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21 results on '"Shulman J.M."'

1. 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

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. 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

4. 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

5. 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

6. Genetic architecture of subcortical brain structures in 38,851 individuals

Author

Satizabal, C.L., Adams, H.H.H., Hibar, D.P., White, C.C., Knol, M.J., Stein, J.L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G.V., Smith, A.V., Bis, J.C., Jian, X., Luciano, M., Hofer, E., Teumer, A., van der Lee, S.J., Yang, J., Yanek, L.R., Lee, T.V., Li, S., Hu, Y., Koh, J.Y., Eicher, J.D., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M.E., Kim, S., Hoehn, D., Armstrong, N.J., Chen, Q., Holmes, A.J., den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A.K., Jones, H.J., Pike, G.B., Stein, D.J., Stevens, A., Bralten, J., Vernooij, M.W., Harris, T.B., Filippi, I., Witte, A.V., Guadalupe, T., Wittfeld, K., Mosley, T.H., Becker, J.T., Doan, N.T., Hagenaars, S.P., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Mirza-Schreiber, N., Arfanakis, K., Becker, D.M., Ames, D., Goldman, A.L., Lee, P.H., Boomsma, D.I., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M.M., Kasperaviciute, D., Schmaal, L., Lawrie, S.M., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G.E., Shin, J., Ipser, J.C., Vinke, L.N., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U.K., Aribisala, B.S., Schmidt, H., Strike, L.T., Cheng, C-Y, Risacher, S.L., Pütz, B., Fleischman, D.A., Assareh, A.A., Mattay, V.S., Buckner, R.L., Mecocci, P., Dale, A.M., Cichon, S., Boks, M.P., Matarin, M., Penninx, B.W.J.H., Calhoun, V.D., Chakravarty, M.M., Marquand, A.F., Macare, C., Kharabian Masouleh, S., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J.I., Schork, A.J., Liewald, D.C.M., de Zubicaray, G.I., Wong, T.Y., Shen, L., Sämann, P.G., Brodaty, H., Roffman, J.L., de Geus, E.J.C., Tsolaki, M., Erk, S., van Eijk, K.R., Cavalleri, G.L., van der Wee, N.J.A., McIntosh, A.M., Gollub, R.L., Bulayeva, K.B., Bernard, M., Richards, J.S., Himali, J.J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L.T., Valdés Hernández, M.C., Hansell, N.K., Van Erp, T.G.M., Wolf, C., Kwok, J.B.J., Vellas, B., Heinz, A., Olde Loohuis, L.M., Delanty, N., Ho, B-C., Ching, C.R.K., Shumskaya, E., Singh, B., Hofman, A., van der Meer, D., Homuth, G., Psaty, B.M., Bastin, M.E., Montgomery, G.W., Foroud, T.M., Reppermund, S., Hottenga, J-J, Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C.D., van Donkelaar, M.M.J., Yang, Q., Hosten, N., Green, R.C., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H.E., Lin, H., Jack, C.R., Schofield, P.R., Mühleisen, T.W., Maillard, P., Potkin, S.G., Wen, W., Fletcher, E., Toga, A.W., Gruber, O., Huentelman, M., Davey Smith, G., Launer, L.J., Nyberg, L., Jönsson, E.G., Crespo-Facorro, B., Koen, N., Greve, D.N., Uitterlinden, A.G., Weinberger, D.R., Steen, V.M., Fedko, I.O., Groenewold, N.A., Niessen, W.J., Toro, R., Tzourio, C., Longstreth, W.T., Ikram, M.K., Smoller, J.W., van Tol, M-J, Sussmann, J.E., Paus, T., Lemaitre, H., Schroeter, M.L., Mazoyer, B., Andreassen, O.A., Holsboer, F., Depondt, C., Veltman, D.J., Turner, J.A., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I.J., McMahon, K.L., Müller-Myhsok, B., Brouwer, R.M., Soininen, H., Pandolfo, M., Wassink, T.H., Cheung, J.W., Wolfers, T., Martinot, J-L, Zwiers, M.P., Nauck, M., Melle, I., Martin, N.G., Kanai, R., Westman, E., Kahn, R.S., Sisodiya, S.M., White, T., Saremi, A., van Bokhoven, H., Brunner, H.G., Völzke, H., Wright, M.J., van ‘t Ent, D., Nöthen, M.M., Ophoff, R.A., Buitelaar, J.K., Fernández, G., Sachdev, P.S., Rietschel, M., van Haren, N.E.M., Fisher, S.E., Beiser, A.S., Francks, C., Saykin, A.J., Mather, K.A., Romanczuk-Seiferth, N., Hartman, C.A., DeStefano, A.L., Heslenfeld, D.J., Weiner, M.W., Walter, H., Hoekstra, P.J., Nyquist, P.A., Franke, B., Bennett, D.A., Grabe, H.J., Johnson, A.D., Chen, C., van Duijn, C.M., Lopez, O.L., Fornage, M., Wardlaw, J.M., Schmidt, R., DeCarli, C., De Jager, P.L., Villringer, A., Debette, S., Gudnason, V., Medland, S.E., Shulman, J.M., Thompson, P.M., Seshadri, S., Ikram, M.A., Satizabal, C.L., Adams, H.H.H., Hibar, D.P., White, C.C., Knol, M.J., Stein, J.L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G.V., Smith, A.V., Bis, J.C., Jian, X., Luciano, M., Hofer, E., Teumer, A., van der Lee, S.J., Yang, J., Yanek, L.R., Lee, T.V., Li, S., Hu, Y., Koh, J.Y., Eicher, J.D., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M.E., Kim, S., Hoehn, D., Armstrong, N.J., Chen, Q., Holmes, A.J., den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A.K., Jones, H.J., Pike, G.B., Stein, D.J., Stevens, A., Bralten, J., Vernooij, M.W., Harris, T.B., Filippi, I., Witte, A.V., Guadalupe, T., Wittfeld, K., Mosley, T.H., Becker, J.T., Doan, N.T., Hagenaars, S.P., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Mirza-Schreiber, N., Arfanakis, K., Becker, D.M., Ames, D., Goldman, A.L., Lee, P.H., Boomsma, D.I., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M.M., Kasperaviciute, D., Schmaal, L., Lawrie, S.M., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G.E., Shin, J., Ipser, J.C., Vinke, L.N., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U.K., Aribisala, B.S., Schmidt, H., Strike, L.T., Cheng, C-Y, Risacher, S.L., Pütz, B., Fleischman, D.A., Assareh, A.A., Mattay, V.S., Buckner, R.L., Mecocci, P., Dale, A.M., Cichon, S., Boks, M.P., Matarin, M., Penninx, B.W.J.H., Calhoun, V.D., Chakravarty, M.M., Marquand, A.F., Macare, C., Kharabian Masouleh, S., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J.I., Schork, A.J., Liewald, D.C.M., de Zubicaray, G.I., Wong, T.Y., Shen, L., Sämann, P.G., Brodaty, H., Roffman, J.L., de Geus, E.J.C., Tsolaki, M., Erk, S., van Eijk, K.R., Cavalleri, G.L., van der Wee, N.J.A., McIntosh, A.M., Gollub, R.L., Bulayeva, K.B., Bernard, M., Richards, J.S., Himali, J.J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L.T., Valdés Hernández, M.C., Hansell, N.K., Van Erp, T.G.M., Wolf, C., Kwok, J.B.J., Vellas, B., Heinz, A., Olde Loohuis, L.M., Delanty, N., Ho, B-C., Ching, C.R.K., Shumskaya, E., Singh, B., Hofman, A., van der Meer, D., Homuth, G., Psaty, B.M., Bastin, M.E., Montgomery, G.W., Foroud, T.M., Reppermund, S., Hottenga, J-J, Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C.D., van Donkelaar, M.M.J., Yang, Q., Hosten, N., Green, R.C., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H.E., Lin, H., Jack, C.R., Schofield, P.R., Mühleisen, T.W., Maillard, P., Potkin, S.G., Wen, W., Fletcher, E., Toga, A.W., Gruber, O., Huentelman, M., Davey Smith, G., Launer, L.J., Nyberg, L., Jönsson, E.G., Crespo-Facorro, B., Koen, N., Greve, D.N., Uitterlinden, A.G., Weinberger, D.R., Steen, V.M., Fedko, I.O., Groenewold, N.A., Niessen, W.J., Toro, R., Tzourio, C., Longstreth, W.T., Ikram, M.K., Smoller, J.W., van Tol, M-J, Sussmann, J.E., Paus, T., Lemaitre, H., Schroeter, M.L., Mazoyer, B., Andreassen, O.A., Holsboer, F., Depondt, C., Veltman, D.J., Turner, J.A., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I.J., McMahon, K.L., Müller-Myhsok, B., Brouwer, R.M., Soininen, H., Pandolfo, M., Wassink, T.H., Cheung, J.W., Wolfers, T., Martinot, J-L, Zwiers, M.P., Nauck, M., Melle, I., Martin, N.G., Kanai, R., Westman, E., Kahn, R.S., Sisodiya, S.M., White, T., Saremi, A., van Bokhoven, H., Brunner, H.G., Völzke, H., Wright, M.J., van ‘t Ent, D., Nöthen, M.M., Ophoff, R.A., Buitelaar, J.K., Fernández, G., Sachdev, P.S., Rietschel, M., van Haren, N.E.M., Fisher, S.E., Beiser, A.S., Francks, C., Saykin, A.J., Mather, K.A., Romanczuk-Seiferth, N., Hartman, C.A., DeStefano, A.L., Heslenfeld, D.J., Weiner, M.W., Walter, H., Hoekstra, P.J., Nyquist, P.A., Franke, B., Bennett, D.A., Grabe, H.J., Johnson, A.D., Chen, C., van Duijn, C.M., Lopez, O.L., Fornage, M., Wardlaw, J.M., Schmidt, R., DeCarli, C., De Jager, P.L., Villringer, A., Debette, S., Gudnason, V., Medland, S.E., Shulman, J.M., Thompson, P.M., Seshadri, S., and Ikram, M.A.

