, Z., Rouleau, G.A., Krohn, L., van Hilten, J.J., Marinus, J., Adarmes-Gómez, A.D, Aguilar Barberà, Miquel, Alvarez, Ignacio, Alvarez, V., Barrero, F. J, Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, Marta, Botía, J., Boungiorno, M.T., Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, M., Dols Icardo, Oriol, Duarte, J., Duran, Raquel, 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, Miguel 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 Mora, Javier, 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, Alexander, Pihlstrom, L., Toft, M., Koks, S., Taba, P., Hassin-Baer, S., Hardy, J., Houlden, Henry, Gagliano Taliun, S. A., Ryten, M., Universitat Autònoma de Barcelona, Universidad de Cantabria, Lord Leonard and Lady Estelle Wolfson Foundation, Medical Research Council (UK), Dementia Research Institute (UK), Alzheimer Society, Alzheimer's Research UK, Wellcome Trust, Dolby Family Fund, National Institute for Health Research (UK), NIHR Biomedical Research Centre (UK), Agencia Estatal de Investigación (España), Fundación Séneca, and Gobierno de la Región de Murcia

Subjects
0301 basic medicine, Apolipoprotein E, Aging, Messenger, General Physics and Astronomy, Neurodegenerative, Alzheimer's Disease, Genome, Linkage Disequilibrium, Negative selection, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, health care economics and organizations, Conserved Sequence, Phylogeny, Multidisciplinary, Brain, Neurodegenerative Diseases, Single Nucleotide, Alzheimer's disease, Phenotype, International Parkinson’s Disease Genomics Consortium, Neurological, Regression Analysis, Long Noncoding, DNA, Intergenic, RNA, Long Noncoding, Human, Biotechnology, Lineage (genetic), Science, 1.1 Normal biological development and functioning, Computational biology, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Chromosomes, 03 medical and health sciences, Apolipoproteins E, Underpinning research, Alzheimer Disease, Genetic variation, Genetics, Acquired Cognitive Impairment, Humans, RNA, Messenger, Polymorphism, Gene, Whole genome sequencing, Intergenic, Pair 19, Genome, Human, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Molecular Sequence Annotation, General Chemistry, DNA, Introns, Brain Disorders, 030104 developmental biology, Gene Ontology, RNA, Dementia, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery
Abstract

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease., Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.

Published
2021

3. Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease

Author

Leonard H, Lake J, Kim JJ, Gibbs JR, Ruskey JA, Pihlstrøm L, Eerola-Rautio J, Tienari PJ, Grosset DG, Wood N, Noyce AJ, Middlehurst B, Kia DA, Tan M, Houlden H, Storm CS, Morris HR, Plun-Favreau H, Holmans P, Hardy J, Trabzuni D, Quinn J, Bubb V, Mok KY, Kinghorn KJ, Wood NW, 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 JC, Martinez M, Schulte C, Brockmann K, Simón-Sánchez J, Heutink P, Rizzu P, Sharma M, Gasser T, Schneider SA, Cookson MR, Bandres-Ciga S, Blauwendraat C, Craig DW, Billingsley K, Makarious MB, Narendra DP, Faghri F, 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 M, Alvarez I, Alvarez V, Barrero FJ, Yarza JAB, Bernal-Bernal I, Blazquez 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, Kulisevsky J, Labrador-Espinosa MA, Lopez-Sendon JL, de Munain Arregui AL, Macias 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 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, Kaiyrzhanov R, Shashkin C, Zharkinbekova N, Akhmetzhanov V, Kaishybayeva G, Karimova A, Khaibullin T, Lynch TL, and International Parkinson's Disease Genomics Consortium (IPDGC)

Abstract

OBJECTIVE: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner. METHODS: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. RESULTS: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). INTERPRETATION: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41-48.

