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1. Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Author

Krohn, L., Heilbron, K., Blauwendraat, C., Reynolds, R. H., Yu, E., Senkevich, K., Rudakou, U., Estiar, M. A., Gustavsson, E. K., Brolin, K., Ruskey, J. A., Freeman, K., Asayesh, F., Chia, R., Arnulf, I., M. T. M., Hu, Montplaisir, J. Y., Gagnon, J. -F., Desautels, A., Dauvilliers, Y., Gigli, G. L., Valente, M., Janes, F., Bernardini, A., Hogl, B., Stefani, A., Ibrahim, A., Sonka, K., Kemlink, D., Oertel, W., Janzen, A., Plazzi, G., Biscarini, F., Antelmi, E., Figorilli, M., Puligheddu, M., Mollenhauer, B., Trenkwalder, C., Sixel-Doring, F., Cochen De Cock, V., Monaca, C. C., Heidbreder, A., Ferini-Strambi, L., Dijkstra, F., Viaene, M., Abril, B., Boeve, B. F., Aslibekyan, S., Auton, A., Babalola, E., Bell, R. K., Bielenberg, J., Bryc, K., Bullis, E., Coker, D., Partida, G. C., Dhamija, D., Das, S., Elson, S. L., Filshtein, T., Fletez-Brant, K., Fontanillas, P., Freyman, W., Gandhi, P. M., Hicks, B., Hinds, D. A., Jewett, E. M., Jiang, Y., Kukar, K., Lin, K. -H., Lowe, M., Mccreight, J. C., Mcintyre, M. H., Micheletti, S. J., Moreno, M. E., Mountain, J. L., Nandakumar, P., Noblin, E. S., O'Connell, J., Petrakovitz, A. A., Poznik, G. D., Schumacher, M., Shastri, A. J., Shelton, J. F., Shi, J., Shringarpure, S., Tran, V., Tung, J. Y., Wang, X., Wang, W., Weldon, C. H., Wilton, P., Hernandez, A., Wong, C., Tchakoute, C. T., Scholz, S. W., Ryten, M., Bandres-Ciga, S., Noyce, A., Cannon, P., Pihlstrom, L., Nalls, M. A., Singleton, A. B., Rouleau, G. A., Postuma, R. B., Gan-Or, Z., and 23andMe Research Team

Subjects
Multidisciplinary, Risk factors, General Physics and Astronomy, Genomics, General Chemistry, Human medicine, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology
Abstract

Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention. REM-sleep behavior disorder often precedes Parkinson's disease or dementia. Here, the authors perform a genome-wide association study for REM-sleep behavior disorder, and discover how it potentially affects gene expression in the brain.

Published
2022

2. 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

3. Investigation of autosomal genetic sex differences in Parkinson’s disease

Author

Blauwendraat, C. (Cornelis), Iwaki, H. (Hirotaka), Makarious, M. B. (Mary B.), Bandres-Ciga, S. (Sara), Leonard, H. L. (Hampton L.), Grenn, F. P. (Francis P.), Lake, J. (Julie), Krohn, L. (Lynne), Tan, M. (Manuela), Kim, J. J. (Jonggeol J.), Gibbs, J. R. (Jesse R.), Hernandez, D. G. (Dena G.), Ruskey, J. A. (Jennifer A.), Pihlstrom, L. (Lasse), Toft, M. (Mathias), van Hilten, J. J. (Jacobus J.), Marinus, J. (Johan), Schulte, C. (Claudia), Brockmann, K. (Kathrin), Sharma, M. (Manu), Siitonen, A. (Ari), Majamaa, K. (Kari), Eerola-Rautio, J. (Johanna), Tienari, P. J. (Pentti J.), Grosset, D. G. (Donald G.), Lesage, S. (Suzanne), Corvol, J.-C. (Jean-Christophe), Brice, A. (Alexis), Wood, N. (Nick), Hardy, J. (John), Gan-Or, Z. (Ziv), Heutink, P. (Peter), Gasser, T. (Thomas), Morris, H. R. (Huw R.), Noyce, A. J. (Alastair J.), Nalls, M. A. (Mike A.), and Singleton, A. B. (Andrew B.)

Abstract

Objective: Parkinson’s disease (PD) is a complex neurodegenerative disorder. Men are on average similar to 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 (similar to 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.

Published
2021

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

Author

Blauwendraat, C, Iwaki, H, Makarious, MB, Bandres-Ciga, S, Leonard, HL, Grenn, FP, Lake, J, Krohn, L, Tan, M, Kim, JJ, Gibbs, JR, Hernandez, DG, Ruskey, JA, Pihlstrom, L, Toft, M, van Hilten, JJ, Marinus, J, Schulte, C, Brockmann, K, Sharma, M, Siitonen, A, Majamaa, K, Eerola-Rautio, J, Tienari, PJ, Grosset, DG, Lesage, S, Corvol, JC, Brice, A, Wood, N, Hardy, J, Gan-Or, Z, Heutink, P, Gasser, T, Morris, HR, Noyce, AJ, Nalls, MA, Singleton, AB, Clarimón J., Dols-Icardo, O, Kulisevsky J., Pagonabarraga, J, and Int Parkinsons Dis Genomics Consor

Abstract

Objective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average similar to 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 (similar to 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.

Published
2021

5. 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

6. 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

7. 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

8. Analysis of heterozygous PRKN variants and copy number variations in Parkinson's disease

Author

Yu, E., primary, Krohn, L., additional, Rudakov, U., additional, Mufti, K., additional, Ruskey, J.A., additional, Asayesh, F., additional, Estiar, M.A., additional, Spiegelman, D., additional, Greenbaum, L., additional, Dauvilliers, Y., additional, Dupre, N., additional, Rouleau, G.A., additional, Hassin-Baer, S., additional, Fon, E.A., additional, Alcalay, R.N., additional, and Gan-Or, Z., additional

Published
2020
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9. GBA variants in REM sleep behavior disorder risk and conversion: a multicenter study