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019

7. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing

Author

Jansen, I.E., Ye, H., Heetveld, S., Lechler, M.C., Michels, H., Seinstra, R.I., Lubbe, S.J., Drouet, V., Lesage, S., Majounie, E., Gibbs, J.R., Nalls, M.A., Ryten, M., Botia, J.A., Vandrovcova, J., Simon-Sanchez, J., Castillo-Lizardo, M., Rizzu, P., Blauwendraat, C., Chouhan, A.K., Li, Y., Yogi, P., Amin, N., Duijn, C.M. van, Morris, H.R., Brice, A., Singleton, A.B., David, D.C., Nollen, E.A., Jain, S., Shulman, J.M., Heutink, P., Bloem, B., Post, B., Scheffer, H., Warrenburg, B.P.C. van de, et al., Jansen, I.E., Ye, H., Heetveld, S., Lechler, M.C., Michels, H., Seinstra, R.I., Lubbe, S.J., Drouet, V., Lesage, S., Majounie, E., Gibbs, J.R., Nalls, M.A., Ryten, M., Botia, J.A., Vandrovcova, J., Simon-Sanchez, J., Castillo-Lizardo, M., Rizzu, P., Blauwendraat, C., Chouhan, A.K., Li, Y., Yogi, P., Amin, N., Duijn, C.M. van, Morris, H.R., Brice, A., Singleton, A.B., David, D.C., Nollen, E.A., Jain, S., Shulman, J.M., Heutink, P., Bloem, B., Post, B., Scheffer, H., Warrenburg, B.P.C. van de, and et al.