Published
2021

4. 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

5. 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

6. 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

7. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Author

Fernandez-Santiago, R., Martin-Flores, N., Antonelli, F., Cerquera, C., Moreno, V., Bandres-Ciga, S., Manduchi, E., Tolosa, E., Singleton, A.B., Moore, J.H., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Kia, D.A., Tan, M., Houlden, H., Morris, H.R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Bras, J., Quinn, J., Mok, K.Y., Kinghorn, K.J., Billingsley, K., Wood, N.W., Lewis, P., Schreglmann, S., Guerreiro, 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., Brice, A., Danjou, F., Lesage, S., Corvol, J.C., Martinez, M., Schulte, C., Brockmann, K., Simoon-Saanchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Nicolas, A., Cookson, M.R., Blauwendraat, C., Craig, D.W., Faghri, F., Gibbs, J.R., Hernandez, D.G., Keuren-Jensen, K. van, Shulman, J.M., Iwaki, H., Leonard, H.L., Nalls, M.A., Robak, L., Lubbe, S., Finkbeiner, S., Mencacci, N.E., Lungu, C., Scholz, S.W., Reed, X., Alcalay, R.N., Gan-Or, Z., Rouleau, G.A., Krohn, L., Hilten, J.J. van, Marinus, J., Adarmes-Goomez, A.D., Aguilar, I., Alvarez, I., Alvarez, V., Barrero, F.J., Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, M., Botia, J.A., Boungiorno, M.T., Buiza-Rueda, D., Camara, A., Carrillo, F., Carrion-Claro, M., Cerdan, D., Clarimon, J., Compta, Y., Casa, B. de la, Diez-Fairen, M., Dols-Icardo, O., Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernandez, M., Garcia, C., Garcia-Ruiz, P., Gomez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesus, S., Jimenez-Escrig, A., Kulisevsky, J., Labrador-Espinosa, M.A., Lopez-Sendon, J.L., Arregui, A.L.D., Macias, D., Torres, I.M., Marin, J., Marti, M.J., Martinez-Castrillo, C., Mendez-del-Barrio, C., Gonzalez, M.M., Mata, M., Minguez, A., Mir, P., Rezola, E.M., Munoz, E., Pagonabarraga, J., Pascual-Sedano, B., Pastor, P., Errazquin, F.P., Perinan-Tocino, T., Ruiz-Martinez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J.P., Tejera-Parrado, C., Valldeoriola, F., Vargas-Gonzalez, L., Vela, L., Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Koks, S., Taba, P., Hassin-Baer, S., Malagelada, C., Int Parkinson's Dis Genomics Conso, Fundació La Marató de TV3, Michael J. Fox Foundation for Parkinson's Research, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), and Ministerio de Ciencia, Innovación y Universidades (España)

Subjects
0301 basic medicine, epistasis, Male, Parkinson's disease, very elderly, alpha-synuclein, Alpha‐synuclein, regulatory associated protein of mTOR, Cohort Studies, 0302 clinical medicine, single nucleotide polymorphism, genetics, Age of Onset, Genetics, Aged, 80 and over, Polymorphism, Single Nucleoti, biology, TOR Serine-Threonine Kinases, target of rapamycin kinase, fchsd1 gene, Age at onset, Chromosome Mapping, glycogen synthase kinase 3beta, Parkinson Disease, Middle Aged, cohort analysis, LRRK2, priority journal, Neurology, chromosomal mapping, neuromodulation, mTOR, alpha-Synuclein, Female, age at onset, Signal Transduction, onset age, Adult, MTOR protein, human, protein kinase LKB1, gene locus, Genotype, multifactor dimensionality reduction, SNP, Single-nucleotide polymorphism, rps6ka2 gene, Polymorphism, Single Nucleotide, Risk Assessment, Article, brain function, 03 medical and health sciences, alpha synuclein, medicine, Humans, controlled study, Genetic Predisposition to Disease, human, ddc:610, SNCA protein, human, gene, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, mammalian target of rapamycin, Aged, RPTOR, Epistasis, Genetic, Odds ratio, medicine.disease, major clinical study, nervous system diseases, 030104 developmental biology, mTOR signaling, biology.protein, Epistasis, pathology, Neurology (clinical), genetic predisposition, 030217 neurology & neurosurgery
Abstract

Special Issue: Focused Ultrasound in Parkinson's Disease., [Background] Single nucleotide polymorphisms (SNPs) in the α‐synuclein (SNCA ) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored., [Objectives] The mechanistic target of rapamycin (mTOR ) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO., [Methods] Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium., [Results] In the discovery series cohort, we found a 4‐loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P, [Conclusions] These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society, Funding Information; Fundació la Marató de TV3. Grant Number: 60510; Michael J. Fox Foundation for Parkinson's Research. Grant Numbers: Dyskinesia Challenge 2014, MJF_PPMI_10_001, PI044024; National Institutes of Health. Grant Number: LM010098; Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Number: SAF2014‐57160R and SAF2017‐88812R.

