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1. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

Author

Chia, Ruth, Sabir, Marya S, Bandres-Ciga, Sara, Saez-Atienzar, Sara, Reynolds, Regina H, Gustavsson, Emil, Walton, Ronald L, Ahmed, Sarah, Viollet, Coralie, Ding, Jinhui, Makarious, Mary B, Diez-Fairen, Monica, Portley, Makayla K, Shah, Zalak, Abramzon, Yevgeniya, Hernandez, Dena G, Blauwendraat, Cornelis, Stone, David J, Eicher, John, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S, Marder, Karen, Lemstra, Afina, St George-Hyslop, Peter, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T, Jaunmuktane, Zane, Galasko, Douglas, Santana, Isabel, Tienari, Pentti J, Myllykangas, Liisa, Oinas, Minna, Cairns, Nigel J, Morris, John C, Halliday, Glenda M, Van Deerlin, Vivianna M, Trojanowski, John Q, Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C, Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T, Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David S, Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Kaufmann, Horacio, Shakkottai, Vikram G, Perkins, Matthew, Newell, Kathy L, Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Kim, Ronald C, Caraway, Chad A, Monuki, Edwin S, Brunetti, Maura, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Flanagan, Margaret E, Mao, Qinwen, Bigio, Eileen H, Rodríguez-Rodríguez, Eloy, Infante, Jon, Lage, Carmen, González-Aramburu, Isabel, Sanchez-Juan, Pascual, Ghetti, Bernardino, Keith, Julia, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J, Tilley, Bension S, Gentleman, Steve, Logroscino, Giancarlo, and Serrano, Geidy E

Subjects
Biological Sciences, Genetics, Human Genome, Alzheimer's Disease Related Dementias (ADRD), Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Aging, Dementia, Brain Disorders, Acquired Cognitive Impairment, Lewy Body Dementia, Biotechnology, Parkinson's Disease, Neurosciences, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Glucosylceramidase, Humans, Lewy Body Disease, Nuclear Proteins, Parkinson Disease, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins, alpha-Synuclein, American Genome Center, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Published
2021

2. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

Author

Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, and Van Broeckhoven, Christine

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Rare Diseases, Acquired Cognitive Impairment, Alzheimer's Disease Related Dementias (ADRD), Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Frontotemporal Dementia (FTD), Genetics, Clinical Research, Dementia, Neurological, Age of Onset, Aged, Aged, 80 and over, Aphasia, Primary Progressive, C9orf72 Protein, Cohort Studies, DNA Repeat Expansion, Europe, Female, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, Geography, Humans, Male, Mediterranean Region, Middle Aged, Principal Component Analysis, Scandinavian and Nordic Countries, Syndrome, International FTD-Genetics Consortium, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.ResultsWe found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.ConclusionsOur results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

Published
2020

3. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Aging, Parkinson's Disease, Genetics, 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences
Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

4. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Author

Nalls, Mike A, Blauwendraat, Cornelis, Vallerga, Costanza L, Heilbron, Karl, Bandres-Ciga, Sara, Chang, Diana, Tan, Manuela, Kia, Demis A, Noyce, Alastair J, Xue, Angli, Bras, Jose, Young, Emily, von Coelln, Rainer, Simón-Sánchez, Javier, Schulte, Claudia, Sharma, Manu, Krohn, Lynne, Pihlstrøm, Lasse, Siitonen, Ari, Iwaki, Hirotaka, Leonard, Hampton, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Scholz, Sonja W, Botia, Juan A, Martinez, Maria, Corvol, Jean-Christophe, Lesage, Suzanne, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Majamaa, Kari, Toft, Mathias, Andreassen, Ole A, Bangale, Tushar, Brice, Alexis, Yang, Jian, Gan-Or, Ziv, Gasser, Thomas, Heutink, Peter, Shulman, Joshua M, Wood, Nicholas W, Hinds, David A, Hardy, John A, Morris, Huw R, Gratten, Jacob, Visscher, Peter M, Graham, Robert R, Singleton, Andrew B, Team, 23andMe Research, Consortium, System Genomics of Parkinson's Disease, Consortium, International Parkinson's Disease Genomics, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Brockmann, Kathrin, Bubb, Vivien, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Chelban, Viorica, Clarimón, Jordi, Clarke, Carl, Compta, Yaroslau, Cookson, Mark R, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, and Finkbeiner, Steven

Subjects
Neurosciences, Parkinson's Disease, Brain Disorders, Aging, Biotechnology, Prevention, Genetics, Human Genome, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Databases, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Parkinson Disease, Risk Factors, 23andMe Research Team, System Genomics of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundGenome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease.MethodsWe did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.FindingsBetween Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10-7).InterpretationThese data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.FundingThe National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).

Published
2019

5. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO (Dementia Genetics Spanish Consortium), EADB, EADB, IFGC (International FTD-Genomics Consortium), IPDGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Alzheimer’s disease, Amyotrophic lateral sclerosis, Dementia with Lewy bodies, Frontotemporal dementia, Longevity, Multiple sclerosis, Neurodegenerative disease, PLCG2, Parkinson’s disease, Phospholipase C Gamma 2, Progressive supranuclear palsy, Alzheimer's disease, Parkinson's disease, Alzheimer's Disease, frontotemporal dementia, dementia with Lewy-bodies, progressive suprauclear palsy, Parkinson's Disease, amyotrophic lateral sclerosis, multiple sclerosis, neurodegenerative disease, longevity, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019

6. The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

Author

Bandres‐Ciga, Sara, Saez‐Atienzar, Sara, Bonet‐Ponce, Luis, Billingsley, Kimberley, Vitale, Dan, Blauwendraat, Cornelis, Gibbs, Jesse Raphael, Pihlstrøm, Lasse, Gan‐Or, Ziv, Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun‐Favreau, Helene, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Bras, Jose, Quinn, John, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, RņBibo, Lea, Manzoni, Claudia, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott‐Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean‐Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, SimɃn‐Sȥnchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R, Craig, David W, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Van Keuren‐Jensen, Kendall, Shulman, Joshua M, Iwaki, Hirotaka, Leonard, Hampton L, Nalls, Mike A, Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Alcalay, Roy N, Rouleau, Guy A, Hilten, Jacobus J, Marinus, Johan, Adarmes‐GɃmez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesɐs Alberto Bergareche, Bernal‐Bernal, Inmaculada, Blazquez, Marta, Bonilla‐Toribio, Marta, Botȷa, Juan A, Boungiorno, Marȷa Teresa, Buiza‐Rueda, Dolores, Cȥmara, Ana, Carrillo, Fȥtima, CarriɃn‐Claro, Mario, Cerdan, Debora, ClarimɃn, Jordi, Compta, Yaroslau, Casa, Beatrȷz, Diez‐Fairen, Monica, Dols‐Icardo, Oriol, and Duarte, Jacinto

Subjects
Parkinson's Disease, Human Genome, Genetics, Neurosciences, Brain Disorders, Prevention, Neurodegenerative, Genetic Testing, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Aetiology, Decent Work and Economic Growth, Endocytosis, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Parkinson Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, International Parkinson's Disease Genomics Consortium, Parkinson's disease, endocytosis, genetic risk, heritability, polygenic risk score, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundPD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed.ObjectivesTo comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD.MethodsLinkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci.ResultsThe heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk.ConclusionsWe provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

7. Smoking is associated with age at disease onset in Parkinson's disease

Author

Adarmes-Gómez, Astrid D., Aguilar, Miquel, Alvarez, Ignacio, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María Teresa, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, Monica, Dols-Icardo, Oriol, de Fabregues, Oriol, Cartagena, Pilar Sanz, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández-Santiago, Rubén, Fernández, Manel, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria Jose, Gonzalez-Aramburu, Isabel, Gorostidi, Ana, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose Luis, López de Munain, Adolfo, Macias-Garcia, Daniel, Martínez-Torres, Irene, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Álvarez-Santullano, Marina Mata, Mínguez-Castellanos, Adolfo, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Periñán, Maria Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Tabernero, Cesar, Tartari, Juan Pablo, Tolosa, Eduard, Valldeoriola, Francesc, Vela, Lydia, Vives, Francisco, Pascual-Sedano, Berta, Hernández-Vara, Jorge, Rolán, Dolores Vilas, Bandrés-Ciga, Sara, Rosas, Irene, Morís, Germán, Coto, Eliecer, Blázquez-Estrada, Marta, Suárez, Esther, García-Fernández, Ciara, Martínez, Carmen, Herrera, Israel Duarte, Pérez-Oliveira, Sergio, Álvarez, Victoria, and Menéndez-González, Manuel

Published
2022
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8. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

Author

Zhang, Ming, Ferrari, Raffaele, Tartaglia, Maria Carmela, Keith, Julia, Surace, Ezequiel I, Wolf, Uri, Sato, Christine, Grinberg, Mark, Liang, Yan, Xi, Zhengrui, Dupont, Kyle, McGoldrick, Philip, Weichert, Anna, McKeever, Paul M, Schneider, Raphael, McCorkindale, Michael D, Manzoni, Claudia, Rademakers, Rosa, Graff-Radford, Neill R, Dickson, Dennis W, Parisi, Joseph E, Boeve, Bradley F, Petersen, Ronald C, Miller, Bruce L, Seeley, William W, van Swieten, John C, van Rooij, Jeroen, Pijnenburg, Yolande, van der Zee, Julie, Van Broeckhoven, Christine, Le Ber, Isabelle, Van Deerlin, Vivianna, Suh, EunRan, Rohrer, Jonathan D, Mead, Simon, Graff, Caroline, Öijerstedt, Linn, Pickering-Brown, Stuart, Rollinson, Sara, Rossi, Giacomina, Tagliavini, Fabrizio, Brooks, William S, Dobson-Stone, Carol, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Binetti, Giuliano, Benussi, Luisa, Ghidoni, Roberta, Nacmias, Benedetta, Sorbi, Sandro, Bruni, Amalia C, Galimberti, Daniela, Scarpini, Elio, Rainero, Innocenzo, Rubino, Elisa, Clarimon, Jordi, Lleó, Alberto, Ruiz, Agustin, Hernández, Isabel, Pastor, Pau, Diez-Fairen, Monica, Borroni, Barbara, Pasquier, Florence, Deramecourt, Vincent, Lebouvier, Thibaud, Perneczky, Robert, Diehl-Schmid, Janine, Grafman, Jordan, Huey, Edward D, Mayeux, Richard, Nalls, Michael A, Hernandez, Dena, Singleton, Andrew, Momeni, Parastoo, Zeng, Zhen, Hardy, John, Robertson, Janice, Zinman, Lorne, Rogaeva, Ekaterina, and International FTD-Genomics Consortium (IFGC)