Abstract

Contains fulltext : 169957.pdf (publisher's version ) (Open Access), BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced alpha-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.

Published
2017

8. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease

Author

Robak, L.A., Jansen, I.E., Rooij, J van, Uitterlinden, A.G., Kraaij, R., Jankovic, J., Heutink, P., Shulman, J.M., Bloem, B., Post, B., Scheffer, H., Warrenburg, B.P.C. van de, et al., Robak, L.A., Jansen, I.E., Rooij, J van, Uitterlinden, A.G., Kraaij, R., Jankovic, J., Heutink, P., Shulman, J.M., Bloem, B., Post, B., Scheffer, H., Warrenburg, B.P.C. van de, and et al.

Abstract

Item does not contain fulltext, Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.

Published
2017

9. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing

Author

Jansen, I. (Iris), Ye, H. (Hui), Heetveld, S. (Sasja), Lechler, M.C. (Marie C.), Michels, H. (Helen), Seinstra, R.I. (Renée I.), Lubbe, S.J. (Steven J.), Drouet, V. (Valérie), Lesage, S. (Suzanne), Majounie, E. (Elisa), Gibbs, J.R. (J.Raphael), Nalls, M.A. (Michael), Ryten, M. (Mina), Botia, J.A. (Juan A.), Vandrovcova, J. (Jana), Simón-Sánchez, J. (Javier), Castillo-Lizardo, M. (Melissa), Rizzu, P. (Patrizia), Blauwendraat, C. (Cornelis), Chouhan, A.K. (Amit K.), Li, Y. (Yarong), Yogi, P. (Puja), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Morris, H.R. (Huw R.), Brice, A. (Alexis), Singleton, A. (Andrew), David, D.C. (Della C.), Nollen, E.A. (Ellen A.), Jain, A. (Ashok), Shulman, J.M., Heutink, P. (Peter), Hernandez, D.G. (Dena), Arepalli, S. (Sampath), Brooks, J. (Janet), Price, R. (Ryan), Nicolas, A. (Aude), Chong, S. (Sean), Cookson, M.R. (Mark), Dillman, A. (Allissa), Moore, M. (Matt), Traynor, B.J. (Bryan), Plagnol, V. (Vincent), Nicholas W Wood, Sheerin, U.-M. (Una-Marie), Jose M Bras, Charlesworth, K. (Kate), Gardner, M. (Mac), Guerreiro, R. (Rita), Trabzuni, D. (Danyah), Hardy, J. (John), Sharma, M., Saad, M. (Mohamad), Javier Simón-Sánchez, Schulte, C. (Claudia), Corvol, J.C. (Jean-Christophe), Dürr, A. (Alexandra), Vidailhet, M. (M.), Sveinbjörnsdóttir, S. (Sigurlaug), Barker, R.A. (Roger), Caroline H Williams-Gray, Ben-Shlomo, Y., Berendse, H.W. (Henk W.), Dijk, K.D. (Karin) van, Berg, D. (Daniela), Brockmann, K., Wurster, K.D. (Kathrin), Mätzler, W. (Walter), Gasser, T. (Thomas), Martinez, M. (Maria), Bie, R.M.A. (Rob) de, Biffi, A. (Alessandro), Velseboer, D. (Daan), Bloem, B.R. (Bastiaan), Post, B. (Bart), Wickremaratchi, M. (Mirdhu), Warrenburg, B. (Bart) van de, Bochdanovits, Z. (Zoltan), Bonin, M. (Malte) von, Pétursson, H. (Hjörvar), Riess, O. (Olaf), Burn, D.J. (David), Lubbe, S. (Steven), Cooper, J.M. (J Mark), McNeill, N.H. (Nathan), Schapira, A. (Anthony), Lungu, C. (Codrin), Chen, H. (Honglei), Dong, J. (Jing), Chinnery, P.F. (Patrick F.), Hudson, G. (Gavin), Clarke, C.E. (Carl E.), Moorby, C. (Catriona), Counsell, C. (Carl), Damier, P. (Philippe), Dartigues, J.-F., Deloukas, P. (Panagiotis), Gray, E. (Emma), Edkins, T. (Ted), Hunt, S.E. (Sarah E.), Potter, S.C. (Simon), Tashakkori-Ghanbaria, A. (Avazeh), Deuschl, G. (Günther), Lorenz, D. (Delia), Dexter, D.T. (David), Durif, F. (Frank), Evans, J. (Jonathan Mark), Langford, C. (Cordelia), Foltynie, T. (Thomas), Goate, A.M. (Alison), Harris, C. (Clare), Hilten, J.J. (Jacobus) van, Hofman, A. (Albert), Hollenbeck, J.R. (John R.), Holton, J.L. (Janice), Hu, M. (Michele), Huang, X. (Xiaohong), Illig, T. (Thomas), Jónsson, P.V. (Pálmi), Lambert, J.