Published
2019

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

Author

Billingsley K.J., Barbosa I.A., Bandrés-Ciga S., Quinn J.P., Bubb V.J., Deshpande C., Botia J.A., Reynolds R.H., Zhang D., Simpson M.A., Blauwendraat C., Gan-Or Z., Gibbs J.R., Nalls M.A., Singleton A., Noyce A., Tucci A., Middlehurst B., Kia D., Tan M., Houlden H., Morris H.R., Plun-Favreau H., Holmans P., Hardy J., Trabzuni D., Bras J., Mok K., Kinghorn K., Wood N., Lewis P., Guerreiro R., Lovering 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., Simón-Sánchez 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-Gómez A., Aguilar M., Alvarez I., Alvarez V., Javier Barrero F., Bergareche Yarza J., Bernal-Bernal I., Blazquez M., Bernal M.B.-T., Boungiorno M., Buiza-Rueda D., Cámara A., Carcel M., 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., Fernández M., Fernández-Santiago R., Garcia C., García-Ruiz P., Gómez-Garre P., Heredia M.G., Gonzalez-Aramburu I., Pagola A.G., Hoenicka J., Infante J., Jesús S., Jimenez-Escrig A., Kulisevsky J., Labrador-Espinosa M., Lopez-Sendon J., de Munain Arregui A.L., Macias D., Torres I.M., Marín J., Marti M.J., Martínez-Castrillo J., Méndez-del-Barrio C., Menéndez González 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., Taba P., Majamaa K., Siitonen A., Okubadejo N., Ojo O., Ryten M., and Koks S.

Subjects
genotype, Mendelian randomization analysis, CLN8 gene, MUC1 gene, genetic analysis, bioenergy, genetic risk, genetic risk score, Article, ATG14 gene, disorders of mitochondrial functions, MRPS34 gene, degenerative disease, mitochondrial gene, EP300 gene, gene mutation, human, MPI gene, gene, molecular phylogeny, LMBRD1 gene, genome-wide association study, monogenic disorder, mitochondrial dynamics, Parkinson disease, E2F1 gene, mitophagy, CAPRIN2 gene, priority journal, risk factor, LGALS3 gene, disease exacerbation, gene expression, gene ontology, meta analysis
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 function-associated 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. © 2019, The Author(s).

Published
2019

9. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Author

Martin-Flores, N, Antonelli, F, Cerquera, C, Moreno, V, Manduchi, E, Moore, JH, Noyce, AJ, Kaiyrzhanov, R, Middlehurst, B, Kia, DA, Tan, M, Houlden, H, Morris, HR, Plun-Favreau, H, Holmans, P, Hardy, J, Trabzuni, D, Bras, J, Quinn, J, Mok, KY, Kinghorn, KJ, Billingsley, K, Wood, NW, Lewis, P, Schreglmann, S, Guerreiro, R, 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, Brice, A, Danjou, F, Lesage, S, Corvol, JC, Martinez, M, Schulte, C, Brockmann, K, Simoon-Saanchez, J, Heutink, P, Rizzu, P, Sharma, M, Gasser, T, Nicolas, A, Cookson, MR, Bandres-Ciga, S, Blauwendraat, C, Craig, DW, Faghri, F, Gibbs, JR, Hernandez, DG, Van Keuren-Jensen, K, Shulman, JM, Iwaki, H, Leonard, HL, Nalls, MA, Robak, L, Lubbe, S, Finkbeiner, S, Mencacci, NE, Lungu, C, Singleton, AB, Scholz, SW, Reed, X, Alcalay, RN, Gan-Or, Z, Rouleau, GA, Krohn, L, van Hilten, JJ, Marinus, J, Adarmes-Goomez, AD, Aguilar, I, Alvarez, I, Alvarez, V, Barrero, FJ, Yarza, JAB, Bernal-Bernal, I, Blazquez, M, Bonilla-Toribio, M, Botia, JA, Boungiorno, MT, Buiza-Rueda, D, Camara, A, Carrillo, F, Carrion-Claro, M, Cerdan, D, Clarimon, J, Compta, Y, de la Casa, B, Diez-Fairen, M, Dols-Icardo, O, Duarte, J, Duran, R, Escamilla-Sevilla, F, Feliz, C, Fernandez, M, Fernandez-Santiago, R, Garcia, C, Garcia-Ruiz, P, Gomez-Garre, P, Heredia, MJG, Gonzalez-Aramburu, I, Pagola, AG, Hoenicka, J, Infante, J, Jesus, S, Jimenez-Escrig, A, Kulisevsky, J, Labrador-Espinosa, MA, Lopez-Sendon, JL, Arregui, ALD, Macias, D, Torres, IM, Marin, J, Marti, MJ, Martinez-Castrillo, C, Mendez-del-Barrio, C, Gonzalez, MM, Mata, M, Minguez, A, Mir, P, Rezola, EM, Munoz, E, Pagonabarraga, J, Pascual-Sedano, B, Pastor, P, Errazquin, FP, Perinan-Tocino, T, Ruiz-Martinez, J, Ruz, C, Rodriguez, AS, Sierra, M, Suarez-Sanmartin, E, Tabernero, C, Tartari, JP, Tejera-Parrado, C, Tolosa, E, Valldeoriola, F, Vargas-Gonzalez, L, Vela, L, Vives, F, Zimprich, A, Pihlstrom, L, Toft, M, Koks, S, Taba, P, Hassin-Baer, S, Ezquerra, M, Malagelada, C, and Int Parkinson's Dis Genomics Conso