Author

Krohn, L., primary, Ruskey, J.A., additional, Rudakou, U., additional, Leveille, E., additional, Asayesh, F., additional, Hu, M.T.M., additional, Arnulf, I., additional, Dauvilliers, Y., additional, Högl, B., additional, Stefani, A., additional, Monaca, C.C., additional, Abril, B., additional, Plazzi, G., additional, Antelmi, E., additional, Ferini-Strambi, L., additional, Heidbreder, A., additional, Boeve, B.F., additional, Espay, A.J., additional, Cochen de Cock, V., additional, Mollenhauer, B., additional, Sixel-Döring, F., additional, Trenkwalder, C., additional, Sonka, K., additional, Kemlink, D., additional, Figorilli, M., additional, Puligheddu, M., additional, Dijkstra, F., additional, Viaene, M., additional, Oertel, W., additional, Janzen, A., additional, Toffoli, M., additional, Gigli, G.L., additional, Valente, M., additional, Gagnon, J.-F., additional, Desautels, A., additional, Montplaisir, J.Y., additional, Postuma, R.B., additional, Rouleau, G.A., additional, and Gan-Or, Z., additional

Published
2020
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10. 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
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11. 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

12. Analyse des Weines

Author

Medicus, L., Kayser, B., Wartha, V., Maumené, E. J., Roesler, L., Haas, B., Weigert, Leopold, Ogáta, Massanori, Jay, Egger, E., Amthor, Carl, Schmitt, C., Cobenzl, A., Bosenhek, Josef, Blarez, Gobba, Lys, Chiappe, Strohmer, F., Uffelmann, J., Vogel, H. W., Krohn, L. Mourad, and Kiticsán, S.

Published
1885
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23. Fine-mapping of SNCA variants in REM sleep behavior disorder identifies distinct associations

Author

Krohn, L., Wu, R., Ruskey, J., Laurent, S., Philstrom, L., Arnulf, I., Hu, M., Dauvilliers, Y., Hogl, B., Stefani, A., Holzknecht, E., Monaca, C., Beatriz, A., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Cochen, V., Mollenhauer, B., Sonka, K., MICHELA FIGORILLI, Dijkstra, F., Viaene, M., Oertel, W., Gagnon, J., Nalls, M., Blauwendraat, C., Singleton, A., Desautels, A., Montplaisir, J., Ross, O., Boeve, B., Dupre, N., Fon, E., Postuma, R., Rouleau, G., and Gan-Or, Z.

28. Acknowledgments

Author

Coales, J.F., primary, Ruppel, G., additional, Truxal, John, additional, Rand, Chr., additional, Holberg, K., additional, Monrad-Krohn, L., additional, Aseltine, John, additional, and Letov, M., additional

Published
1965
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29. Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Author

Edward A. Fon, Armaghan Alam, Richard Y.J. Wu, Cornelis Blauwendraat, Jennifer A. Ruskey, Luigi Ferini-Strambi, Paul Cannon, Mathias Toft, Mariarosaria Valente, Alex Desautels, Andrew B. Singleton, Valérie Cochen De Cock, Yves Dauvilliers, Elena Antelmi, C. Trenkwalder, Kari Anne Bjørnarå, Abril Beatriz, Christelle Charley Monaca, Jacques Montplaisir, Nicolas Dupré, Mineke Viaene, Peter Young, Birgit Högl, Giuseppe Plazzi, Monica Puligheddu, W. H. Oertel, Marco Toffoli, Bradley F. Boeve, Owen A. Ross, Friederike Sixel-Döring, Lasse Pihlstrøm, Michele T.M. Hu, Isabelle Arnulf, Sandra B. Laurent, Karl Heilbron, Michela Figorilli, Anna Heidbreder, Lynne Krohn, Guy A. Rouleau, Karel Sonka, Ziv Gan-Or, Mike A. Nalls, Jean-François Gagnon, David Kemlink, Evi Holzknecht, Femke Dijkstra, Ambra Stefani, Gian Luigi Gigli, Brit Mollenhauer, Ronald B. Postuma, Krohn L., Wu R.Y.J., Heilbron K., Ruskey J.A., Laurent S.B., Blauwendraat C., Alam A., Arnulf I., Hu M.T.M., Dauvilliers Y., Hogl B., Toft M., Bjornara K.A., Stefani A., Holzknecht E., Monaca C.C., Abril B., Plazzi G., Antelmi E., Ferini-Strambi L., Young P., Heidbreder A., Cochen De Cock V., Mollenhauer B., Sixel-Doring F., Trenkwalder C., Sonka K., Kemlink D., Figorilli M., Puligheddu M., Dijkstra F., Viaene M., Oertel W., Toffoli M., Gigli G.L., Valente M., Gagnon J.-F., Nalls M.A., Singleton A.B., Desautels A., Montplaisir J.Y., Cannon P., Ross O.A., Boeve B.F., Dupre N., Fon E.A., Postuma R.B., Pihlstrom L., Rouleau G.A., Gan-Or Z., Krohn, L., R. Y. J., Wu, Heilbron, K., Ruskey, J. A., Laurent, S. B., Blauwendraat, C., Alam, A., Arnulf, I., M. T. M., Hu, Dauvilliers, Y., Hogl, B., Toft, M., Bjornara, K. A., Stefani, A., Holzknecht, E., Monaca, C. C., Abril, B., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Young, P., Heidbreder, A., Cochen De Cock, V., Mollenhauer, B., Sixel-Doring, F., Trenkwalder, C., Sonka, K., Kemlink, D., Figorilli, M., Puligheddu, M., Dijkstra, F., Viaene, M., Oertel, W., Toffoli, M., Gigli, G. L., Valente, M., Gagnon, J. -F., Nalls, M. A., Singleton, A. B., Desautels, A., Montplaisir, J. Y., Cannon, P., Ross, O. A., Boeve, B. F., Dupre, N., Fon, E. A., Postuma, R. B., Pihlstrom, L., Rouleau, G. A., Gan-Or, Z., McGill University Health Center [Montreal] (MUHC), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Imperial College London, 23andMe Inc., National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Oxford [Oxford], Nuffield Department of Clinical Neurosciences [Oxford], Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Innsbruck Medical University [Austria] (IMU), Oslo University Hospital [Oslo], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Alma Mater Studiorum University of Bologna (UNIBO), University of Bologna, Department of Biomedical and Neuromotor Sciences [Bologna, Italy], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Münster, Clinique Beau Soleil [Montpellier], EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), Paracelsus-Elena-Klinik, Kassel, Germany., University Medical Center Göttingen (UMG), First Faculty of Medicine Charles University [Prague], Universita degli Studi di Cagliari [Cagliari], Algemeen Ziekenhuis Sint-Dimpna, Philipps University of Marburg, Università degli Studi di Udine - University of Udine [Italie], University College of London [London] (UCL), Department of Mathematics and Computer Science [Udine], Hôpital du Sacré-Coeur de Montréal, Université du Québec à Montréal = University of Québec in Montréal (UQAM), Data Tecnica International, Centre d'études avancées en Médecine du Sommeil (CEAMS), Université de Montréal (UdeM)-Hôpital du Sacré-Coeur de Montréal, Mayo Clinic [Jacksonville], Mayo Clinic [Rochester], Laval University Medical center, and Université Laval [Québec] (ULaval)