-C., O'Sullivan, S.S. (Sean), Revesz, T. (Tamas), Shaw, K. (Karen), Lees, A.J. (Andrew), Lichtner, P. (Peter), Limousin, P. (Patricia), Lopez, G., Escott-Price, V. (Valentina), Pearson, J. (Justin), Williams, N. (Nigel), Mudanohwo, E. (Ese), Perlmutter, J.S. (Joel), Pollak, P. (Pierre), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Sawcer, S.J. (Stephen), Scheffer, H. (Hans), Shoulson, I. (Ira), Shulman, L. (Lee), Smith, C. (Colin), Walker, R. (Robert), Spencer, C.C.A. (Chris C.), Strange, A. (Amy), Stefansson, H. (Hreinn), Bettella, F. (Francesco), Zwart, J-A. (John-Anker), Stockton, J.D. (Joanna D.), Talbot, D., Tanner, C.M. (Carlie), Tison, F. (François), Winder-Rhodes, S. (Sophie), Bhatia, K.P. (Kailash), Jansen, I. (Iris), Ye, H. (Hui), Heetveld, S. (Sasja), Lechler, M.C. (Marie C.), Michels, H. (Helen), Seinstra, R.I. (Renée I.), Lubbe, S.J. (Steven J.), Drouet, V. (Valérie), Lesage, S. (Suzanne), Majounie, E. (Elisa), Gibbs, J.R. (J.Raphael), Nalls, M.A. (Michael), Ryten, M. (Mina), Botia, J.A. (Juan A.), Vandrovcova, J. (Jana), Simón-Sánchez, J. (Javier), Castillo-Lizardo, M. (Melissa), Rizzu, P. (Patrizia), Blauwendraat, C. (Cornelis), Chouhan, A.K. (Amit K.), Li, Y. (Yarong), Yogi, P. (Puja), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Morris, H.R. (Huw R.), Brice, A. (Alexis), Singleton, A. (Andrew), David, D.C. (Della C.), Nollen, E.A. (Ellen A.), Jain, A. (Ashok), Shulman, J.M., Heutink, P. (Peter), Hernandez, D.G. (Dena), Arepalli, S. (Sampath), Brooks, J. (Janet), Price, R. (Ryan), Nicolas, A. (Aude), Chong, S. (Sean), Cookson, M.R. (Mark), Dillman, A. (Allissa), Moore, M. (Matt), Traynor, B.J. (Bryan), Plagnol, V. (Vincent), Nicholas W Wood, Sheerin, U.-M. (Una-Marie), Jose M Bras, Charlesworth, K. (Kate), Gardner, M. (Mac), Guerreiro, R. (Rita), Trabzuni, D. (Danyah), Hardy, J. (John), Sharma, M., Saad, M. (Mohamad), Javier Simón-Sánchez, Schulte, C. (Claudia), Corvol, J.C. (Jean-Christophe), Dürr, A. (Alexandra), Vidailhet, M. (M.), Sveinbjörnsdóttir, S. (Sigurlaug), Barker, R.A. (Roger), Caroline H Williams-Gray, Ben-Shlomo, Y., Berendse, H.W. (Henk W.), Dijk, K.D. (Karin) van, Berg, D. (Daniela), Brockmann, K., Wurster, K.D. (Kathrin), Mätzler, W. (Walter), Gasser, T. (Thomas), Martinez, M. (Maria), Bie, R.M.A. (Rob) de, Biffi, A. (Alessandro), Velseboer, D. (Daan), Bloem, B.R. (Bastiaan), Post, B. (Bart), Wickremaratchi, M. (Mirdhu), Warrenburg, B. (Bart) van de, Bochdanovits, Z. (Zoltan), Bonin, M. (Malte) von, Pétursson, H. (Hjörvar), Riess, O. (Olaf), Burn, D.J. (David), Lubbe, S. (Steven), Cooper, J.M. (J Mark), McNeill, N.H. (Nathan), Schapira, A. (Anthony), Lungu, C. (Codrin), Chen, H. (Honglei), Dong, J. (Jing), Chinnery, P.F. (Patrick F.), Hudson, G. (Gavin), Clarke, C.E. (Carl E.), Moorby, C. (Catriona), Counsell, C. (Carl), Damier, P. (Philippe), Dartigues, J.-F., Deloukas, P. (Panagiotis), Gray, E. (Emma), Edkins, T. (Ted), Hunt, S.E. (Sarah E.), Potter, S.C. (Simon), Tashakkori-Ghanbaria, A. (Avazeh), Deuschl, G. (Günther), Lorenz, D. (Delia), Dexter, D.T. (David), Durif, F. (Frank), Evans, J. (Jonathan Mark), Langford, C. (Cordelia), Foltynie, T. (Thomas), Goate, A.M. (Alison), Harris, C. (Clare), Hilten, J.J. (Jacobus) van, Hofman, A. (Albert), Hollenbeck, J.R. (John R.), Holton, J.L. (Janice), Hu, M. (Michele), Huang, X. (Xiaohong), Illig, T. (Thomas), Jónsson, P.V. (Pálmi), Lambert, J.-C., O'Sullivan, S.S. (Sean), Revesz, T. (Tamas), Shaw, K. (Karen), Lees, A.J. (Andrew), Lichtner, P. (Peter), Limousin, P. (Patricia), Lopez, G., Escott-Price, V. (Valentina), Pearson, J. (Justin), Williams, N. (Nigel), Mudanohwo, E. (Ese), Perlmutter, J.S. (Joel), Pollak, P. (Pierre), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Sawcer, S.J. (Stephen), Scheffer, H. (Hans), Shoulson, I. (Ira), Shulman, L. (Lee), Smith, C. (Colin), Walker, R. (Robert), Spencer, C.C.A. (Chris C.), Strange, A. (Amy), Stefansson, H. (Hreinn), Bettella, F. (Francesco), Zwart, J-A. (John-Anker), Stockton, J.D. (Joanna D.), Talbot, D., Tanner, C.M. (Carlie), Tison, F. (François), Winder-Rhodes, S. (Sophie), and Bhatia, K.P. (Kailash)

Abstract

Background: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. Results: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. Conclusions: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.