Subjects
epistasis, alpha-synuclein, Parkinson's disease, mTOR, SNP, age at onset
Abstract

Background Single nucleotide polymorphisms (SNPs) in the alpha-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. (c) 2019 International Parkinson and Movement Disorder Society

Published
2019

10. 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

11. NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases

Author

Blauwendraat, C., Faghri, F., Pihlstrom, L., Geiger, J. T., Elbaz, A., Lesage, S., Corvol, J. -C., May, P., Nicolas, A., Abramzon, Y., Murphy, N. A., Gibbs, J. R., Ryten, M., Ferrari, R., Bras, J., Guerreiro, R., Williams, J., Sims, R., Lubbe, S., Hernandez, D. G., Mok, K. Y., Robak, L., Campbell, R. H., Rogaeva, E., Traynor, B. J., Chia, R., Chung, S. J., Hardy, J. A., Brice, A., Wood, N. W., Houlden, H., Shulman, J. M., Morris, H. R., Gasser, T., Kruger, R., Heutink, P., Sharma, M., Simon-Sanchez, J., Nalls, M. A., Singleton, A. B., Scholz, S. W., Noyce, A. J., Giri, A., Oehmig, A., Tucci, A., Schulte, C., Cookson, M. R., Kia, D., Danjou, F., Charlesworth, G., Plun-Favreau, H., Holmans, P., Jansen, I., Hardy, J., Bras, J. M., Quinn, J., Botia, J. A., Billingsley, K., R'Bibo, L., Lungu, C., Martinez, M., Escott-Price, V., Mencacci, N. E., Topley, Lewis, Denny, P., Rizzu, P., Taba, P., Lovering, R., Ogalla, R. D., Foulger, R., Finkbeiner, S., Sveinbjornsdottir, S., Scholz, S., Koks, S., Foltynie, T., Price, T. R., Sheerin, U. -M., Williams, N., Reed, X., Wang, L., Brockmann, K., Oertel, W., Klein, C., Mohamed, F., Malard, L., Corti, O., Drouet, V., Goldwurm, S., Tesei, S., Canesi, M., Valente, E. M., Petrucci, S., Ginevrino, M., Toft, M., Aasly, J., Henriksen, S. P., Saetehaug, C., Orr-Urtreger, A., Giladi, N., Ferreira, J., Guedes, L. C., Bouca-Machado, R., Coelho, M., Rosa, M. M., Tolosa, E., Fernandez-Santiago, R., Ezquerra, M., Marti, M. J., Glaab, E., Balling, R., and Chung, S. -J.

Subjects
0301 basic medicine, Aging, methods [Genome-Wide Association Study], 0302 clinical medicine, Corticobasal degeneration, neurodegenerative diseases, humans, risk, high-throughput screening assays, education.field_of_study, General Neuroscience, neurodegeneration, genetics [Genetic Variation], 3. Good health, Neurochip, alleles, methods [Genotyping Techniques], Frontotemporal dementia, Risk, Population, methods [High-Throughput Screening Assays], Computational biology, Genetic screening, genotyping, NeuroChip, NeuroX, apolipoproteins E, genetic variation, genome-wide association study, genotyping techniques, Article, Progressive supranuclear palsy, 03 medical and health sciences, Apolipoproteins E, medicine, Humans, Dementia, ddc:610, education, Genotyping, Alleles, business.industry, medicine.disease, 030104 developmental biology, genetics [Neurodegenerative Diseases], genetics [Apolipoproteins E], Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience, 030217 neurology & neurosurgery, Imputation (genetics), Developmental Biology
Abstract

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.

Published
2017

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