Subjects
Male, 0301 basic medicine, Oncology, Linkage disequilibrium, Synucleinopathies, REM sleep behavior disorder, MESH: Logistic Models, REM Sleep Behavior Disorder, 0302 clinical medicine, synucleinopathy, SNCA, Odds Ratio, RBD-specific risk variants, MESH: Aged, MESH: Middle Aged, Rapid eye movement sleep behavior disorder (RBD), MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Parkinson Disease, Middle Aged, MESH: Case-Control Studies, 3. Good health, Neurology, MESH: Synucleinopathies, alpha-Synuclein, Female, Adult, Lewy Body Disease, medicine.medical_specialty, Prodromal Symptoms, Single-nucleotide polymorphism, Locus (genetics), Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, MESH: alpha-Synuclein, medicine, Humans, Genetic Predisposition to Disease, MESH: Prodromal Symptoms, Allele frequency, MESH: Lewy Body Disease, Aged, MESH: Humans, business.industry, Dementia with Lewy bodies, [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Adult, Odds ratio, medicine.disease, MESH: Odds Ratio, MESH: Male, synucleinopathies, Logistic Models, 030104 developmental biology, MESH: REM Sleep Behavior Disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Synuclein, Neurology (clinical), business, MESH: Female, MESH: Parkinson Disease, 030217 neurology & neurosurgery
Abstract

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.

Published
2020
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30. Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies

Author

Uladzislau Rudakou, Edward A. Fon, Petra Oliva, Guy A. Rouleau, Yves Dauvilliers, Elena Antelmi, Birgit Högl, Anna Heidbreder, Jean-François Trempe, Christopher Liong, Bouchra Ouled Amar Bencheikh, Pavlina Wolf, Isabelle Arnulf, Luigi Ferini-Strambi, A. Desautels, Jennifer A. Ruskey, Peter Young, Nicolas Dupré, Valérie Cochen De Cock, Giuseppe Plazzi, Lior Greenbaum, Michele T.M. Hu, Lynne Krohn, Roy N. Alcalay, Guillaume Lamoureux, Ziv Gan-Or, Xiaokui Kate Zhang, Jacques Montplaisir, S. Hassin-Baer, Dan Spiegelman, Ronald B. Postuma, Ambra Stefani, Jean-François Gagnon, Christelle Charley Monaca, Benoît Vanderperre, Sandra B. Laurent, Tugba N. Ozturk, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Montreal Neurological Institute and Hospital, Concordia University [Montreal], Centre for Research in Molecular Modeling and Department of Chemistry & Biochemistry, PROTEO, The Quebec Network for Research on Protein Function, Engineering, and Applications, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Université de Sherbrooke (UdeS)-Université Laval [Québec] (ULaval)-McGill University = Université McGill [Montréal, Canada]-University of Ottawa [Ottawa]-Université du Québec à Trois-Rivières (UQTR)-Université de Montréal (UdeM)-TransBiotech, Lévis-Concordia University [Montreal]-Université du Québec à Montréal = University of Québec in Montréal (UQAM), Department of Neurology and Neurosurgery [Montreal], McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford [Oxford], Nuffield Department of Clinical Neurosciences [Oxford], Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Innsbruck [Innsbruck], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Alma Mater Studiorum University of Bologna (UNIBO), Institute of Neurological Sciences of Bologna IRCCS, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Münster, Clinique Beau Soleil [Montpellier], Euromov (EuroMov), Université de Montpellier (UM), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Sanofi Genzyme, The Danek Gertner Institute of Genetics, Chaim Sheba Medical Center, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Columbia University College of Physicians and Surgeons, Center for advanced research in sleep medicine, Montreal, Université de Montréal (UdeM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Research Center of CIUSSS of the North of Montreal and Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada, Laval University Medical center, Université Laval [Québec] (ULaval), McGill University Health Center [Montreal] (MUHC), Department of Pharmacology and Therapeutics [Montréal], Center for Computational and Integrative Biology [Camden] (CCIB), Rutgers University [Camden], Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Krohn, L., Ozturk, T. N., Vanderperre, B., Ouled Amar Bencheikh, B., Ruskey, J. A., Laurent, S. B., Spiegelman, D., Postuma, R. B., Arnulf, I., M. T. M., Hu, Dauvilliers, Y., Hogl, B., Stefani, A., Monaca, C. C., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Rudakou, U., Cochen De Cock, V., Young, P., Wolf, P., Oliva, P., Zhang, X. K., Greenbaum, L., Liong, C., Gagnon, J. -F., Desautels, A., Hassin-Baer, S., Montplaisir, J. Y., Dupre, N., Rouleau, G. A., Fon, E. A., Trempe, J. -F., Lamoureux, G., Alcalay, R. N., Gan-Or, Z., Krohn L., Ozturk T.N., Vanderperre B., Ouled Amar Bencheikh B., Ruskey J.A., Laurent S.B., Spiegelman D., Postuma R.B., Arnulf I., Hu M.T.M., Dauvilliers Y., Hogl B., Stefani A., Monaca C.C., Plazzi G., Antelmi E., Ferini-Strambi L., Heidbreder A., Rudakou U., Cochen De Cock V., Young P., Wolf P., Oliva P., Zhang X.K., Greenbaum L., Liong C., Gagnon J.-F., Desautels A., Hassin-Baer S., Montplaisir J.Y., Dupre N., Rouleau G.A., Fon E.A., Trempe J.-F., Lamoureux G., Alcalay R.N., and Gan-Or Z.