Published
2017
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10. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author

Ibrahim-Verbaas, C.A. (Carla), Bressler, J. (Jan), Debette, S. (Stéphanie), Schuur, M. (Maaike), Smith, A.V. (Albert), Bis, J.C. (Joshua), Davies, G. (Gail), Trompet, S. (Stella), Smith, J.A., Björnsson, A. (Asgeir), Chibnik, L.B. (Lori), Liu, Y., Vitart, V. (Veronique), Kirin, M. (Mirna), Petrovic, K. (Katja), Polasek, O. (Ozren), Zgaga, L. (Lina), Fawns-Ritchie, C., Hoffmann, P. (Per), Karjalainen, J. (Juha), Lahti, J., Llewellyn, D.J., Schmidt, C.O. (Carsten O.), Mather, R., Chouraki, V. (Vincent), Sun, Q., Resnick, S.M. (Susan), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Stewart, M., Smith, B.H., Gudnason, V. (Vilmundur), Yang, Q. (Qiong), Mirza, S.S. (Saira), Jukema, J.W., DeJager, P.L. (Philip L.), Harris, T.B. (Tamara), Liewald, D.C. (David C.), Amin, N. (Najaf), Coker, L.H. (Laura), Stegle, O. (Oliver), Lopez, O.L., Schmidt, R., Teumer, A. (Alexander), Ford, I., Karbalai, N. (Nazanin), Becker, J.T. (James), Jonsdottir, M.K. (Maria K.), Au, R. (Rhoda), Fehrmann, R.S.N. (Rudolf), Herms, S. (Stefan), Nalls, M.A. (Michael), Zhao, W., Turner, S.T. (Stephen), Yaffe, K., Lohman, K. (Kurt), Swieten, J.C. (John) van, Kardia, S.L. (Sharon L.r), Knopman, D.S. (David), Meeks, W.M. (William), Heiss, G. (Gerardo), Holliday, E.G. (Elizabeth), Schofield, P.W., Tanaka, T. (Toshiko), Stott, D.J. (David J.), Wang, J. (Jing), Ridker, P.M. (Paul), Gow, A.J., Pattie, A. (Alison), Starr, J.M. (John), Hocking, L.J., Armstrong, N.J. (Nicola), McLachlan, S. (Stela), Shulman, J.M., Pilling, L.C. (Luke), Eiriksdottir, G. (Gudny), Scott, R. (Rodney), Kochan, N.A. (Nicole A.), Palotie, A. (Aarno), Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Penman, A.D. (Alan), Gottesman, R.F. (Rebecca), Oostra, B.A. (Ben), Yu, L. (Lei), DeStefano, A.L. (Anita), Beiser, A. (Alexa), Garcia, M., Rotter, J.I. (Jerome I.), Nöthen, M.M. (Markus M.), Hofman, A. (Albert), Slagboom, P.E. (Eline), Westendorp, R.G.J., Buckley, B.M. (Brendan M.), Wolf, P.A., Uitterlinden, A.G. (André), Psaty, B.M. (Bruce), Grabe, H.J. (Hans Jörgen), Bandinelli, S. (Stefania), Chasman, D.I. (Daniel), Grodstein, F. (Francine), Räikkönen, K. (Katri), Lambert, J.-C. (J.), Porteous, D.J. (David J.), Price, J.F. (Jackie F.), Sachdev, P.S. (Perminder), Ferrucci, L. (Luigi), Attia, J. (John), Rudan, I. (Igor), Hayward, C., Wright, A.F., Wilson, J.F. (James F), Cichon, S., Franke, L. (Lude), Schmidt, H., Ding, J. (Jingzhong), Craen, A.J. (Anton) de, Fornage, M. (Myriam), Bennett, D.A. (David), Deary, I.J. (Ian), Ikram, M.A. (Arfan), Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), Duijn, C.M. (Cornelia) van, Mosley, T.H. (Thomas H.), Ibrahim-Verbaas, C.A. (Carla), Bressler, J. (Jan), Debette, S. (Stéphanie), Schuur, M. (Maaike), Smith, A.V. (Albert), Bis, J.C. (Joshua), Davies, G. (Gail), Trompet, S. (Stella), Smith, J.A., Björnsson, A. (Asgeir), Chibnik, L.B. (Lori), Liu, Y., Vitart, V. (Veronique), Kirin, M. (Mirna), Petrovic, K. (Katja), Polasek, O. (Ozren), Zgaga, L. (Lina), Fawns-Ritchie, C., Hoffmann, P. (Per), Karjalainen, J. (Juha), Lahti, J., Llewellyn, D.J., Schmidt, C.O. (Carsten O.), Mather, R., Chouraki, V. (Vincent), Sun, Q., Resnick, S.M. (Susan), Rose, L.M. (Lynda), Oldmeadow, C. (Christopher), Stewart, M., Smith, B.H., Gudnason, V. (Vilmundur), Yang, Q. (Qiong), Mirza, S.S. (Saira), Jukema, J.W., DeJager, P.L. (Philip L.), Harris, T.B. (Tamara), Liewald, D.C. (David C.), Amin, N. (Najaf), Coker, L.H. (Laura), Stegle, O. (Oliver), Lopez, O.L., Schmidt, R., Teumer, A. (Alexander), Ford, I., Karbalai, N. (Nazanin), Becker, J.T. (James), Jonsdottir, M.K. (Maria K.), Au, R. (Rhoda), Fehrmann, R.S.N. (Rudolf), Herms, S. (Stefan), Nalls, M.A. (Michael), Zhao, W., Turner, S.T. (Stephen), Yaffe, K., Lohman, K. (Kurt), Swieten, J.C. (John) van, Kardia, S.L. (Sharon L.r), Knopman, D.S. (David), Meeks, W.M. (William), Heiss, G. (Gerardo), Holliday, E.G. (Elizabeth), Schofield, P.W., Tanaka, T. (Toshiko), Stott, D.J. (David J.), Wang, J. (Jing), Ridker, P.M. (Paul), Gow, A.J., Pattie, A. (Alison), Starr, J.M. (John), Hocking, L.J., Armstrong, N.J. (Nicola), McLachlan, S. (Stela), Shulman, J.M., Pilling, L.C. (Luke), Eiriksdottir, G. (Gudny), Scott, R. (Rodney), Kochan, N.A. (Nicole A.), Palotie, A. (Aarno), Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Penman, A.D. (Alan), Gottesman, R.F. (Rebecca), Oostra, B.A. (Ben), Yu, L. (Lei), DeStefano, A.L. (Anita), Beiser, A. (Alexa), Garcia, M., Rotter, J.I. (Jerome I.), Nöthen, M.M. (Markus M.), Hofman, A. (Albert), Slagboom, P.E. (Eline), Westendorp, R.G.J., Buckley, B.M. (Brendan M.), Wolf, P.A., Uitterlinden, A.G. (André), Psaty, B.M. (Bruce), Grabe, H.J. (Hans Jörgen), Bandinelli, S. (Stefania), Chasman, D.I. (Daniel), Grodstein, F. (Francine), Räikkönen, K. (Katri), Lambert, J.-C. (J.), Porteous, D.J. (David J.), Price, J.F. (Jackie F.), Sachdev, P.S. (Perminder), Ferrucci, L. (Luigi), Attia, J. (John), Rudan, I. (Igor), Hayward, C., Wright, A.F., Wilson, J.F. (James F), Cichon, S., Franke, L. (Lude), Schmidt, H., Ding, J. (Jingzhong), Craen, A.J. (Anton) de, Fornage, M. (Myriam), Bennett, D.A. (David), Deary, I.J. (Ian), Ikram, M.A. (Arfan), Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), Duijn, C.M. (Cornelia) van, and Mosley, T.H. (Thomas H.)