Subjects
International FTD-Genomics Consortium, Humans, Amyotrophic Lateral Sclerosis, Age of Onset, DNA Methylation, Gene Expression Regulation, CpG Islands, Genotype, Heterozygote, Polymorphism, Single Nucleotide, Aged, Middle Aged, Female, Male, Frontotemporal Dementia, C9orf72 Protein, C9orf72, genetic association, age of onset, amyotrophic lateral sclerosis, frontotemporal dementia, Polymorphism, Single Nucleotide, Neurology & Neurosurgery, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Published
2018

9. Exome-wide rare variant analysis in familial essential tremor

Author

Diez-Fairen, Monica, Houle, Gabrielle, Ortega-Cubero, Sara, Bandres-Ciga, Sara, Alvarez, Ignacio, Carcel, Maria, Ibañez, Laura, Fernandez, Maria Victoria, Budde, John P., Trotta, Jean-Rémi, Tonda, Raúl, Chong, Jessica X., Bamshad, Michael J., Nickerson, Deborah A., Aguilar, Miquel, Tartari, Juan P., Gironell, Alexandre, García-Martín, Elena, Agundez, Jose AG., Alonso-Navarro, Hortensia, Jimenez-Jimenez, Felix Javier, Fernandez, Manel, Valldeoriola, Francesc, Marti, Maria Jose, Tolosa, Eduard, Coria, Francisco, Pastor, Maria A., Vilariño-Güell, Carles, Rajput, Alex, Dion, Patrick A., Cruchaga, Carlos, Rouleau, Guy A., and Pastor, Pau

Published
2021
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11. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Author

Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Bandres-Ciga, Sara, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blauwendraat, Cornelis, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Bras, Jose, Brice, Alexis, Brockmann, Kathrin, Bubb, Vivien, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Chelban, Viorica, Clarimón, Jordi, Clarke, Carl, Compta, Yaroslau, Cookson, Mark R, Corvol, Jean-Christophe, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Faghri, Faraz, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Finkbeiner, Steven, Foltynie, Thomas, Gan-Or, Ziv, Garcia, Ciara, García-Ruiz, Pedro, Gasser, Thomas, Gibbs, J Raphael, Gomez Heredia, Maria Jose, Gómez-Garre, Pilar, González, Manuel Menéndez, Gonzalez-Aramburu, Isabel, Guelfi, Sebastian, Guerreiro, Rita, Hardy, John, Hassin-Baer, Sharon, Hernandez, Dena G, Heutink, Peter, Hoenicka, Janet, Holmans, Peter, Houlden, Henry, Infante, Jon, Iwaki, Hirotaka, Jesús, Silvia, Jimenez-Escrig, Adriano, Kaishybayeva, Gulnaz, Kaiyrzhanov, Rauan, Karimova, Altynay, Kia, Demis A, Kinghorn, Kerri J, Koks, Sulev, Krohn, Lynne, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Leonard, Hampton L, Lesage, Suzanne, Lewis, Patrick, Lopez-Sendon, Jose Luis, Lovering, Ruth, Lubbe, Steven, Lungu, Codrin, Macias, Daniel, Majamaa, Kari, Manzoni, Claudia, Marín, Juan, Marinus, Johan, Marti, Maria Jose, Martinez, Maria, Martínez Torres, Irene, Martínez-Castrillo, Juan Carlos, Mata, Marina, Mencacci, Niccolo E, Méndez-del-Barrio, Carlota, Middlehurst, Ben, Mínguez, Adolfo, Mir, Pablo, Mok, Kin Y, Morris, Huw R, Muñoz, Esteban, Nalls, Mike A, Narendra, Derek, Noyce, Alastair J, Ojo, Oluwadamilola O, Okubadejo, Njideka U, Pagola, Ana Gorostidi, Pastor, Pau, Perez Errazquin, Francisco, Periñán-Tocino, Teresa, Pihlstrom, Lasse, Plun-Favreau, Helene, Quinn, John, R'Bibo, Lea, Reed, Xylena, Rezola, Elisabet Mondragon, Rizig, Mie, Rizzu, Patrizia, Robak, Laurie, Rodriguez, Antonio Sanchez, Rouleau, Guy A, Ruiz-Martínez, Javier, Ruz, Clara, Ryten, Mina, Sadykova, Dinara, Scholz, Sonja W, Schreglmann, Sebastian, Schulte, Claudia, Sharma, Manu, Shashkin, Chingiz, Shulman, Joshua M, Sierra, María, Siitonen, Ari, Simón-Sánchez, Javier, Singleton, Andrew B, Suarez-Sanmartin, Esther, Taba, Pille, Tabernero, Cesar, Tan, Manuela X, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Toft, Mathias, Tolosa, Eduard, Trabzuni, Daniah, Valldeoriola, Francesc, van Hilten, Jacobus J, Van Keuren-Jensen, Kendall, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Williams, Nigel, Wood, Nicholas W, Zharkinbekova, Nazira, Zharmukhanov, Zharkyn, Zholdybayeva, Elena, Zimprich, Alexander, Ylikotila, Pauli, Shulman, Lisa M., von Coelln, Rainer, Reich, Stephen, Savitt, Joseph, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Huber, Karen E., Hicks, Barry, Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., McCreight, Jennifer C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A.M., Pitts, Steven J., Poznik, G. David, Sathirapongsasuti, J. Fah, Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce, Vacic, Vladimir, Wang, Xin, Wilson, Catherine H., Anderson, Tim, Bentley, Steven, Dalrymple-Alford, John, Fowdar, Javed, Gratten, Jacob, Halliday, Glenda, Henders, Anjali K., Hickie, Ian, Kassam, Irfahan, Kennedy, Martin, Kwok, John, Lewis, Simon, Mellick, George, Montgomery, Grant, Pearson, John, Pitcher, Toni, Sidorenko, Julia, Silburn, Peter A., Vallerga, Costanza L., Visscher, Peter M., Wallace, Leanne, Wray, Naomi R., Xue, Angli, Yang, Jian, Zhang, Futao, Vallerga, Costanza L, Heilbron, Karl, Chang, Diana, Tan, Manuela, Young, Emily, Pihlstrøm, Lasse, Leonard, Hampton, Botia, Juan A, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Andreassen, Ole A, Bangale, Tushar, Hinds, David A, Hardy, John A, Visscher, Peter M, and Graham, Robert R

Published
2019
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13. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Author

Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, Elbaz, Ales, JPND Courage-PD [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center]

Subjects
Male, Lung Neoplasms, Parkinson's disease, Neurology [D14] [Human health sciences], RESEARCH ARTICLES, RESEARCH ARTICLE, SDG 3 - Good Health and Well-being, genetics [Parkinson Disease], Risk Factors, pleiotropy, Humans, cancer, ddc:610, genetics [Genetic Predisposition to Disease], Ovarian Neoplasms, Neurologie [D14] [Sciences de la santé humaine], Prostatic Neoplasms, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], genetic correlation, parkinson's disease, polygenic risk score, epidemiology [Melanoma], Neurology, genetics [Melanoma], genetics [Polymorphism, Single Nucleotide], Female, epidemiology [Parkinson Disease], Genetics & genetic processes [F10] [Life sciences], Neurology (clinical), Génétique & processus génétiques [F10] [Sciences du vivant], Genome-Wide Association Study
Abstract

BackgroundEpidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties.ObjectiveWe used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors.MethodsWe used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses.ResultsWe confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31).ConclusionsWe show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Published
2023

14. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Author

Guerreiro, Rita, Ross, Owen A, Kun-Rodrigues, Celia, Hernandez, Dena G, Orme, Tatiana, Eicher, John D, Shepherd, Claire E, Parkkinen, Laura, Darwent, Lee, Heckman, Michael G, Scholz, Sonja W, Troncoso, Juan C, Pletnikova, Olga, Ansorge, Olaf, Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Clark, Lorraine, Honig, Lawrence S, Marder, Karen, Lemstra, Afina, Rogaeva, Ekaterina, St George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda, Braae, Anne, Brown, Kristelle, Morgan, Kevin, Troakes, Claire, Al-Sarraj, Safa, Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Serrano, Geidy E, Beach, Thomas G, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Pastor, Pau, Diez-Fairen, Monica, Aguilar, Miquel, Tienari, Pentti J, Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Brad F, Petersen, Ronald C, Ferman, Tanis J, Escott-Price, Valentina, Graff-Radford, Neill, Cairns, Nigel J, Morris, John C, Pickering-Brown, Stuart, Mann, David, Halliday, Glenda M, Hardy, John, Trojanowski, John Q, Dickson, Dennis W, Singleton, Andrew, Stone, David J, and Bras, Jose

Published
2018
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15. C9orf72, AAO and ancestry help discriminating behavioural from language variants in FTLD cohorts

Author

Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, Van Broeckhoven, Christine, van Rooij, Jeroen, Van Swieten, John C, Veronesi, Arianna, Vitale, Emilia, Waldö, Maria L, Woodward, Cathy, Yokoyama, Jennifer, Escott-Price, Valentina, Polke, James M, and Ferrari, Raffaele

Published
2020
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16. Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease

Author

Ibanez, Laura, Bahena, Jorge A., Yang, Chengran, Dube, Umber, Farias, Fabiana H. G., Budde, John P., Bergmann, Kristy, Brenner-Webster, Carol, Morris, John C., Perrin, Richard J., Cairns, Nigel J., O’Donnell, John, Álvarez, Ignacio, Diez-Fairen, Monica, Aguilar, Miquel, Miller, Rebecca, Davis, Albert A., Pastor, Pau, Kotzbauer, Paul, Campbell, Meghan C., Perlmutter, Joel S., Rhinn, Herve, Harari, Oscar, Cruchaga, Carlos, and Benitez, Bruno A.