Subjects
0301 basic medicine, Male, Models, Molecular, Potassium Channels, Synucleinopathies, Genome-wide association study, REM Sleep Behavior Disorder, MESH: Glucosylceramidase, MESH: Genotype, 0302 clinical medicine, TMEM175/GAK/DGKQ, genetics, MESH: Molecular Dynamics Simulation, Parkinson, Genetics, MESH: Aged, MESH: Middle Aged, synucleinopaties, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Parkinson Disease, MESH: Potassium Channels, Middle Aged, MESH: Case-Control Studies, Transmembrane protein, Neurology, MESH: Synucleinopathies, Glucosylceramidase, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, synucleinopathies, MESH: Models, Molecular, Adult, Genotype, Locus (genetics), Single-nucleotide polymorphism, Biology, Molecular Dynamics Simulation, Polymorphism, Single Nucleotide, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Homology modeling, Genetic association, Aged, MESH: Humans, MESH: Adult, MESH: Male, 030104 developmental biology, REM sleep behavior disorder, MESH: REM Sleep Behavior Disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Neurology (clinical), Lysosomes, Glucocerebrosidase, MESH: Female, 030217 neurology & neurosurgery, synucleinopathie, MESH: Parkinson Disease, MESH: Lysosomes
Abstract

Objective The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. Methods Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. Results Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. Interpretation Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.

Published
2018
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31. Comprehensive Analysis of Familial Parkinsonism Genes in Rapid‐Eye‐Movement Sleep Behavior Disorder

Author

Christelle Charley Monaca, Alex Desautels, Yves Dauvilliers, Beatriz Abril, Elena Antelmi, Ambra Stefani, Giuseppe Plazzi, Karel Sonka, Monica Puligheddu, Brit Mollenhauer, Birgit Högl, Sandra B. Laurent, Eric Yu, Farnaz Asayesh, Luigi Ferini-Strambi, Mariarosaria Valente, Jennifer A. Ruskey, Michela Figorilli, Uladzislau Rudakou, Annette Janzen, Ziv Gan-Or, Francesco Janes, Mineke Viaene, Ronald B. Postuma, Valérie Cochen De Cock, Bradley F. Boeve, David Kemlink, Evi Holzknecht, Dan Spiegelman, Jacques Montplaisir, Anna Heidbreder, Gian Luigi Gigli, Michele T.M. Hu, Friederike Sixel-Döring, Lynne Krohn, Kheireddin Mufti, Guy A. Rouleau, Isabelle Arnulf, Claudia Trenkwalder, Wolfgang H. Oertel, Femke Dijkstra, Jean-François Gagnon, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Clinique Beau Soleil [Montpellier], EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), CHU Lille, Université de Lille, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Mufti, K., Rudakou, U., Yu, E., Krohn, L., Ruskey, J. A., Asayesh, F., Laurent, S. B., Spiegelman, D., Arnulf, I., M. T. M., Hu, Montplaisir, J. Y., Gagnon, J. -F., Desautels, A., Dauvilliers, Y., Gigli, G. L., Valente, M., Janes, F., Hogl, B., Stefani, A., Holzknecht, E., Sonka, K., Kemlink, D., Oertel, W., Janzen, A., Plazzi, G., Antelmi, E., Figorilli, M., Puligheddu, M., Mollenhauer, B., Trenkwalder, C., Sixel-Doring, F., Cochen De Cock, V., Monaca, C. C., Heidbreder, A., Ferini-Strambi, L., Dijkstra, F., Viaene, M., Abril, B., Boeve, B. F., Postuma, R. B., Rouleau, G. A., and Gan-Or, Z.

Subjects
0301 basic medicine, Heterozygote, Parkinson's disease, MESH: Sleep, [SDV]Life Sciences [q-bio], REM sleep behavior disorder, Rapid eye movement sleep, Disease, genetic analysis, Compound heterozygosity, Genetic analysis, 03 medical and health sciences, 0302 clinical medicine, Parkinsonian Disorders, Medicine, Humans, MESH: Heterozygote, Genetics, MESH: Humans, business.industry, MESH: Parkinsonian Disorders, PARK7, Parkinson Disease, medicine.disease, LRRK2, 3. Good health, 030104 developmental biology, Neurology, MESH: REM Sleep Behavior Disorder, Human medicine, Neurology (clinical), business, Sleep, 030217 neurology & neurosurgery, MESH: Parkinson Disease
Abstract

International audience; Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

Published
2021
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32. GBA variants in REM sleep behavior disorder: a multicenter study

Author

Jennifer A. Ruskey, Friederike Sixel-Döring, David Kemlink, Michela Figorilli, Giuseppe Plazzi, Gian Luigi Gigli, Christelle Charley Monaca, Alberto J. Espay, Michele T.M. Hu, Monica Puligheddu, Bradley F. Boeve, Abril Beatriz, Lynne Krohn, Wolfgang H. Oertel, Yves Dauvilliers, Elena Antelmi, Marco Toffoli, Ziv Gan-Or, Uladzislau Rudakou, Mariarosaria Valente, Anna Heidbreder, Valérie Cochen De Cock, Etienne Leveille, Mineke Viaene, Ronald B. Postuma, Jean-François Gagnon, Jacques Montplaisir, Ambra Stefani, Claudia Trenkwalder, Birgit Högl, Guy A. Rouleau, Farnaz Asayesh, Luigi Ferini-Strambi, Karel Sonka, Isabelle Arnulf, Brit Mollenhauer, Alex Desautels, Femke Dijkstra, Krohn, L., Ruskey, J. A., Rudakou, U., Leveille, E., Asayesh, F., M. T. M., Hu, Arnulf, I., Dauvilliers, Y., Hogl, B., Stefani, A., Monaca, C. C., Abril, B., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Boeve, B. F., Espay, A. J., De Cock, V. C., Mollenhauer, B., Sixel-Doring, F., Trenkwalder, C., Sonka, K., Kemlink, D., Figorilli, M., Puligheddu, M., Dijkstra, F., Viaene, M., Oertel, W., Toffoli, M., Gigli, G. L., Valente, M., Gagnon, J. -F., Desautels, A., Montplaisir, J. Y., Postuma, R. B., Rouleau, G. A., Gan-Or, Z., McGill University = Université McGill [Montréal, Canada], McGill University Health Center [Montreal] (MUHC), Institut Interdisciplinaire d'Innovation Technologique [Sherbrooke] (3IT), Université de Sherbrooke (UdeS), Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), University of Bologna/Università di Bologna, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Mayo Clinic [Rochester], University of Cincinnati (UC), Euromov (EuroMov), Université de Montpellier (UM), University Medical Center Göttingen (UMG), Philipps Universität Marburg = Philipps University of Marburg, Charles University [Prague] (CU), First Faculty of Medicine Charles University [Prague], University of Cagliari, Università degli Studi di Udine - University of Udine [Italie], University of Alberta, Université de Montréal (UdeM), Hôpital du Sacré-Coeur de Montréal, National Institutes of Health [Bethesda] (NIH), Service de Pathologies du sommeil [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Retiveau, Nolwenn