Abstract

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semant

Published
2016
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11. Genome-wide studies of verbal declarative memory in nondemented older people: The cohorts for heart and aging research in genomic epidemiology consortium

Author

Debette, S., Ibrahim Verbaas, C.A., Bressler, J., Schuur, M., Smith, A., Bis, J.C., Davies, G., Wolf, C., Gudnason, V., Chibnik, L.B., Yang, Q., DeStefano, A.L., de Quervain, D.J.F., Srikanth, V., Lahti, J., Grabe, H.J., Smith, J.A., Priebe, L., Yu, L., Karbalai, N., Hayward, C., Wilson, J.F., Campbell, H., Petrovic, K., Fornage, M., Chauhan, G., Yeo, R., Boxall, R., Becker, J., Stegle, O., Mather, K.A., Chouraki, V., Sun, Q., Rose, L.M., Resnick, S., Oldmeadow, C., Kirin, M., Wright, A.F., Jonsdottir, M.K., Au, R., Becker, A., Amin, N., Nalls, M.A., Turner, S.T., Kardia, S.L.R., Oostra, B., Windham, G., Coker, L.H., Zhao, W., Knopman, D.S., Heiss, G., Griswold, M.E., Gottesman, R.F., Vitart, V., Hastie, N.D., Zgaga, L., Rudan, I., Polasek, O., Holliday, E.G., Schofield, P., Choi, S.H., Tanaka, T., An, Y., Perry, R.T., Kennedy, R.E., Sale, M.M., Wang, J., Wadley, V.G., Liewald, D.C., Ridker, P.M., Gow, A.J., Pattie, A., Starr, J.M., Porteous, D., Liu, X., Thomson, R., Armstrong, N.J., Eiriksdottir, G., Assareh, A.A., Kochan, N.A., Widen, E., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Vogler, C., van Swieten, J.C., Shulman, J.M., Beiser, A., Rotter, J., Schmidt, C.O., Hoffmann, W., Nöthen, M.M., Ferrucci, L., Attia, J., Uitterlinden, A.G., Amouyel, P., Dartigues, J-F, Amieva, H., Räikkönen, K., Garcia, M., Wolf, P.A., Hofman, A., Longstreth, W.T., Psaty, B.M., Boerwinkle, E., DeJager, P.L., Sachdev, P.S., Schmidt, R., Breteler, M.M.B., Teumer, A., Lopez, O.L., Cichon, S., Chasman, D.I., Grodstein, F., Müller-Myhsok, B., Tzourio, C., Papassotiropoulos, A., Bennett, D.A., Ikram, M.A., Deary, I.J., van Duijn, C.M., Launer, L., Fitzpatrick, A.L., Seshadri, S., Mosley, T.H., Debette, S., Ibrahim Verbaas, C.A., Bressler, J., Schuur, M., Smith, A., Bis, J.C., Davies, G., Wolf, C., Gudnason, V., Chibnik, L.B., Yang, Q., DeStefano, A.L., de Quervain, D.J.F., Srikanth, V., Lahti, J., Grabe, H.J., Smith, J.A., Priebe, L., Yu, L., Karbalai, N., Hayward, C., Wilson, J.F., Campbell, H., Petrovic, K., Fornage, M., Chauhan, G., Yeo, R., Boxall, R., Becker, J., Stegle, O., Mather, K.A., Chouraki, V., Sun, Q., Rose, L.M., Resnick, S., Oldmeadow, C., Kirin, M., Wright, A.F., Jonsdottir, M.K., Au, R., Becker, A., Amin, N., Nalls, M.A., Turner, S.T., Kardia, S.L.R., Oostra, B., Windham, G., Coker, L.H., Zhao, W., Knopman, D.S., Heiss, G., Griswold, M.E., Gottesman, R.F., Vitart, V., Hastie, N.D., Zgaga, L., Rudan, I., Polasek, O., Holliday, E.G., Schofield, P., Choi, S.H., Tanaka, T., An, Y., Perry, R.T., Kennedy, R.E., Sale, M.M., Wang, J., Wadley, V.G., Liewald, D.C., Ridker, P.M., Gow, A.J., Pattie, A., Starr, J.M., Porteous, D., Liu, X., Thomson, R., Armstrong, N.J., Eiriksdottir, G., Assareh, A.A., Kochan, N.A., Widen, E., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Vogler, C., van Swieten, J.C., Shulman, J.M., Beiser, A., Rotter, J., Schmidt, C.O., Hoffmann, W., Nöthen, M.M., Ferrucci, L., Attia, J., Uitterlinden, A.G., Amouyel, P., Dartigues, J-F, Amieva, H., Räikkönen, K., Garcia, M., Wolf, P.A., Hofman, A., Longstreth, W.T., Psaty, B.M., Boerwinkle, E., DeJager, P.L., Sachdev, P.S., Schmidt, R., Breteler, M.M.B., Teumer, A., Lopez, O.L., Cichon, S., Chasman, D.I., Grodstein, F., Müller-Myhsok, B., Tzourio, C., Papassotiropoulos, A., Bennett, D.A., Ikram, M.A., Deary, I.J., van Duijn, C.M., Launer, L., Fitzpatrick, A.L., Seshadri, S., and Mosley, T.H.