Published
2020
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18. Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia

Author

Rosas, Irene, Martínez, Carmen, Coto, Eliecer, Clarimón, Jordi, Lleó, Alberto, Illán-Gala, Ignacio, Dols-Icardo, Oriol, Borroni, Barbara, Almeida, Maria Rosário, van der Zee, Julie, Van Broeckhoven, Christine, Bruni, Amalia C., Anfossi, Maria, Bernardi, Livia, Maletta, Raffaele, Serpente, María, Galimberti, Daniela, Scarpini, Elio, Rossi, Giacomina, Caroppo, Paola, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Nacmias, Benedetta, Sorbi, Sandro, Piaceri, Irene, Bagnoli, Silvia, Antonell, Anna, Sánchez-Valle, Raquel, De la Casa-Fages, Beatriz, Grandas, Francisco, Diez-Fairen, Mónica, Pastor, Pau, Ferrari, Raffaele, Queimaliños-Perez, Daniel, Pérez-Oliveira, Sergio, Álvarez, Victoria, and Menéndez-González, Manuel

Published
2021
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19. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND Courage-PD [sponsor], Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, Elbaz, Ales, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], JPND Courage-PD [sponsor], Sugier, Pierre-Emmanuel, Lucotte, Elise A., Domenighetti, Cloé, Law, Matthew H., Iles, Mark M., Brown, Kevin, Amos, Christopher, McKay, James D., Hung, Rayjean J., Karimi, Mojgan, Bacq-Daian, Delphine, Boland-Augé, Anne, Olaso, Robert, Deleuze, Jean-François, Lesueur, Fabienne, Ostroumova, Evgenia, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, consortium, The Epithyr, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimios, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy, Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Rödström, Emil Ygland, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Landoulsi, Zied, consortium, Courage-PD, Truong, Thérèse, and Elbaz, Ales

Abstract

Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly dri

Published
2023

20. Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease

Author

Rosas, Irene, Martínez, Carmen, Clarimón, Jordi, Lleó, Alberto, Illán-Gala, Ignacio, Dols-Icardo, Oriol, Borroni, Barbara, Almeida, Maria Rosário, van der Zee, Julie, Van Broeckhoven, Christine, Bruni, Amalia C., Anfossi, Maria, Bernardi, Livia, Maletta, Raffaele, Serpente, María, Galimberti, Daniela, Scarpini, Elio, Rossi, Giacomina, Caroppo, Paola, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Nacmias, Benedetta, Sorbi, Sandro, Piaceri, Irene, Bagnoli, Silvia, Antonell, Anna, Sánchez-Valle, Raquel, De la Casa-Fages, Beatriz, Grandas, Francisco, Diez-Fairen, Mónica, Pastor, Pau, Ferrari, Raffaele, Álvarez, Victoria, and Menéndez-González, Manuel

Published
2020
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21. Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Author

García-González, Pablo, primary, de Rojas, Itziar, additional, Moreno-Grau, Sonia, additional, Montrreal, Laura, additional, Puerta, Raquel, additional, Alarcón-Martín, Emilio, additional, Quintela, Inés, additional, Orellana, Adela, additional, Andrade, Victor, additional, Adami, Pamela V. Martino, additional, Heilmann-Heimbach, Stefanie, additional, Gomez-Garre, Pilar, additional, Periñán, María Teresa, additional, Alvarez, Ignacio, additional, Diez-Fairen, Monica, additional, Nuñez Llaves, Raul, additional, Olivé Roig, Claudia, additional, Garcia-Ribas, Guillermo, additional, Menéndez-González, Manuel, additional, Martínez, Carmen, additional, Aguilar, Miquel, additional, Buongiorno, Mariateresa, additional, Franco-Macías, Emilio, additional, Saez, Maria Eugenia, additional, Cano, Amanda, additional, Bullido, Maria J., additional, Real, Luis Miguel, additional, Rodríguez-Rodríguez, Eloy, additional, Royo, Jose Luís, additional, Álvarez, Victoria, additional, Pastor, Pau, additional, Piñol-Ripoll, Gerard, additional, Mir, Pablo, additional, Lara, Miguel Calero, additional, Padilla, Miguel Medina, additional, Sánchez-Juan, Pascual, additional, Carracedo, Angel, additional, Valero, Sergi, additional, Hernandez, Isabel, additional, Tàrraga, Lluis, additional, Ramirez, Alfredo, additional, Boada, Mercé, additional, and Ruiz, Agustín, additional

Published
2023
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22. Association Between Insulin‐Like Growth Factor‐1 and Social Cognition in Huntington's Disease

Author

Gil‐Polo, Cecilia, primary, Martinez‐Horta, Saul‐Indra, additional, Sampedro Santalo, Frederic, additional, Martín‐Palencia, María, additional, Gundín‐Menéndez, Simón, additional, Alvarez‐Baños, Pilar, additional, Maza‐Pereg, Laura, additional, Calvo, Sara, additional, Collazo, Carla, additional, Alonso‐García, Esther, additional, Riñones‐Mena, Esther, additional, Arrabal‐Alonso, Angela, additional, Núñez Rodriguez, Juan, additional, Saiz‐Rodriguez, Miriam, additional, Aguado, Laura, additional, Mariscal, Natividad, additional, Muñoz‐Siscart, Ignacio, additional, Piñeiro, Dolores, additional, Rivadeneyra, Jessica, additional, Diez‐Fairen, Monica, additional, Miguel‐Pérez, Irene, additional, and Cubo, Esther, additional

Published
2022
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23. Identification of a sex-specific genetic signature in dementia with Lewy bodies: a meta-analysis of genome-wide association studies

Author

Gibbons, Elizabeth, primary, Rongve, Arvid, additional, de Rojas, Itziar, additional, Shadrin, Alexey, additional, Westra, Kaitlyn, additional, Baumgartner, Allison, additional, Rosendall, Levi, additional, Madaj, Zachary, additional, Hernandez, Dena G., additional, Ross, Owen A., additional, Escott-Price, Valentina, additional, Shepherd, Claire, additional, Parkkinen, Laura, additional, Scholz, Sonja W., additional, Troncoso, Juan C., additional, Pletnikova, Olga, additional, Dawson, Ted, additional, Rosenthal, Liana, additional, Ansorge, Olaf, additional, Clarimon, Jordi, additional, Lleo, Alberto, additional, Morenas-Rodriguez, Estrella, additional, Clark, Lorraine, additional, Honig, Lawrence S, additional, Marder, Karen, additional, Lemstra, Afina, additional, Rogaeva, Ekaterina, additional, George-Hyslop, Peter St., additional, Londos, Elisabet, additional, Zetterberg, Henrik, additional, Morgan, Kevin, additional, Troakes, Claire, additional, Al-Sarraj, Safa, additional, Lashley, Tammaryn, additional, Holton, Janice, additional, Compta, Yaroslau, additional, Van Deerlin, Vivianna, additional, Serrano, Geidy E, additional, Beach, Thomas G, additional, Lesage, Suzanne, additional, Galasko, Douglas, additional, Masliah, Eliezer, additional, Santana, Isabel, additional, Pastor, Pau, additional, Diez-Fairen, Monica, additional, Aguilar, Miquel, additional, Marquie, Marta, additional, Garcia-Gonzalez, Pablo, additional, Olive, Claudia, additional, Puerta, Raquel, additional, Cano, Amanda, additional, Sotolongo-Grau, Oscar, additional, Valero, Sergi, additional, Pytel, Vanesa Veronica, additional, Rosende-Roca, Maitee, additional, Alegret, Montserrat, additional, Tarraga, Lluis, additional, Boada, Merce, additional, Carracedo, Angel, additional, Franco-Macias, Emilio, additional, Perez-Tur, Jordi, additional, Royo, Jose Luis, additional, Garcia-Alberca, Jose Maria, additional, Real, Luis Miguel, additional, Saez, Maria Eugenia, additional, Bullido, Maria Jesus, additional, Calero, Miguel, additional, Medina, Miguel, additional, Mir, Pablo, additional, Sanchez-Juan, Pascual, additional, Alvarez, Victoria, additional, Parveen, Kayenat, additional, Tripathi, Kumar Parijat, additional, Heilmann-Heimbach, Stefanie, additional, Ramirez, Alfredo, additional, Tienari, Pentti J., additional, Bousiges, Olivier, additional, Blanc, Frederic, additional, Fenoglio, Chiara, additional, Padovani, Alessandro, additional, Borroni, Barbara, additional, Pilotto, Andrea, additional, Nobili, Flavio, additional, Saltvedt, Ingvild, additional, Fladby, Tormod, additional, Selbaek, Geir, additional, Bosnes, Ingunn, additional, Brathen, Geir, additional, Hartmann, Annette, additional, Lemstra, Afina W., additional, Rujescu, Dan, additional, Mollenhauer, Brit, additional, Creese, Byron, additional, Chartier-Harlin, Marie-Christine, additional, Athanasiu, Lavinia, additional, Djurovic, Srdjan, additional, Chouliaras, Leonidas, additional, OBrien, John T., additional, Myllykangas, Liisa, additional, Oinas, Minna, additional, Revesz, Tamas, additional, Lees, Andrew, additional, Boeve, Brad F, additional, Petersen, Ronald C., additional, Ferman, Tanis J, additional, Graff-Radford, Neill, additional, Cairns, Nigel J., additional, Morris, John C., additional, Halliday, Glenda M., additional, Hardy, John, additional, Dickson, Dennis W., additional, Singleton, Andrew, additional, Stone, David J., additional, Andreassen, Ole A., additional, Ruiz, Agustin, additional, Aarsland, Dag, additional, Guerreiro, Rita, additional, and Bras, Jose, additional

Published
2022
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24. Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium