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], REM Sleep Behavior Disorder, MESH: Glucosylceramidase, Gastroenterology, MESH: Neurodegenerative Diseases, Behavior disorder, 0302 clinical medicine, MESH: Genetic Variation, Age of Onset, MESH: Aged, Sanger sequencing, 0303 health sciences, MESH: Middle Aged, Genetic analysis, MESH: Genetic Predisposition to Disease, Neurodegenerative Diseases, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Disease Progression, symbols, Glucosylceramidase, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], GBA, Female, medicine.medical_specialty, MESH: Age of Onset, REM sleep behavior disorder, 03 medical and health sciences, symbols.namesake, Internal medicine, medicine, Humans, Dementia with Lewy Bodies, Genetic Predisposition to Disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, Aged, MESH: Humans, business.industry, Dementia with Lewy bodies, Parkinson’s disease, Genetic Variation, Odds ratio, medicine.disease, MESH: Male, Confidence interval, 030104 developmental biology, MESH: REM Sleep Behavior Disorder, Multicenter study, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery
Abstract

ObjectiveTo study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.MethodsA total of 4,147 individuals were included: 1,061 iRBD patients and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk for iRBD, age at onset (AAO) and conversion rates.ResultsGBA variants were found in 9.5% of iRBD patients compared to 4.1% in controls (odds ratio [OR]=2.45, 95% CI=1.87–3.22, p=1×10−10). The estimated OR for mild p.N370S variant carriers was 3.69, 95% CI=1.90–7.14, p=3.5×10−5, while for severe variant carriers it was 17.55, 95% CI=2.11–145.9, p=0.0015. Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or non-carriers (p=0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% in non-carriers (p=0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be taken with caution.ConclusionsGBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

Published
2019
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33. SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder

Author

Marco Toffoli, Uladzislau Rudakou, Anna Heidbreder, Michele T.M. Hu, Isabelle Arnulf, Lynne Krohn, Jean-François Gagnon, Femke Dijkstra, Yves Dauvilliers, Beatriz Abril, Elena Antelmi, Brit Mollenhauer, Annette Janzen, Naomi C. Futhey, Ambra Stefani, Jacques Montplaisir, W. H. Oertel, David Kemlink, Evi Holzknecht, Armaghan Alam, Paul Cannon, Luigi Ferini-Strambi, Guy A. Rouleau, Claudia Trenkwalder, Mineke Viaene, Karel Sonka, Birgit Högl, Christelle Charley Monaca, Ronald B. Postuma, Monica Puligheddu, Alex Desautels, Mariarosaria Valente, Bradley F. Boeve, Karl Heilbron, Valérie Cochen De Cock, Michela Figorilli, Friederike Sixel-Döring, Ziv Gan-Or, Gian Luigi Gigli, Jennifer A. Ruskey, Giuseppe Plazzi, Rudakou, U., Futhey, N. C., Krohn, L., Ruskey, J. A., Heilbron, K., Cannon, P., Alam, A., Arnulf, I., M. T. M., Hu, Montplaisir, J. Y., Gagnon, J. -F., Desautels, A., Dauvilliers, Y., Toffoli, M., Gigli, G. L., Valente, M., Hogl, B., Stefani, A., Holzknecht, E., Sonka, K., Kemlink, D., Oertel, W., Janzen, A., Plazzi, G., Antelmi, E., Figorilli, M., Puligheddu, M., Mollenhauer, B., Trenkwalder, C., Sixel-Doring, F., De Cock, V. C., Monaca, C. C., Heidbreder, A., Ferini-Strambi, L., Dijkstra, F., Viaene, M., Abril, B., Boeve, B. F., Postuma, R. B., Rouleau, G. A., Gan-Or, Z., Salvy-Córdoba, Nathalie, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], 23andMe Inc., Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Nuffield Department of Clinical Neurosciences [Oxford], University of Oxford, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Centre d'études avancées en Médecine du Sommeil (CEAMS), Université de Montréal (UdeM)-Hôpital du Sacré-Coeur de Montréal, Université du Québec à Montréal = University of Québec in Montréal (UQAM), Hôpital Gui de Chauliac [Montpellier], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Università degli Studi di Udine - University of Udine [Italie], UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, University of Udine and University Hospital of Udine, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), First Faculty of Medicine Charles University [Prague], Philipps Universität Marburg = Philipps University of Marburg, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Neurological Sciences of Bologna IRCCS, University of Cagliari, Paracelsus-Elena-Klinik, Kassel, Germany., department of neurology, clinical dementia center and DZNE, goettingen, Allemagne., Georg-August-University = Georg-August-Universität Göttingen, Department of Psychiatry and Psychotherapy, University Medical Center Goettingen (UMG), Göttingen, Clinique Beau Soleil [Montpellier], Euromov (EuroMov), Université de Montpellier (UM), CHU Lille, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Algemeen Ziekenhuis Sint-Dimpna, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Mayo Clinic [Rochester], Hôpital du Sacré-Coeur de Montréal, and Department of Human Genetics [Montréal]

Subjects
Male, 0301 basic medicine, Aging, REM sleep behavior disorder, Disease, Bioinformatics, European descent, Behavior disorder, 0302 clinical medicine, Medicine, MESH: Genetic Variation, MESH: High-Throughput Nucleotide Sequencing, MESH: Genetic Association Studies, education.field_of_study, General Neuroscience, sphingomyelin phosphodiesterase 1, High-Throughput Nucleotide Sequencing, MESH: Negative Results, MESH: Sleep Wake Disorders, Association study, Sphingomyelin Phosphodiesterase, Female, Sphingomyelin phosphodiesterase 1, Sleep Wake Disorders, Rapid eye movement sleep, Sleep, REM, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, association study, 03 medical and health sciences, Humans, education, Genetic Association Studies, MESH: Humans, business.industry, Dementia with Lewy bodies, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Genetic Variation, medicine.disease, MESH: Sleep, REM, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Sphingomyelin Phosphodiesterase, Neurology (clinical), Geriatrics and Gerontology, business, MESH: Female, Negative Results, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.