Abstract

Background Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. Methods We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. Results rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. Conclusions This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Published
2015

12. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author

Ibrahim-Verbaas, C.A., Bressler, J., Debette, S., Schuur, M., Smith, A.V., Bis, J.C., Davies, G., Trompet, S., Smith, J.A., Wolf, C., Chibnik, L.B., Liu, Y., Vitart, V., Kirin, M., Petrovic, K., Polasek, O., Zgaga, L., Fawns-Ritchie, C., Hoffmann, P., Karjalainen, J., Lahti, J., Llewellyn, D.J., Schmidt, C.O., Mather, K.A., Chouraki, V., Sun, Q., Resnick, S.M., Rose, L.M., Oldmeadow, C., Stewart, M., Smith, B.H., Gudnason, V., Yang, Q., Mirza, S.S., Jukema, J.W., deJager, P.L., Harris, T.B., Liewald, D.C., Amin, N., Coker, L.H., Stegle, O., Lopez, O.L., Schmidt, R., Teumer, A., Ford, I., Karbalai, N., Becker, J.T., Jonsdottir, M.K., Au, R., Fehrmann, R.S.N., Herms, S., Nalls, M., Zhao, W., Turner, S.T., Yaffe, K., Lohman, K., van Swieten, J.C., Kardia, S.L.R, Knopman, D.S., Meeks, W.M., Heiss, G., Holliday, E.G., Schofield, P.W., Tanaka, T., Stott, D.J., Wang, J., Ridker, P., Gow, A.J., Pattie, A, Starr, J.M., Hocking, L.J., Armstrong, N.J., McLachlan, S., Shulman, J.M., Pilling, L.C., Eiriksdottir, G., Scott, R.J., Kochan, N.A., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Penman, A., Gottesman, R.F., Oostra, B.A., Yu, L., DeStefano, A.L., Beiser, A., Garcia, M., Rotter, J.I., Nöthen, M.M., Hofman, A., Slagboom, P.E., Westendorp, R.G.J., Buckley, B.M., Wolf, P.A., Uitterlinden, A.G., Psaty, B.M., Grabe, H.J., Bandinelli, S., Chasman, D.I., Grodstein, F., Räikkönen, K., Lambert, J-C, Porteous, D.J., Price, J.F., Sachdev, P.S., Ferrucci, L., Attia, J.R., Rudan, I., Hayward, C., Wright, A.F., Wilson, J.F., Cichon, S., Franke, L., Schmidt, H., Ding, J., de Craen, A.J.M., Fornage, M., Bennett, D.A., Deary, I.J., Ikram, M.A., Launer, L.J., Fitzpatrick, A.L., Seshadri, S., van Duijn, C.M., Mosley, T.H., Ibrahim-Verbaas, C.A., Bressler, J., Debette, S., Schuur, M., Smith, A.V., Bis, J.C., Davies, G., Trompet, S., Smith, J.A., Wolf, C., Chibnik, L.B., Liu, Y., Vitart, V., Kirin, M., Petrovic, K., Polasek, O., Zgaga, L., Fawns-Ritchie, C., Hoffmann, P., Karjalainen, J., Lahti, J., Llewellyn, D.J., Schmidt, C.O., Mather, K.A., Chouraki, V., Sun, Q., Resnick, S.M., Rose, L.M., Oldmeadow, C., Stewart, M., Smith, B.H., Gudnason, V., Yang, Q., Mirza, S.S., Jukema, J.W., deJager, P.L., Harris, T.B., Liewald, D.C., Amin, N., Coker, L.H., Stegle, O., Lopez, O.L., Schmidt, R., Teumer, A., Ford, I., Karbalai, N., Becker, J.T., Jonsdottir, M.K., Au, R., Fehrmann, R.S.N., Herms, S., Nalls, M., Zhao, W., Turner, S.T., Yaffe, K., Lohman, K., van Swieten, J.C., Kardia, S.L.R, Knopman, D.S., Meeks, W.M., Heiss, G., Holliday, E.G., Schofield, P.W., Tanaka, T., Stott, D.J., Wang, J., Ridker, P., Gow, A.J., Pattie, A, Starr, J.M., Hocking, L.J., Armstrong, N.J., McLachlan, S., Shulman, J.M., Pilling, L.C., Eiriksdottir, G., Scott, R.J., Kochan, N.A., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Penman, A., Gottesman, R.F., Oostra, B.A., Yu, L., DeStefano, A.L., Beiser, A., Garcia, M., Rotter, J.I., Nöthen, M.M., Hofman, A., Slagboom, P.E., Westendorp, R.G.J., Buckley, B.M., Wolf, P.A., Uitterlinden, A.G., Psaty, B.M., Grabe, H.J., Bandinelli, S., Chasman, D.I., Grodstein, F., Räikkönen, K., Lambert, J-C, Porteous, D.J., Price, J.F., Sachdev, P.S., Ferrucci, L., Attia, J.R., Rudan, I., Hayward, C., Wright, A.F., Wilson, J.F., Cichon, S., Franke, L., Schmidt, H., Ding, J., de Craen, A.J.M., Fornage, M., Bennett, D.A., Deary, I.J., Ikram, M.A., Launer, L.J., Fitzpatrick, A.L., Seshadri, S., van Duijn, C.M., and Mosley, T.H.