Author

Grover, Sandeep, Kumar Sreelatha, Ashwin Ashok, Landoulsi, Zied, May, Patrick, Bobbili, Dheeraj, Edsall, Connor, Bartusch, Felix, Hanussek, Maximilian, Krüger, Jens, Hernandez, Dena G, Blauwendraat, Cornelis, Mellick, George D, Pihlstrom, Lasse, Zimprich, Alexander, Pirker, Walter, Tan, Manuela, Rogaeva, Ekaterina, Lang, Anthony, Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Domenighetti, Cloé, Chartier-Harlin, Marie-Christine, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B, Hadjigeorgiou, Georges M, Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Schulte, Claudia, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Burbulla, Lena F, Matsuo, Hirotaka, Sugier, Pierre-Emmanuel, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Pavelka, Lukas, van de Warrenburg, Bart P C, Bloem, Bastiaan R, Singleton, Andrew B, Aasly, Jan, Radivojkov-Blagojevic, Milena, Toft, Mathias, Guedes, Leonor Correia, Ferreira, Joaquim J, Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Lichtner, Peter, Pedersen, Nancy L, Ran, Caroline, Belin, Andrea C, Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E, Morrison, Karen E, Krainc, Dimitri, Farrer, Matt J, Kruger, Rejko, Mohamed, Océane, Elbaz, Alexis, Gasser, Thomas, Sharma, Manu, Genetics, and the Comprehensive Unbiased Risk Factor Assessment for, Disease, Environment in Parkinson's, Portugal, Berta, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, 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), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FOR2488, INTER/DFG/17/11583046, INTER/DFG/19/14429377, Michael J. Fox Foundation for Parkinson's Research, MJFF, EU Joint Programme – Neurodegenerative Disease Research, JPND: 01ED1406, Multiple System Atrophy Coalition, MSA, European Commission, EC: EP1802749, Deutsche Forschungsgemeinschaft, DFG: DFG/SH 599/6-1, Fonds National de la Recherche Luxembourg, FNR: FNR/P13/6682797, Bundesministerium für Bildung und Forschung, BMBF, Université Paris-Saclay, The COURAGE-PD Consortium is conducted under a partnership agreement between 35 studies. The COURAGE-PD Consortium is supported by the EU Joint Program for Neurodegenerative Disease Research (JPND, neurodegenerationresearch.eu/initiatives/annual-calls-for-proposals/closed-calls/risk-factors-2012/risk-factor-call-results/courage-pd/ , Grant ID: 01ED1406)., and The Article Processing Charge was funded by the authors.

Subjects
parkinson’s disease, [SDV]Life Sciences [q-bio], burden of disease, Polymorphism, Single Nucleotide, Duration of disease, genetic heritability, duration of disease, genetics [Parkinson Disease], age at onset, Humans, Genetic Predisposition to Disease, ddc:610, Age of Onset, genetics [Genetic Predisposition to Disease], Burden of disease, Age at onset, Parkinson Disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Courage, Parkinson’s disease, Genetic heritability, Female, Neurology (clinical), epidemiology [Parkinson Disease], Genome-Wide Association Study
Abstract

Background and ObjectivesConsiderable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.MethodsA meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC).ResultsThe COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10−8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10−9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10−8).DiscussionOur study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.

Published
2022

25. A comprehensive screening of copy number variability in dementia with Lewy bodies

Author

Kun-Rodrigues, Celia, Orme, Tatiana, Carmona, Susana, Hernandez, Dena G., Ross, Owen A., Eicher, John D., Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Heckman, Michael G., Scholz, Sonja W., Troncoso, Juan C., Pletnikova, Olga, Dawson, Ted, Rosenthal, Liana, Ansorge, Olaf, Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Clark, Lorraine, Honig, Lawrence S., Marder, Karen, Lemstra, Afina, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda, Braae, Anne, Brown, Kristelle, Morgan, Kevin, Troakes, Claire, Al-Sarraj, Safa, Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Serrano, Geidy E., Beach, Thomas G., Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Pastor, Pau, Diez-Fairen, Monica, Aguilar, Miquel, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Brad F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill, Cairns, Nigel J., Morris, John C., Pickering-Brown, Stuart, Mann, David, Halliday, Glenda M., Hardy, John, Trojanowski, John Q., Dickson, Dennis W., Singleton, Andrew, Stone, David J., Guerreiro, Rita, and Bras, Jose

Published
2019
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26. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W., Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C., Damotte, Vincent, Naj, Adam C., Boland, Anne, Vronskaya, Maria, van der Lee, Sven J., Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R., Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L., Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B., Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N., Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W., Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L., Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V., Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C., Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T., Adams, Hieab H., Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A., Dombroski, Beth A., Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B., Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S., Meslage, Stéphane, Kornhuber, Johannes, White, Charles C., Song, Yuenjoo, Barber, Robert C., Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M., Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L. Adrienne, Albert, Marilyn S., De Deyn, Peter P., Gu, Wei, Himali, Jayanadra J., Beekly, Duane, Squassina, Alessio, Hartmann, Annette M., Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E., Doody, Rachelle S., Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J., Benito, Yolanda A., Holmes, Clive, Karamujić-Čomić, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roshchupkin, Gennady, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernández, Isabel, Kamboh, M. Ilyas, Brundin, RoseMarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluís, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, Jr, W. T., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome I., Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Uitterlinden, A. G. Andre, Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, George-Hyslop, Peter St, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Inés, Carracedo, Ángel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Frölich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Kölsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Hüll, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Jöckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan I., Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Nöthen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O’Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossù, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Alzheimer Disease Genetics Consortium (ADGC), The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stéphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, O’Donovan, Michael C., DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, and Pericak-Vance, Margaret A.

Published
2019
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27. Genome-wide Association and Meta-analysis of Age-at-Onset in Parkinson Disease: Evidence From COURAGE-PD Consortium 10.1212/WNL.0000000000200699

Author

Grover, Sandeep, Ashwin, Ashok Kumar Sreelatha, Pihlstrom, Lasse, Domenighetti, Cloé, Schulte, Claudia, Sugier, Pierre-Emmanuel, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Mohamed, Océane, Portugal, Berta, Landoulsi, Zied, May, Patrick, Bobbili, Dheeraj Reddy, Edsall, Connor, Bartusch, Felix, Hanussek, Maximilian, Krüger, Jens, Hernandez, Dena G., Blauwendraat, Cornelis, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Tan, Manuela, Rogaeva, Ekaterina, Lang, Anthony, Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Burbulla, Lena F., Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Pavelka, Lukas, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Singleton, Andrew B., Aasly, Jan, Toft, Mathias, Guedes, Leonor Correia, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Krainc, Dimitri, Farrer, Matt J., Krüger, Rejko, Elbaz, Alexis, Gasser, Thomas, Sharma, Manu, of, On Behalf, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, consortium, Environment In Parkinson Textquoterights Disease Courage-P. D., Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center]

Subjects
Neurologie [D14] [Sciences de la santé humaine], Parkinson's disease, Neurology [D14] [Human health sciences], Age of onset, GWAS, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant]
Abstract

Background and Objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson\textquoterights disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.Methods: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson\textquoterights Disease (COURAGE-PD) consortium. This was followed up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).Results: The COURAGE-PD included a cohort of 8,535 patients with PD (91.9\%: Europeans, 9.1\%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation of females (40.2\%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE=0.057). None of the loci reached genome-wide significance (P\

Published
2022

28. The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited

Author

Domenighetti, Cloé, Douillard, Venceslas, Sugier, Pierre-Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Gourraud, Pierre-Antoine, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Ygland Rödström, Emil, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, KraincMD, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Vince, Nicolas, Elbaz, Alexis, Genetics, Comprehensive Unbiased Risk Factor Assessment For, Consortium, Environment In Parkinson S Disease Courage-P. D., Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center]

Subjects
Neurologie [D14] [Sciences de la santé humaine], genetics [HLA-DRB1 Chains], Neurology [D14] [Human health sciences], Parkinson's disease, Smoking, Parkinson Disease, genetics [Smoking], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Polymorphism, Single Nucleotide, smoking, gene-environment interaction, HLA, Neurology, genetics [Parkinson Disease], genetics [Polymorphism, Single Nucleotide], Humans, Genetic Predisposition to Disease, ddc:610, Genetics & genetic processes [F10] [Life sciences], Neurology (clinical), Génétique & processus génétiques [F10] [Sciences du vivant], HLA-DRB1 Chains
Abstract

Contains fulltext : 282469.pdf (Publisher’s version ) (Open Access) BACKGROUND: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. OBJECTIVE: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. METHODS: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. RESULTS: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, P(Interaction) = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. CONCLUSIONS: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2022

29. Mendelian randomization confirms the role of Y-chromosome loss in Alzheimer’s Disease etiopathogenesis in males

Author

García-González, Pablo, primary, de Rojas, Itziar, additional, Moreno-Grau, Sonia, additional, Montrreal, Laura, additional, Puerta, Raquel, additional, Alarcón-Martín, Emilio, additional, Quintela, Inés, additional, Orellana, Adela, additional, Andrade, Victor, additional, Adami, Pamela Martino, additional, Heilmann-Heimbach, Stefanie, additional, Gomez-Garre, Pilar, additional, Teresa Periñán, María, additional, Alvarez, Ignacio, additional, Diez-Fairen, Monica, additional, Nuñez Llaves, Raul, additional, Olivé Roig, Claudia, additional, Garcia-Ribas, Guillermo, additional, Menéndez-González, Manuel, additional, Martínez, Carmen, additional, Aguilar, Miquel, additional, Buongiorno, Mariateresa, additional, Franco-Macías, Emilio, additional, Saez, Maria Eugenia, additional, Cano, Amanda, additional, Bullido, Maria, additional, Real, Luis, additional, Rodríguez-Rodríguez, Eloy, additional, Royo, Jose, additional, Álvarez, Victoria, additional, Pastor, Pau, additional, Piñol-Ripoll, Gerard, additional, Mir, Pablo, additional, Lara, Miguel Calero, additional, Padilla, Miguel Medina, additional, Sánchez-Juan, Pascual, additional, Carracedo, Angel, additional, Valero, Sergi, additional, Hernandez, Isabel, additional, Tàrraga, Lluis, additional, Ramirez, Alfredo, additional, Boada, Mercé, additional, and Ruiz, Agustín, additional

Published
2022
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31. Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

Author

Philtjens, Stéphanie, Van Mossevelde, Sara, van der Zee, Julie, Wauters, Eline, Dillen, Lubina, Vandenbulcke, Mathieu, Vandenberghe, Rik, Ivanoiu, Adrian, Sieben, Anne, Willems, Christiana, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Borroni, Barbara, Padovani, Alessandro, Pastor, Pau, Diez-Fairen, Monica, Aguilar, Miquel, de Mendonça, Alexandre, Miltenberger-Miltényi, Gabriel, Hernández, Isabel, Boada, Merce, Ruiz, Agustín, Nacmias, Benedetta, Sorbi, Sandro, Almeida, Maria Rosário, Santana, Isabel, Clarimón, Jordi, Lleó, Alberto, Frisoni, Giovanni B., Sanchez-Valle, Raquel, Lladó, Albert, Gómez-Tortosa, Estrella, Gelpi, Ellen, Van den Broeck, Marleen, Peeters, Karin, Cras, Patrick, De Deyn, Peter P., Engelborghs, Sebastiaan, Cruts, Marc, and Van Broeckhoven, Christine

Published
2018
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32. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], JPND Courage-PD [sponsor], Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Ashok Kumar Sreelatha, Ashwin, Schulte, Claudia, Grover, Sandeep, Mohamed, Océane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, Consortium, Environment In Parkinson S Disease Courage-P. D., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], JPND Courage-PD [sponsor], Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Ashok Kumar Sreelatha, Ashwin, Schulte, Claudia, Grover, Sandeep, Mohamed, Océane, Portugal, Berta, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, The Comprehensive Unbiased Risk Factor Assessment For, and Consortium, Environment In Parkinson S Disease Courage-P. D.