Published
2020
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39. Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.

Author

Sosero YL, Bandres-Ciga S, Ferwerda B, Tocino MTP, Belloso DR, Gómez-Garre P, Faouzi J, Taba P, Pavelka L, Marques TM, Gomes CPC, Kolodkin A, May P, Milanowski LM, Wszolek ZK, Uitti RJ, Heutink P, van Hilten JJ, Simon DK, Eberly S, Alvarez I, Krohn L, Yu E, Freeman K, Rudakou U, Ruskey JA, Asayesh F, Menéndez-Gonzàlez M, Pastor P, Ross OA, Krüger R, Corvol JC, Koks S, Mir P, De Bie RMA, Iwaki H, and Gan-Or Z

Subjects
Humans, Male, Female, Aged, Middle Aged, Dopamine metabolism, Antiparkinson Agents adverse effects, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide genetics, Levodopa adverse effects, Parkinson Disease genetics, Parkinson Disease drug therapy, Dyskinesia, Drug-Induced genetics, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics, Glucosylceramidase genetics, Genome-Wide Association Study
Abstract

Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2., Objectives: Our goal was to investigate the effects of genetic variants on risk and time to LID., Methods: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID., Results: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (OR fourth&#95;quartile  = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HR third&#95;quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HR fourth&#95;quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147)., Conclusions: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Published
2024
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40. Genome-wide association study of glucocerebrosidase activity modifiers.

Author

Somerville EN, Krohn L, Senkevich K, Yu E, Ahmad J, Asayesh F, Ruskey JA, Speigelman D, Fahn S, Waters C, Sardi SP, Alcalay RN, and Gan-Or Z

Abstract

One of the most common genetic risk factors for Parkinson's disease (PD) are variants in GBA1 , which encodes the lysosomal enzyme glucocerebrosidase (GCase). GCase deficiency has been associated with an increased PD risk, but not all individuals with low GCase activity are carriers of GBA1 mutations, suggesting other factors may be acting as modifiers. We aimed to discover common variants associated with GCase activity, as well as replicate previously reported associations, by performing a genome-wide association study using two independent cohorts: a Columbia University cohort consisting of 697 PD cases and 347 controls and the Parkinson's Progression Markers Initiative (PPMI) cohort consisting of 357 PD cases and 163 controls. As expected, GBA1 variants have the strongest association with decreased activity, led by p.N370S (beta = -4.36, se = 0.32, p = 5.05e-43). We also identify a novel association in the GAA locus (encoding for acid alpha-glucosidase, beta = -0.96, se = 0.17, p = 5.23e-09) that may be the result of an interaction between GCase and acid alpha-glucosidase based on various interaction analyses. Lastly, we show that several PD-risk loci are potentially associated with GCase activity. Further research will be needed to replicate and validate our findings and to uncover the functional connection between acid alpha-glucosidase and GCase., Competing Interests: 5.2Z.G.O received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua bio, Congruence Therapeutics, Takeda, Jazz Guidepoint, Lighthouse and Deerfield.

Published
2024
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41. Transcript-aware analysis of rare predicted loss-of-function variants in the UK Biobank elucidate new isoform-trait associations.

Author

Hoffing RA, Deaton AM, Holleman AM, Krohn L, LoGerfo PJ, Plekan ME, Akle Serrano S, Nioi P, and Ward LD

Subjects
Humans, Computational Biology, Phenotype, Protein Isoforms genetics, UK Biobank, Biological Specimen Banks
Abstract

A single gene can produce multiple transcripts with distinct molecular functions. Rare-variant association tests often aggregate all coding variants across individual genes, without accounting for the variants' presence or consequence in resulting transcript isoforms. To evaluate the utility of transcript-aware variant sets, rare predicted loss-of-function (pLOF) variants were aggregated for 17,035 protein-coding genes using 55,558 distinct transcript-specific variant sets. These sets were tested for their association with 728 circulating proteins and 188 quantitative phenotypes across 406,921 individuals in the UK Biobank. The transcript-specific approach resulted in larger estimated effects of pLOF variants decreasing serum cis-protein levels compared to the gene-based approach (pbinom ≤ 2x10-16). Additionally, 251 quantitative trait associations were identified as being significant using the transcript-specific approach but not the gene-based approach, including PCSK5 transcript ENST00000376752 and standing height (transcript-specific statistic, P = 1.3x10-16, effect = 0.7 SD decrease; gene-based statistic, P = 0.02, effect = 0.05 SD decrease) and LDLR transcript ENST00000252444 and apolipoprotein B (transcript-specific statistic, P = 5.7x10-20, effect = 1.0 SD increase; gene-based statistic, P = 3.0x10-4, effect = 0.2 SD increase). This approach demonstrates the importance of considering the effect of pLOFs on specific transcript isoforms when performing rare-variant association studies.

Published
2024

42. Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia.

Author

Sosero YL, Bandres-Ciga S, Ferwerda B, Tocino MTP, Belloso DR, Gómez-Garre P, Faouzi J, Taba P, Pavelka L, Marques TM, Gomes CPC, Kolodkin A, May P, Milanowski LM, Wszolek ZK, Uitti RJ, Heutink P, van Hilten JJ, Simon DK, Eberly S, Alvarez I, Krohn L, Yu E, Freeman K, Rudakou U, Ruskey JA, Asayesh F, Menéndez-Gonzàlez M, Pastor P, Ross OA, Krüger R, Corvol JC, Koks S, Mir P, De Bie RMA, Iwaki H, and Gan-Or Z

Abstract

Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2 ., Objectives: To investigate the effects of genetic variants on risk and time to LID., Methods: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1,612 PD patients with and 3,175 without LID., Results: We found that GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and LRRK2 variants with reduced time to LID onset (HR=1.42, 95% CI=1.09-1.84, p=0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (OR fourth&#95;quartile =1.27, 95% CI=1.03-1.56, p =0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HR third&#95;quartile =1.38, 95% CI=1.07-1.79, p =0.0128; HR fourth&#95;quartile =1.38, 95% CI=1.06-1.78, p =0.0147)., Conclusions: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care., Competing Interests: ZGO has received consulting fees from Lysosomal Therapeutics Inc., Idorsia, Prevail Therapeutics, Denali, Ono Therapeutics, Neuron23, Handl Therapeutics, UBC, Bial Biotech Inc., Bial, Deerfield, Guidepoint, Lighthouse and VanquaBio. None of these companies were involved in any parts of preparing, drafting and publishing this study. ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206) and Vigil Neuroscience, Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Cfthsf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company.