Abstract

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10-8) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10-9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10-4). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10-15), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10-11) and neuron cell-cell adhesion (P-value=1.48 × 10-13). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37.

Published
2015

16. Common variants at 12q14 and 12q24 are associated with hippocampal volume.

Author

Bis, J.C., DeCarli, C., Smith, A.V., Lijn, F. van der, Crivello, F., Fornage, M., Debette, S., Shulman, J.M., Schmidt, H., Srikanth, V., Schuur, M., Yu, L., Choi, S.H., Sigurdsson, S., Verhaaren, B.F., DeStefano, A.L., Lambert, J.C., Jack Jr., C.R., Struchalin, M., Stankovich, J., Ibrahim-Verbaas, C.A., Fleischman, D., Zijdenbos, A., Heijer, T., Mazoyer, B., Coker, L.H., Enzinger, C., Danoy, P., Amin, N., Arfanakis, K., Buchem, M.A. van, Bruijn, R.F. de, Beiser, A., Dufouil, C., Huang, J., Cavalieri, M., Thomson, R., Niessen, W.J., Chibnik, L.B., Gislason, G.K., Hofman, A., Pikula, A., Amouyel, P., Freeman, K.B., Phan, T.G., Oostra, B.A., Stein, J.L., Medland, S.E., Arias Vasquez, A., Hibar, D.P., Wright, M.J., Franke, B., Martin, N.G., Thompson, P.M., Nalls, M.A., Uitterlinden, A.G., Au, R., Elbaz, A., Beare, R.J., Swieten, J.C. van, Lopez, O.L., Harris, T.B., Chouraki, V., Breteler, M.M.B., Jager, P.L., Becker, J.T., Vernooij, M.W., Knopman, D., Fazekas, F., Wolf, P.A., Lugt, A. van der, Gudnason, V., Longstreth Jr, W.T., Brown, M.A., Bennett, D.A., Duijn, C.M. van, Mosley, T.H., Schmidt, R., Tzourio, C., Launer, L.J., Ikram, M.A., Seshadri, S., Rijpkema, M.J.P., Fernandez, G.S.E., et al., Bis, J.C., DeCarli, C., Smith, A.V., Lijn, F. van der, Crivello, F., Fornage, M., Debette, S., Shulman, J.M., Schmidt, H., Srikanth, V., Schuur, M., Yu, L., Choi, S.H., Sigurdsson, S., Verhaaren, B.F., DeStefano, A.L., Lambert, J.C., Jack Jr., C.R., Struchalin, M., Stankovich, J., Ibrahim-Verbaas, C.A., Fleischman, D., Zijdenbos, A., Heijer, T., Mazoyer, B., Coker, L.H., Enzinger, C., Danoy, P., Amin, N., Arfanakis, K., Buchem, M.A. van, Bruijn, R.F. de, Beiser, A., Dufouil, C., Huang, J., Cavalieri, M., Thomson, R., Niessen, W.J., Chibnik, L.B., Gislason, G.K., Hofman, A., Pikula, A., Amouyel, P., Freeman, K.B., Phan, T.G., Oostra, B.A., Stein, J.L., Medland, S.E., Arias Vasquez, A., Hibar, D.P., Wright, M.J., Franke, B., Martin, N.G., Thompson, P.M., Nalls, M.A., Uitterlinden, A.G., Au, R., Elbaz, A., Beare, R.J., Swieten, J.C. van, Lopez, O.L., Harris, T.B., Chouraki, V., Breteler, M.M.B., Jager, P.L., Becker, J.T., Vernooij, M.W., Knopman, D., Fazekas, F., Wolf, P.A., Lugt, A. van der, Gudnason, V., Longstreth Jr, W.T., Brown, M.A., Bennett, D.A., Duijn, C.M. van, Mosley, T.H., Schmidt, R., Tzourio, C., Launer, L.J., Ikram, M.A., Seshadri, S., Rijpkema, M.J.P., Fernandez, G.S.E., and et al.

Abstract

01 mei 2012, Contains fulltext : 110608.pdf (publisher's version ) (Closed access), Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 x 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 x 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 x 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 x 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 x 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

Published
2012

19. Genetic variation at CR1increases risk of cerebral amyloid angiopathy

Author

Biffi, A., Shulman, J.M., Jagiella, J.M., Cortellini, L., Ayres, A.M., Schwab, K., Brown, D.L., Silliman, S.L., Selim, M., Worrall, B.B., Meschia, J.F., Slowik, A., De Jager, P.L., Greenberg, S.M., Schneider, J.A., Bennett, D.A., and Rosand, J.

Abstract

Accumulated evidence suggests that a variant within the CR1gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences -amyloid (A) deposition in brain tissue. Given the biologic overlap between AD and cerebral amyloid angiopathy (CAA), a leading cause of intracerebral hemorrhage (ICH) in elderly individuals, we investigated whether rs6656401 increases the risk of CAA-related ICH and influences vascular A deposition.

Published
2012
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