Abstract

Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95 confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

Published
2022

33. New insights into the genetic etiology of Alzheimer's disease and related dementias

Author

Bellenguez, Celine, Kucukali, Fahri, Jansen, Iris E., Kleineidam, Luca, Moreno-Grau, Sonia, Amin, Najaf, Naj, Adam C., Campos-Martin, Rafael, Grenier-Boley, Benjamin, Andrade, Victor, Holmans, Peter A., Boland, Anne, Damotte, Vincent, van der Lee, Sven J., Costa, Marcos R., Kuulasmaa, Teemu, Yang, Qiong, De Rojas, Itziar, Bis, Joshua C., Yaqub, Amber, Prokic, Ivana, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcon-Martin, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Alvarez, Victoria, Armstrong, Nicola J., Tsolaki, Anthoula, Antunez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Arias Pastor, Alfonso, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belen, Below, Jennifer E., Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Celine, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Merce, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossu, Paola, Brathen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J., Ignacio Brusco, Luis, Buiza-Rueda, Dolores, Burger, Katharina, Burholt, Vanessa, Bush, William S., Calero, Miguel, Cantwell, Laura B., Chene, Genevieve, Chung, Jaeyoon, Cuccaro, Michael L., Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A. H. R., Clark, Christopher, Conti, Elisa, Corma-Gomez, Anais, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-Francois, de Deyn, Peter Paul, Lopes, Katia de Paiva, De Witte, Lot D., Debette, Stephanie, Deckert, Jurgen, del Ser, Teodoro, Denning, Nicola, Destefano, Anita, Dichgans, Martin, Diehl-Schmid, Janine, Diez-Fairen, Monica, Rossi, Paolo Dionigi, Djurovic, Srdjan, Duron, Emmanuelle, Duzel, Emrah, Dufouil, Carole, Eiriksdottir, Gudny, Engelborghs, Sebastiaan, Escott-Price, Valentina, Espinosa, Ana, Ewers, Michael, Faber, Kelley M., Fabrizio, Tagliavini, Nielsen, Sune Fallgaard, Fardo, David W., Farotti, Lucia, Fenoglio, Chiara, Fernandez-Fuertes, Marta, Ferrari, Raffaele, Ferreira, Catarina B., Ferri, Evelyn, Fin, Bertrand, Fischer, Peter, Fladby, Tormod, Fliessbach, Klaus, Fongang, Bernard, Fornage, Myriam, Fortea, Juan, Foroud, Tatiana M., Fostinelli, Silvia, Fox, Nick C., Franco-Macias, Emlio, Bullido, Maria J., Frank-Garcia, Ana, Froelich, Lutz, Fulton-Howard, Brian, Galimberti, Daniela, Maria Garcia-Alberca, Jose, Garcia-Madrona, Sebastian, Garcia-Ribas, Guillermo, Ghidoni, Roberta, Giegling, Ina, Giorgio, Giaccone, Goate, Alison M., Goldhardt, Oliver, Gomez-Fonseca, Duber, Gonzalez-Perez, Antonio, Graff, Caroline, Grande, Giulia, Green, Emma, Grimmer, Timo, Grunblatt, Edna, Grunin, Michelle, Gudnason, Vilmundur, Guetta-Baranes, Tamar, Haapasalo, Annakaisa, Hadjigeorgiou, Georgios, Haines, Jonathan L., Hamilton-Nelson, Kara L., Hampel, Harald, Hanon, Olivier, Hardy, John, Hartmann, Annette M., Hausner, Lucrezia, Harwood, Janet, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernandez, Isabel, Herrmann, Martin J., Hoffmann, Per, Holmes, Clive, Holstege, Henne, Huerto Vilas, Raquel, Hulsman, Marc, Humphrey, Jack, Biessels, Geert Jan, Jian, Xueqiu, Johansson, Charlotte, Jun, Gyungah R., Kastumata, Yuriko, Kauwe, John, Kehoe, Patrick G., Kilander, Lena, Stahlbom, Anne Kinhult, Kivipelto, Miia, Koivisto, Anne, Kornhuber, Johannes, Kosmidis, Mary H., Kukull, Walter A., Kuksa, Pavel P., Kunkle, Brian W., Kuzma, Amanda B., Lage, Carmen, Laukka, Erika J., Launer, Lenore, Lauria, Alessandra, Lee, Chien-Yueh, Lehtisalo, Jenni, Lerch, Ondrej, Lleo, Alberto, Longstreth, William, Jr., Lopez, Oscar, Lopez de Munain, Adolfo, Love, Seth, Lowemark, Malin, Luckcuck, Lauren, Lunetta, Kathryn L., Ma, Yiyi, Macias, Juan, Macleod, Catherine A., Maier, Wolfgang, Mangialasche, Francesca, Spallazzi, Marco, Marquie, Marta, Marshall, Rachel, Martin, Eden R., Martin Montes, Angel, Martinez Rodriguez, Carmen, Masullo, Carlo, Mayeux, Richard, Mead, Simon, Mecocci, Patrizia, Medina, Miguel, Meggy, Alun, Mehrabian, Shima, Mendoza, Silvia, Menendez-Gonzalez, Manuel, Mir, Pablo, Moebus, Susanne, Mol, Merel, Molina-Porcel, Laura, Montrreal, Laura, Morelli, Laura, Moreno, Fermin, Morgan, Kevin, Mosley, Thomas, Nothen, Markus M., Muchnik, Carolina, Mukherjee, Shubhabrata, Nacmias, Benedetta, Ngandu, Tiia, Nicolas, Gael, Nordestgaard, Borge G., Olaso, Robert, Orellana, Adelina, Orsini, Michela, Ortega, Gemma, Padovani, Alessandro, Paolo, Caffarra, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peloso, Gina, Perez-Cordon, Alba, Perez-Tur, Jordi, Pericard, Pierre, Peters, Oliver, Pijnenburg, Yolande A. L., Pineda, Juan A., Pinol-Ripoll, Gerard, Pisanu, Laudia, Polak, Thomas, Popp, Julius, Posthuma, Danielle, Priller, Josef, Puerta, Raquel, Quenez, Olivier, Quintela, Ines, Thomassen, Jesper Qvist, Rabano, Alberto, Rainero, Innocenzo, Rajabli, Farid, Ramakers, Inez, Real, Luis M., Reinders, Marcel J. T., Reitz, Christiane, Reyes-Dumeyer, Dolly, Ridge, Perry, Riedel-Heller, Steffi, Riederer, Peter, Roberto, Natalia, Rodriguez-Rodriguez, Eloy, Rongve, Arvid, Rosas Allende, Irene, Rosende-Roca, Maitee, Luis Royo, Jose, Rubino, Elisa, Rujescu, Dan, Eugenia Saez, Maria, Sakka, Paraskevi, Saltvedt, Ingvild, Bernal Sanchez-Arjona, Maria, Sanchez-Garcia, Florentino, Sanchez Juan, Pascual, Sanchez-Valle, Raquel, Sando, Sigrid B., Sarnowski, Chloe, Satizabal, Claudia L., Scamosci, Michela, Scarmeas, Nikolaos, Scarpini, Elio, Scheltens, Philip, Scherbaum, Norbert, Scherer, Martin, Schmid, Matthias, Schneider, Anja, Schott, Jonathan M., Selbaek, Geir, Seripa, Davide, Serrano, Manuel, Sha, Jin, Shadrin, Alexey A., Skrobot, Olivia, Slifer, Susan, Snijders, Gijsje J. L., Soininen, Hilkka, Solfrizzi, Vincenzo, Solomon, Alina, Song, Yeunjoo, Sorbi, Sandro, Sotolongo-Grau, Oscar, Spalletta, Gianfranco, Spottke, Annika, Squassina, Alessio, Stordal, Eystein, Pablo Tartan, Juan, Tarraga, Lluis, Tesi, Niccolo, Thalamuthu, Anbupalam, Thomas, Tegos, Tosto, Giuseppe, Traykov, Latchezar, Tremolizzo, Lucio, Tybjaerg-Hansen, Anne, Uitterlinden, Andre, Ullgren, Abbe, Ulstein, Ingun, Valero, Sergi, Valladares, Otto, Van Broeckhoven, Christine, Vance, Jeffery, Vardarajan, Badri N., van der Lugt, Aad, Van Dongen, Jasper, van Rooij, Jeroen, van Swieten, John, Vandenberghe, Rik, Verhey, Frans, Vidal, Jean-Sebastien, Vogelgsang, Jonathan, Vyhnalek, Martin, Wagner, Michael, Wallon, David, Wang, Li-San, Wang, Ruiqi, Weinhold, Leonie, Wiltfang, Jens, Windle, Gill, Woods, Bob, Yannakoulia, Mary, Zare, Habil, Zhao, Yi, Zhang, Xiaoling, Zhu, Congcong, Zulaica, Miren, Farrer, Lindsay A., Psaty, Bruce M., Ghanbari, Mohsen, Raj, Towfique, Sachdev, Perminder, Mather, Karen, Jessen, Frank, Ikram, M. Arfan, de Mendonca, Alexandre, Hort, Jakub, Tsolaki, Magda, Pericak-Vance, Margaret A., Amouyel, Philippe, Williams, Julie, Frikke-Schmidt, Ruth, Clarimon, Jordi, Deleuze, Jean-Francois, Rossi, Giacomina, Seshadri, Sudha, Andreassen, Ole A., Ingelsson, Martin, Hiltunen, Mikko, Sleegers, Kristel, Schellenberg, Gerard D., van Duijn, Cornelia M., Sims, Rebecca, van der Flier, Wiesje M., Ruiz, Agustin, Ramirez, Alfredo, Lambert, Jean-Charles, Bellenguez, Celine, Kucukali, Fahri, Jansen, Iris