Published
2023
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43. HLA in isolated REM sleep behavior disorder and Lewy body dementia.

Author

Yu E, Krohn L, Ruskey JA, Asayesh F, Spiegelman D, Shah Z, Chia R, Arnulf I, Hu MTM, Montplaisir JY, Gagnon JF, Desautels A, Dauvilliers Y, Gigli GL, Valente M, Janes F, Bernardini A, Högl B, Stefani A, Ibrahim A, Heidbreder A, Sonka K, Dusek P, Kemlink D, Oertel W, Janzen A, Plazzi G, Antelmi E, Figorilli M, Puligheddu M, Mollenhauer B, Trenkwalder C, Sixel-Döring F, Cochen De Cock V, Ferini-Strambi L, Dijkstra F, Viaene M, Abril B, Boeve BF, Rouleau GA, Postuma RB, Scholz SW, and Gan-Or Z

Subjects
Humans, HLA-DRB1 Chains genetics, HLA Antigens, Lewy Body Disease genetics, REM Sleep Behavior Disorder genetics, REM Sleep Behavior Disorder complications, Synucleinopathies genetics
Abstract

Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27-1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95%CI = 1.12-1.41, p = 8.76e-05), 70Q (OR = 0.81, 95%CI = 0.72-0.91, p = 3.65e-04) and 71R (OR = 1.21, 95%CI = 1.08-1.35, p = 1.35e-03). Position 71 (p omnibus  = 0.00102) and 70 (p omnibus  = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Published
2023
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44. Maximal and Explosive Muscle Strength During Hip Adduction Squeeze and Hip Abduction Press Test Using A Handheld Dynamometer: An Intra- and Inter-tester Reliability Study.

Author

Ishøi L, Thorborg K, Krohn L, Louis Andersen L, Møller Nielsen A, and Bek Clausen M

Abstract

Background: Hip adduction and abduction muscle function plays an important role for risk of groin pain in athletes. Maximal isometric strength can be obtained clinically using a handheld dynamometer. However, in very strong athletes this is challenging, as external fixation of the dynamometer is needed for reliable measures. An alternative to unilateral testing, is the long-lever hip adduction squeeze test and a novel bilateral hip abduction press test. While promising intra-tester reliability has been found for maximal strength during the long-lever hip adduction squeeze test, inter-tester reliability may be more challenging during both maximal and explosive strength measurements., Hypothesis/purpose: The aim of the present study was to assess intra- and inter-tester reliability of maximal, and explosive strength during the long lever hip adduction squeeze test and the long lever hip abduction press test in healthy adults using a hand-held dynamometer., Study Design: Intra- and interrater reliability study., Methods: Forty-nine healthy subjects were included for intra- (n=20) and inter-tester reliability (n=29). Subjects performed the hip adduction long lever squeeze test and the bilateral hip abduction press test in a randomized order. Maximal isometric strength and early (0-100 ms) and late (0-200 ms) phase rate of force development (explosive muscle strength) was obtained using a hand-held dynamometer. Relative reliability for all tests was assessed using ICC 2,1 two-way mixed model with absolute agreement, thereby taking bias between testers into account., Results: Maximal isometric strength showed good intra- and inter-tester reliability for adduction (ICC: 0.93-0.97) and abduction (ICC: 0.88-0.92). For 0-200 ms rate of force development, both the squeeze and press test showed good intra-tester reliability (ICC: 0.85-0.87), whereas inter-tester reliability was good for hip adduction squeeze (ICC: 0.75) and moderate for hip abduction press (ICC: 0.71). For 0-100 ms rate of force development, the hip abduction press test showed good intra-tester reliability (ICC: 0.78). Remaining tests for intra- and inter-tester reliability showed moderate reliability (ICC: 0.50-0.71)., Conclusion: Assessment of maximal isometric strength in hip adduction squeeze and abduction press test showed good intra- and inter-tester reliability, whereas only 0-200 ms rate of force development demonstrated good intra-tester reliability of both tests. Therefore, rate of force development should preferably be conducted by the same tester, while the long lever squeeze and press test can reliably be used within- and between testers to measure maximal isometric strength., Level of Evidence: 3©The Author(s)., Competing Interests: The authors report no conflicts of interest.

Published
2023
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45. NPC1 variants are not associated with Parkinson's disease, REM-sleep behavior disorder or dementia with Lewy bodies in European cohorts.

Author

Somerville EN, Krohn L, Yu E, Rudakou U, Senkevich K, Ruskey JA, Asayesh F, Ahmad J, Spiegelman D, Dauvilliers Y, Arnulf I, Hu MTM, Montplaisir JY, Gagnon JF, Desautels A, Ibrahim A, Stefani A, Högl B, Gigli GL, Valente M, Janes F, Bernardini A, Dusek P, Sonka K, Kemlink D, Plazzi G, Antelmi E, Biscarini F, Mollenhauer B, Trenkwalder C, Sixel-Doring F, Figorilli M, Puligheddu M, De Cock VC, Oertel W, Janzen A, Ferini-Strambi L, Heibreder A, Monaca CC, Abril B, Dijkstra F, Viaene M, Boeve BF, Postuma RB, Rouleau GA, and Gan-Or Z

Subjects
Humans, Sleep, Niemann-Pick C1 Protein, Parkinson Disease genetics, Synucleinopathies, Lewy Body Disease genetics, REM Sleep Behavior Disorder genetics
Abstract

NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinson's disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement-sleep behavior disorder (RBD). We analyzed common and rare variants from 3 cohorts of European descent: 1084 RBD cases and 2945 controls, 2852 PD cases and 1686 controls, and 2610 DLB cases and 1920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rare NPC1 variants do not play an important role in alpha synucleinopathies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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46. Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins.