E., Kleineidam, Luca, Moreno-Grau, Sonia, Amin, Najaf, Naj, Adam C., Campos-Martin, Rafael, Grenier-Boley, Benjamin, Andrade, Victor, Holmans, Peter A., Boland, Anne, Damotte, Vincent, van der Lee, Sven J., Costa, Marcos R., Kuulasmaa, Teemu, Yang, Qiong, De Rojas, Itziar, Bis, Joshua C., Yaqub, Amber, Prokic, Ivana, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcon-Martin, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Alvarez, Victoria, Armstrong, Nicola J., Tsolaki, Anthoula, Antunez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Arias Pastor, Alfonso, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belen, Below, Jennifer E., Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Celine, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Merce, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossu, Paola, Brathen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J., Ignacio Brusco, Luis, Buiza-Rueda, Dolores, Burger, Katharina, Burholt, Vanessa, Bush, William S., Calero, Miguel, Cantwell, Laura B., Chene, Genevieve, Chung, Jaeyoon, Cuccaro, Michael L., Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A. H. R., Clark, Christopher, Conti, Elisa, Corma-Gomez, Anais, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-Francois, de Deyn, Peter Paul, Lopes, Katia de Paiva, De Witte, Lot D., Debette, Stephanie, Deckert, Jurgen, del Ser, Teodoro, Denning, Nicola, Destefano, Anita, Dichgans, Martin, Diehl-Schmid, Janine, Diez-Fairen, Monica, Rossi, Paolo Dionigi, Djurovic, Srdjan, Duron, Emmanuelle, Duzel, Emrah, Dufouil, Carole, Eiriksdottir, Gudny, Engelborghs, Sebastiaan, Escott-Price, Valentina, Espinosa, Ana, Ewers, Michael, Faber, Kelley M., Fabrizio, Tagliavini, Nielsen, Sune Fallgaard, Fardo, David W., Farotti, Lucia, Fenoglio, Chiara, Fernandez-Fuertes, Marta, Ferrari, Raffaele, Ferreira, Catarina B., Ferri, Evelyn, Fin, Bertrand, Fischer, Peter, Fladby, Tormod, Fliessbach, Klaus, Fongang, Bernard, Fornage, Myriam, Fortea, Juan, Foroud, Tatiana M., Fostinelli, Silvia, Fox, Nick C., Franco-Macias, Emlio, Bullido, Maria J., Frank-Garcia, Ana, Froelich, Lutz, Fulton-Howard, Brian, Galimberti, Daniela, Maria Garcia-Alberca, Jose, Garcia-Madrona, Sebastian, Garcia-Ribas, Guillermo, Ghidoni, Roberta, Giegling, Ina, Giorgio, Giaccone, Goate, Alison M., Goldhardt, Oliver, Gomez-Fonseca, Duber, Gonzalez-Perez, Antonio, Graff, Caroline, Grande, Giulia, Green, Emma, Grimmer, Timo, Grunblatt, Edna, Grunin, Michelle, Gudnason, Vilmundur, Guetta-Baranes, Tamar, Haapasalo, Annakaisa, Hadjigeorgiou, Georgios, Haines, Jonathan L., Hamilton-Nelson, Kara L., Hampel, Harald, Hanon, Olivier, Hardy, John, Hartmann, Annette M., Hausner, Lucrezia, Harwood, Janet, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernandez, Isabel, Herrmann, Martin J., Hoffmann, Per, Holmes, Clive, Holstege, Henne, Huerto Vilas, Raquel, Hulsman, Marc, Humphrey, Jack, Biessels, Geert Jan, Jian, Xueqiu, Johansson, Charlotte, Jun, Gyungah R., Kastumata, Yuriko, Kauwe, John, Kehoe, Patrick G., Kilander, Lena, Stahlbom, Anne Kinhult, Kivipelto, Miia, Koivisto, Anne, Kornhuber, Johannes, Kosmidis, Mary H., Kukull, Walter A., Kuksa, Pavel P., Kunkle, Brian W., Kuzma, Amanda B., Lage, Carmen, Laukka, Erika J., Launer, Lenore, Lauria, Alessandra, Lee, Chien-Yueh, Lehtisalo, Jenni, Lerch, Ondrej, Lleo, Alberto, Longstreth, William, Jr., Lopez, Oscar, Lopez de Munain, Adolfo, Love, Seth, Lowemark, Malin, Luckcuck, Lauren, Lunetta, Kathryn L., Ma, Yiyi, Macias, Juan, Macleod, Catherine A., Maier, Wolfgang, Mangialasche, Francesca, Spallazzi, Marco, Marquie, Marta, Marshall, Rachel, Martin, Eden R., Martin Montes, Angel, Martinez Rodriguez, Carmen, Masullo, Carlo, Mayeux, Richard, Mead, Simon, Mecocci, Patrizia, Medina, Miguel, Meggy, Alun, Mehrabian, Shima, Mendoza, Silvia, Menendez-Gonzalez, Manuel, Mir, Pablo, Moebus, Susanne, Mol, Merel, Molina-Porcel, Laura, Montrreal, Laura, Morelli, Laura, Moreno, Fermin, Morgan, Kevin, Mosley, Thomas, Nothen, Markus M., Muchnik, Carolina, Mukherjee, Shubhabrata, Nacmias, Benedetta, Ngandu, Tiia, Nicolas, Gael, Nordestgaard, Borge G., Olaso, Robert, Orellana, Adelina, Orsini, Michela, Ortega, Gemma, Padovani, Alessandro, Paolo, Caffarra, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peloso, Gina, Perez-Cordon, Alba, Perez-Tur, Jordi, Pericard, Pierre, Peters, Oliver, Pijnenburg, Yolande A. L., Pineda, Juan A., Pinol-Ripoll, Gerard, Pisanu, Laudia, Polak, Thomas, Popp, Julius, Posthuma, Danielle, Priller, Josef, Puerta, Raquel, Quenez, Olivier, Quintela, Ines, Thomassen, Jesper Qvist, Rabano, Alberto, Rainero, Innocenzo, Rajabli, Farid, Ramakers, Inez, Real, Luis M., Reinders, Marcel J. T., Reitz, Christiane, Reyes-Dumeyer, Dolly, Ridge, Perry, Riedel-Heller, Steffi, Riederer, Peter, Roberto, Natalia, Rodriguez-Rodriguez, Eloy, Rongve, Arvid, Rosas Allende, Irene, Rosende-Roca, Maitee, Luis Royo, Jose, Rubino, Elisa, Rujescu, Dan, Eugenia Saez, Maria, Sakka, Paraskevi, Saltvedt, Ingvild, Bernal Sanchez-Arjona, Maria, Sanchez-Garcia, Florentino, Sanchez Juan, Pascual, Sanchez-Valle, Raquel, Sando, Sigrid B., Sarnowski, Chloe, Satizabal, Claudia L., Scamosci, Michela, Scarmeas, Nikolaos, Scarpini, Elio, Scheltens, Philip, Scherbaum, Norbert, Scherer, Martin, Schmid, Matthias, Schneider, Anja, Schott, Jonathan M., Selbaek, Geir, Seripa, Davide, Serrano, Manuel, Sha, Jin, Shadrin, Alexey A., Skrobot, Olivia, Slifer, Susan, Snijders, Gijsje J. L., Soininen, Hilkka, Solfrizzi, Vincenzo, Solomon, Alina, Song, Yeunjoo, Sorbi, Sandro, Sotolongo-Grau, Oscar, Spalletta, Gianfranco, Spottke, Annika, Squassina, Alessio, Stordal, Eystein, Pablo Tartan, Juan, Tarraga, Lluis, Tesi, Niccolo, Thalamuthu, Anbupalam, Thomas, Tegos, Tosto, Giuseppe, Traykov, Latchezar, Tremolizzo, Lucio, Tybjaerg-Hansen, Anne, Uitterlinden, Andre, Ullgren, Abbe, Ulstein, Ingun, Valero, Sergi, Valladares, Otto, Van Broeckhoven, Christine, Vance, Jeffery, Vardarajan, Badri N., van der Lugt, Aad, Van Dongen, Jasper, van Rooij, Jeroen, van Swieten, John, Vandenberghe, Rik, Verhey, Frans, Vidal, Jean-Sebastien, Vogelgsang, Jonathan, Vyhnalek, Martin, Wagner, Michael, Wallon, David, Wang, Li-San, Wang, Ruiqi, Weinhold, Leonie, Wiltfang, Jens, Windle, Gill, Woods, Bob, Yannakoulia, Mary, Zare, Habil, Zhao, Yi, Zhang, Xiaoling, Zhu, Congcong, Zulaica, Miren, Farrer, Lindsay A., Psaty, Bruce M., Ghanbari, Mohsen, Raj, Towfique, Sachdev, Perminder, Mather, Karen, Jessen, Frank, Ikram, M. Arfan, de Mendonca, Alexandre, Hort, Jakub, Tsolaki, Magda, Pericak-Vance, Margaret A., Amouyel, Philippe, Williams, Julie, Frikke-Schmidt, Ruth, Clarimon, Jordi, Deleuze, Jean-Francois, Rossi, Giacomina, Seshadri, Sudha, Andreassen, Ole A., Ingelsson, Martin, Hiltunen, Mikko, Sleegers, Kristel, Schellenberg, Gerard D., van Duijn, Cornelia M., Sims, Rebecca, van der Flier, Wiesje M., Ruiz, Agustin, Ramirez, Alfredo, and Lambert, Jean-Charles

Abstract

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE epsilon 4 allele. Meta-analysis of genome-wide association studies on Alzheimer's disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer's disease and dementia.

Published
2022

34. Association Between Insulin‐Like Growth Factor‐1 and Social Cognition in Huntington's Disease.

Author

Gil‐Polo, Cecilia, Martinez‐Horta, Saul‐Indra, Sampedro Santalo, Frederic, Martín‐Palencia, María, Gundín‐Menéndez, Simón, Alvarez‐Baños, Pilar, Maza‐Pereg, Laura, Calvo, Sara, Collazo, Carla, Alonso‐García, Esther, Riñones‐Mena, Esther, Arrabal‐Alonso, Angela, Núñez Rodriguez, Juan, Saiz‐Rodriguez, Miriam, Aguado, Laura, Mariscal, Natividad, Muñoz‐Siscart, Ignacio, Piñeiro, Dolores, Rivadeneyra, Jessica, and Diez‐Fairen, Monica

Subjects
HUNTINGTON disease, SOCIAL perception, SOMATOMEDIN C, VOXEL-based morphometry, CEREBRAL atrophy
Abstract

Background: Insulin‐like growth factor 1 (IGF‐1) seems to be involved in the neural circuits associated with social cognition and brain structure. Objectives: To investigate the association of IGF‐1 levels with social cognition and brain structure in Huntington's disease (HD). Methods: We evaluated social cognition using the Ekman test in 22 HD patients and 19 matched controls. Brain structure was assessed using standard volume‐based voxel‐based morphometry and surface‐based cortical thickness pipeline. We analyzed the association of IGF‐1 levels with social cognition and brain structure using adjusted regression analysis. Results: Social cognition was worse in HD patients (P < 0.001), on antidopaminergic drugs (P = 0.02), and with lower IGF‐1 levels (P = 0.04). In neuroimaging analyses, lower IGF‐1 levels were associated with social cognition impairment and atrophy mainly in frontotemporal regions (P < 0.05 corrected). Conclusions: In HD, abnormal IGF‐1 function seems to be associated with brain atrophy leading to clinical deficits in social cognition. [ABSTRACT FROM AUTHOR]

Published
2023
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35. Smoking is associated with age at disease onset in Parkinson's disease

Author

Rosas, Irene, primary, Morís, Germán, additional, Coto, Eliecer, additional, Blázquez-Estrada, Marta, additional, Suárez, Esther, additional, García-Fernández, Ciara, additional, Martínez, Carmen, additional, Herrera, Israel Duarte, additional, Pérez-Oliveira, Sergio, additional, Álvarez, Victoria, additional, Menéndez-González, Manuel, additional, Adarmes-Gómez, Astrid D., additional, Aguilar, Miquel, additional, Alvarez, Ignacio, additional, Barrero, Francisco Javier, additional, Bergareche Yarza, Jesús Alberto, additional, Bonilla-Toribio, Marta, additional, Botía, Juan A., additional, Boungiorno, María Teresa, additional, Buiza-Rueda, Dolores, additional, Cámara, Ana, additional, Carrillo, Fátima, additional, Cerdan, Debora, additional, Clarimón, Jordi, additional, Compta, Yaroslau, additional, Diez-Fairen, Monica, additional, Dols-Icardo, Oriol, additional, de Fabregues, Oriol, additional, Cartagena, Pilar Sanz, additional, Duarte, Jacinto, additional, Duran, Raquel, additional, Escamilla-Sevilla, Francisco, additional, Ezquerra, Mario, additional, Feliz, Cici, additional, Fernández-Santiago, Rubén, additional, Fernández, Manel, additional, García-Ruiz, Pedro, additional, Gómez-Garre, Pilar, additional, Gomez Heredia, Maria Jose, additional, Gonzalez-Aramburu, Isabel, additional, Gorostidi, Ana, additional, Hoenicka, Janet, additional, Infante, Jon, additional, Jesús, Silvia, additional, Jimenez-Escrig, Adriano, additional, Kulisevsky, Jaime, additional, Labrador-Espinosa, Miguel A., additional, Lopez-Sendon, Jose Luis, additional, López de Munain, Adolfo, additional, Macias-Garcia, Daniel, additional, Martínez-Torres, Irene, additional, Marín, Juan, additional, Marti, Maria Jose, additional, Martínez-Castrillo, Juan Carlos, additional, Álvarez-Santullano, Marina Mata, additional, Mínguez-Castellanos, Adolfo, additional, Mir, Pablo, additional, Rezola, Elisabet Mondragon, additional, Muñoz, Esteban, additional, Pagonabarraga, Javier, additional, Pastor, Pau, additional, Errazquin, Francisco Perez, additional, Periñán, Maria Teresa, additional, Ruiz-Martínez, Javier, additional, Ruz, Clara, additional, Rodriguez, Antonio Sanchez, additional, Sierra, María, additional, Tabernero, Cesar, additional, Tartari, Juan Pablo, additional, Tolosa, Eduard, additional, Valldeoriola, Francesc, additional, Vela, Lydia, additional, Vives, Francisco, additional, Pascual-Sedano, Berta, additional, Hernández-Vara, Jorge, additional, Rolán, Dolores Vilas, additional, and Bandrés-Ciga, Sara, additional

Published
2022
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36. Association of Essential Tremor With Novel Risk Loci

Author

Liao, Calwing, Castonguay, Charles-Etienne, Heilbron, Karl, Vuokila, Veikko, Medeiros, Miranda, Houle, Gabrielle, Akçimen, Fulya, Ross, Jay P., Catoire, Helene, Diez-Fairen, Monica, Kang, Jooeun, Mueller, Stefanie H., Girard, Simon L., Hopfner, Franziska, Lorenz, Delia, Clark, Lorraine N., Soto-Beasley, Alexandra I., Klebe, Stephan, Hallett, Mark, Wszolek, Zbigniew K., Pendziwiat, Manuela, Lorenzo-Betancor, Oswaldo, Seppi, Klaus, Berg, Daniela, Vilariño-Güell, Carles, Postuma, Ronald B., Bernard, Geneviève, Dupré, Nicolas, Jankovic, Joseph, Testa, Claudia M., Ross, Owen A., Arzberger, Thomas, Chouinard, Sylvain, Louis, Elan D., Mandich, Paola, Vitale, Carmine, Barone, Paolo, García-Martín, Elena, Alonso-Navarro, Hortensia, Agúndez, José A. G., Jiménez-Jiménez, Félix Javier, Pastor, Pau, Rajput, Alex, Deuschl, Günther, Kuhlenbaümer, Gregor, Meijer, Inge A., Dion, Patrick A., and Rouleau, Guy A.

Subjects
Research, Online First, Comments, Original Investigation
Abstract

Key Points Question Can common genetic variants associated with essential tremor (ET) be identified? Findings In this genome-wide association study and meta-analysis including genetic data on 483 054 individuals, 5 genome-wide significant loci were associated with risk of ET and common variants were associated with approximately 18% of ET heritability. Meaning Findings of this study may help identify new genes and inform ET biology., This genome-wide association study identifies common variants associated with risk of essential tremor., Importance Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. Objective To identify common genetic factors associated with risk of ET. Design, Setting, and Participants Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used. Main Outcomes and Measures Genotypes of common variants associated with risk of ET. Results Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10−8) and depression (r, 0.12; P = 9.78 × 10−4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. Conclusions and Relevance The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.

Published
2022

37. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Author

Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Lichtner, Peter, Singleton, Andrew B, Hernandez, Dena Michelle Godwin, Edsall, Connor, Mellick, George D, Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E, Koks, Sulev, Ashok Kumar Sreelatha, Ashwin, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B, Hadjigeorgiou, Georges M, Dardiotis, Efthimos, Schulte, Claudia, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Grover, Sandeep, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, Mohamed, Océane, van de Warrenburg, Bart P C, Bloem, Bastiaan R, Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J, Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Portugal, Berta, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L, Ran, Caroline, Belin, Andrea C, Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E, May, Patrick, Morrison, Karen E, Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F, Farrer, Matt J, Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, and the Comprehensive Unbiased Risk Factor Assessment for, Bobbili, Dheeraj R, Disease, Environment in Parkinson's, Radivojkov-Blagojevic, Milena, and Repositório da Universidade de Lisboa

Subjects
Male, dairy intake, Parkinson's disease, Mendelian randomization, Parkinson Disease, Dairy intake, Mendelian Randomization Analysis, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Polymorphism, Single Nucleotide, Neurology, genetics [Parkinson Disease], Risk Factors, adverse effects [Dairy Products], genetics [Polymorphism, Single Nucleotide], Humans, Genetic Predisposition to Disease, Female, Dairy Products, Neurology (clinical), ddc:610, epidemiology [Parkinson Disease], genetics [Genetic Predisposition to Disease], Genome-Wide Association Study
Abstract

© 2022 International Parkinson and Movement Disorder Society, Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029). Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society., This study used data from the Courage-PD consortium, conducted under a partnership agreement among 35 studies. The Courage-PD consortium is supported by the EU Joint Program for Neurodegenerative Disease research (JPND; https://www.neurodegenerationresearch.eu/initiatives/annual-calls-for-proposals/closed-calls/risk-factors-2012/risk-factor-call-results/courage-pd/). C.D. is the recipient of a doctoral grant from Université Paris-Saclay, France. P.M. was funded by the Fonds National de Recherche (FNR), Luxembourg, as part of the National Centre of Excellence in Research on Parkinson's Disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377). A.B.S., D.G.H., and C.E. are funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project ZO1 AG000949. E.R. is funded by the Canadian Consortium on Neurodegeneration in Aging. S.K. is funded by MSWA. P.T. is the recipient of an Estonian Research Council Grant PRG957. E.M.V. is funded by the Italian Ministry of Health (Ricerca Corrente 2021). S.B. and J.C. are supported by grants from the National Research Foundation of South Africa (grant number: 106052); the South African Medical Research Council (Self-Initiated Research Grant); and Stellenbosch University, South Africa; they also acknowledge the support of the NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; and Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town. P.P. and M.D.-F. have received funding from the Spanish Ministry of Science and Innovation (SAF2013-47939-R). K.W. and N.L.P. are funded by the Swedish Research Council, grant numbers K2002-27X-14056-02B, 521-2010-2479, 521-2013-2488, and 2017-02175. N.L.P. is funded by the National Institutes of Health, grant numbers ES10758 and AG 08724. C.R. is funded by the Märta Lundkvist Foundation, Swedish Brain Foundation, and Karolinska Institutet Research Fund. A.C.B. is funded by the Swedish Brain Foundation, Swedish Research Council, and Karolinska Institutet Research Funds. M.T. (M. Tan) is funded by the Parkinson's UK. M.S. was supported by grants from the German Research Council (DFG/SH 599/6-1), MSA Coalition, and The Michael J. Fox Foundation (USA Genetic Diversity in PD Program: GAP-India Grant ID: 17473). PG GEN sample collection was funded by the MRC and UK Medical Research Council (C.E.C. and K.E.M.).