Author

DeForest N, Kavitha B, Hu S, Isaac R, Krohn L, Wang M, Du X, De Arruda Saldanha C, Gylys J, Merli E, Abagyan R, Najmi L, Mohan V, Flannick J, Peloso GM, Gordts PLSM, Heinz S, Deaton AM, Khera AV, Olefsky J, Radha V, and Majithia AR

Abstract

Loss-of-function mutations in hepatocyte nuclear factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare, protein-coding HNF1A variant, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found that ∼1:5 rare protein-coding HNF1A variants in the general population cause molecular gain of function (GOF), increasing the transcriptional activity of HNF1A by up to 50% and conferring protection from type 2 diabetes (odds ratio [OR] = 0.77, p = 0.007). Increased hepatic expression of HNF1A promoted a pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including ANGPTL3 and PCSK9 . In summary, ∼1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of atherogenic lipoproteins., Competing Interests: A.M.D. and L.K. are employees and shareholders of Alnylam Pharmaceuticals.

Published
2023
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47. Genome-wide association study stratified by MAPT haplotypes identifies potential novel loci in Parkinson's disease.

Author

Senkevich K, Bandres-Ciga S, Cisterna-García A, Yu E, Bustos BI, Krohn L, Lubbe SJ, Botía JA, and Gan-Or Z

Abstract

Objective: To identify genetic factors that may modify the effects of the MAPT locus in Parkinson's disease (PD)., Methods: We used data from the International Parkinson's Disease Genomics Consortium (IPDGC) and the UK biobank (UKBB). We stratified the IPDGC cohort for carriers of the H1/H1 genotype (PD patients n=8,492 and controls n=6,765) and carriers of the H2 haplotype (with either H1/H2 or H2/H2 genotypes, patients n=4,779 and controls n=4,849) to perform genome-wide association studies (GWASs). Then, we performed replication analyses in the UKBB data. To study the association of rare variants in the new nominated genes, we performed burden analyses in two cohorts (Accelerating Medicines Partnership - Parkinson Disease and UKBB) with a total sample size PD patients n=2,943 and controls n=18,486., Results: We identified a novel locus associated with PD among MAPT H1/H1 carriers near EMP1 (rs56312722, OR=0.88, 95%CI= 0.84-0.92, p= 1.80E-08), and a novel locus associated with PD among MAPT H2 carriers near VANGL1 (rs11590278, OR=1.69 95%CI=1.40-2.03, p=2.72E-08). Similar analysis of the UKBB data did not replicate these results and rs11590278 near VANGL1 did have similar effect size and direction in carriers of H2 haplotype, albeit not statistically significant (OR= 1.32, 95%CI= 0.94-1.86, p=0.17). Rare EMP1 variants with high CADD scores were associated with PD in the MAPT H2 stratified analysis (p=9.46E-05), mainly driven by the p.V11G variant., Interpretation: We identified several loci potentially associated with PD stratified by MAPT haplotype and larger replication studies are required to confirm these associations., Competing Interests: Financial Disclosure Authors have nothing to report.

Published
2023
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48. Gene-based burden analysis of damaging private variants in PRKN, PARK7 and PINK1 in Parkinson's disease cohorts of European descent.

Author

Hu J, Waters CH, Spiegelman D, Fon EA, Yu E, Asayesh F, Krohn L, Saini P, Alcalay RN, Hassin-Baer S, Gan-Or Z, Krainc D, Zhang B, Bustos BI, and Lubbe SJ

Subjects
Humans, Age of Onset, Genetic Testing, Mutation, Parkinson Disease genetics, Parkinson Disease epidemiology, Protein Deglycase DJ-1 genetics, Protein Kinases genetics, Ubiquitin-Protein Ligases genetics
Abstract

Recessive mutations in PRKN, PARK7, and PINK1 are established causes of early-onset Parkinson's disease (EOPD). Previous studies have interrogated the role of heterozygous variants in these genes but mainly focused on rare (minor allele frequency [MAF] &lt;1%) damaging variants or established mutations. Here, we assessed heterozygous private PRKN, PARK7 and PINK1 variants in PD risk in four large-scale PD case-control datasets by performing gene-wise burden analyses using sequencing data totaling 5,829 PD cases and 7,221 controls, and summary allele counts from 9,501 PD cases and 48,207 controls. Results showed no significant burden in all three genes after meta-analyses. Burden in EOPD (age at onset &lt;50 years) and late-onset PD (≥50 years) remained nonsignificant. In summary, we found no evidence to support the association of the excess burden of heterozygous private variants in PRKN, PARK7, and PINK1 with PD risk in the European population. Larger, more diverse cohorts are needed to accurately determine their role in PD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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49. Rapid eye movement sleep behaviour disorder: Past, present, and future.

Author

Högl B, Arnulf I, Bergmann M, Cesari M, Gan-Or Z, Heidbreder A, Iranzo A, Krohn L, Luppi PH, Mollenhauer B, Provini F, Santamaria J, Trenkwalder C, Videnovic A, and Stefani A

Subjects
Humans, Polysomnography, Sleep, REM physiology, REM Sleep Behavior Disorder diagnosis
Abstract

This manuscript presents an overview of REM sleep behaviour disorder (RBD) with a special focus on European contributions. After an introduction examining the history of the disorder, we address the pathophysiological and clinical aspects, as well as the diagnostic issues. Further, implications of RBD diagnosis and biomarkers are discussed. Contributions of European researchers to this field are highlighted., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Published
2022
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50. Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder.

Author

Sosero YL, Yu E, Estiar MA, Krohn L, Mufti K, Rudakou U, Ruskey JA, Asayesh F, Laurent SB, Spiegelman D, Trempe JF, Quinnell TG, Oscroft N, Arnulf I, Montplaisir JY, Gagnon JF, Desautels A, Dauvilliers Y, Gigli GL, Valente M, Janes F, Bernardini A, Sonka K, Kemlink D, Oertel W, Janzen A, Plazzi G, Antelmi E, Biscarini F, Figorilli M, Puligheddu M, Mollenhauer B, Trenkwalder C, Sixel-Döring F, Cochen De Cock V, Monaca CC, Heidbreder A, Ferini-Strambi L, Dijkstra F, Viaene M, Abril B, Boeve BF, Postuma RB, Rouleau GA, Ibrahim A, Stefani A, Högl B, Hu MTM, and Gan-Or Z

Subjects
Glucosylceramidase genetics, Humans, Parkinson Disease complications, REM Sleep Behavior Disorder diagnosis, Saposins genetics, Synucleinopathies
Abstract

Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy., Objective: To examine the role of PSAP mutations in iRBD., Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018)., Results: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332&#95;333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332&#95;333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more., Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

Published
2022
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