Published
2022

38. Identification of candidate parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Author

Kia, Demis A., Zhang, David, Guelfi, Sebastian, Manzoni, Claudia, Hubbard, Leon, Reynolds, Regina H., Botía, Juan, Ryten, Mina, Ferrari, Raffaele, Lewis, Patrick A., Williams, Nigel, Trabzuni, Daniah, Hardy, John, Wood, Nicholas W., Noyce, Alastair J., Kaiyrzhanov, Rauan, Middlehurst, Ben, Tan, Manuela, Houlden, Henry, Morris, Huw R., Plun-Favreau, Helene, Holmans, Peter, Bras, Jose, PhD, John Quinn, Mok, Kin Y., Kinghorn, Kerri J., Billingsley, Kimberley, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, R'Bibo, Lea, Rizig, Mie, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R., Bandres-Ciga, Sara, Blauwendraat, Cornelis, Craig, David W., Faghri, Faraz, Gibbs, J. Raphael, Hernandez, Dena G., Van Keuren-Jensen, Kendall, Shulman, Joshua M., Leonard, Hampton L., Nalls, Mike A., Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E., Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W., Reed, Xylena, Alcalay, Roy N., Gan-Or, Ziv, Rouleau, Guy A., Krohn, Lynne, van Hilten, Jacobus J., Marinus, Johan, Adarmes-Gómez, Astrid D., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Javier Barrero, Francisco, Bergareche Yarza, Jesús A., Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María T., Buiza-Rueda, Dolores, Càmara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernàndez, Manel, Fernàndez-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria J., Gonzalez-Aramburu, Isabel, Pagola, Ana G., Hoenicka, Janet, Infante, Jon, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose Luis, Arregui, Adolfo López de Munain, Macias, Daniel, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Mèndez-del-Barrio, Carlota, González, Manuel Menéndez, Adolfo Mínguez, Marina Mata, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Perinán-Tocino, Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Weale, Michael, Ramasamy, Adaikalavan, Smith, Colin, Guelfi, Manuel Sebastian, D'sa, Karishma, Forabosco, Paola, Botiá, Juan A., and Universidad de Cantabria

Subjects
Candidate gene, Protein catabolic process, Gene Expression, Genome-wide association study, Computational biology, Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, Humans, Online First, 030212 general & internal medicine, Epigenetics, Gene, Genetic Association Studies, Genetic association, Original Investigation, Research, Parkinson Disease, Protein ubiquitination, Neurology (clinical), Candidate Disease Gene, 030217 neurology & neurosurgery, Comments, Genome-Wide Association Study
Abstract

Key Points Question What genes and genomic processes underlie risk of sporadic Parkinson disease? Findings This genetic association study integrated Parkinson disease genome-wide association study data and brain-derived gene regulation data using various complementary bioinformatic tools and identified 11 candidate genes with evidence of disease-associated regulatory changes. Coexpression and protein level analyses of these genes demonstrated a significant functional association with known mendelian Parkinson disease genes. Meaning This study suggests that gene regulation data may be used to identify candidate genes and pathways involved in sporadic Parkinson disease., Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies., This genetic association study investigates what genes and genomic processes underlie the risk of sporadic Parkinson disease.

Published
2021

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

Author

Blauwendraat, Cornelis, Iwaki, Hirotaka, Gibbs, Jesse R, Bras, Jose, Guerreiro, Rita, Lubbe, Steven, Troycoco, Timothy, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Hernandez, Dena Michelle Godwin, Uitti, Ryan J, Ross, Owen A, Grenn, Francis P, Moore, Anni, Alcalay, Roy N, Wszolek, Zbigniew K, Gan-Or, Ziv, Rouleau, Guy A, Krohn, Lynne, Mufti, Kheireddin, Ruskey, Jennifer A, van Hilten, Jacobus J, Marinus, Johan, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Blazquez, Marta, Pihlstrøm, Lasse, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Toft, Mathias, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Heredia, Maria Jose Gomez, Gonzalez-Aramburu, Isabel, Pagola, Ana Gorostidi, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Lopez-Sendon, Jose Luis, de Munain Arregui, Adolfo López, Macias, Daniel, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Méndez-Del-Barrio, Carlota, González, Manuel Menéndez, Schulte, Claudia, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Periñán-Tocino, Teresa, Ruiz-Martínez, Javier, Brockmann, Kathrin, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Sharma, Manu, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Taba, Pille, Koks, Sulev, Hassin-Baer, Sharon, Majamaa, Kari, Siitonen, Ari, Makarious, Mary B, Tienari, Pentti, Okubadejo, Njideka U, Ojo, Oluwadamilola O, Kaiyrzhanov, Rauan, Shashkin, Chingiz, Zharkinbekova, Nazira, Akhmetzhanov, Vadim, Kaishybayeva, Gulnaz, Karimova, Altynay, Khaibullin, Talgat, Lynch, Timothy L, Eerola-Rautio, Johanna, Tienari, Pentti J, Grosset, Donald G, Lesage, Suzanne, Corvol, Jean-Christophe, Brice, Alexis, Wood, Nick, Hardy, John, Bandres-Ciga, Sara, Heutink, Peter, Gasser, Thomas, Morris, Huw R, Noyce, Alastair J, Nalls, Mike A, Consortium, and the International Parkinson's Disease Genomics, Leonard, Hampton L, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Storm, Catherine S, Plun-Favreau, Helene, Holmans, Peter, Trabzuni, Daniah, Quinn, John, Bubb, Vivien, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian R, Lovering, Ruth, R'Bibo, Lea, Manzoni, Claudia, Lake, Julie, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Clarke, Carl, Harvey, Kirsten, Jacobs, Benjamin M, Danjou, Fabrice, Martinez, Maria, Simón-Sánchez, Javier, Rizzu, Patrizia, Schneider, Susanne A, Cookson, Mark R, Craig, David W, Billingsley, Kimberley, Kim, Jonggeol J, Narendra, Derek P, Faghri, Faraz, Gibbs, J Raphael, Van Keuren-Jensen, Kendall, Shulman, Joshua M, Robak, Laurie, Universidad de Cantabria, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, University of Helsinki, Clinicum, Research Programs Unit, and Eija Pirinen / Principal Investigator

Subjects
0301 basic medicine, Male, Genotype, EFFICIENT, Physiology, Genome-wide association study, Disease, Biology, Genetic correlation, 3124 Neurology and psychiatry, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, genetics [Parkinson Disease], Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Parkinson Disease/genetics, METAANALYSIS, Research Articles, Genetic association, Aged, RISK, Sex Characteristics, Autosome, 3112 Neurosciences, Parkinson Disease, Heritability, Middle Aged, Genetic architecture, 3. Good health, 030104 developmental biology, Neurology, Female, GENDER, Neurology (clinical), 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study
Abstract

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 13,020male 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 GWASmeta-analyses to identify distinct patterns of genetic risk contributing to disease inmale 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. FUNDING: This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; Project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986. In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128), and The Michael J. Fox Foundation for Parkinson’s Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, and P50NS071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme - Neurodegenerative Diseases Research (JPND) project under the aegis of JPND -www.jpnd.eu – through Germany, BMBF, funding code 01ED1406 and iMed – the Helmholtz Initiative on Personalized Medicine. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. We thank P. Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T. Peuralinna (Department of Neurology, Helsinki University Central Hospital), L. Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R. Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). This study was also funded by the Sigrid Juselius Foundation (KM). We used genomewide association data generated by the Wellcome Trust Case–Control Consortium 2 (WTCCC2) from UK patients with Parkinson’s disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. UK population control data was made available through WTCCC1. As with previous IPDGC efforts, this study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113, 085475, and 090355. This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943 and G1100643). Sequencing and genotyping done in McGill University was supported by grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program and Parkinson’s Society Canada. The access to part of the participants at McGill has been made possible thanks to the Quebec Parkinson’s Network (http://rpq-qpn.ca/en). We thank the Quebec Parkinson’s Network (http://rpq-qpn.org) and its members. Harvard NeuroDiscovery Biomarker Study (HBS) is a collaboration of HBS investigators and funded through philanthropy and NIH and Non-NIH funding sources. The HBS Investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, the full names of all of the PPMI funding partners can be found at www.ppmi-info.org/ fundingpartners. The PPMI Investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit www.ppmi-info.org. Parkinson’s Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/ policy. The PDBP Investigators have not participated in reviewing the data analysis or content of the manuscript

Published
2021

41. Identification of sixteen novel candidate genes for late onset Parkinson's disease

Author

Gialluisi, Alessandro, Reccia, Mafalda Giovanna, Modugno, Nicola, Nutile, Teresa, Lombardi, Alessia, Di Giovannantonio, Luca Giovanni, Pietracupa, Sara, Ruggiero, Daniela, Scala, Simona, Gambardella, Stefano, Noyce, Alastair J., Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A., Tan, Manuela, Houlden, Henry, Morris, Huw R., Plun-Favreau, Helen, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Quinn, John, Bubb, Vivien, Mok, Kin Y., Kinghorn, Kerri J., Billingsley, Kimberley, Wood, Nicholas W., Lewis, Patrick, Schreglmann, Sebastian, Lovering, Rruth, R'Bibo, Lea, Manzoni, Claudia, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E., Clarke, Carl, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Cookson, Mark R., Bandres-Ciga, Sara, Blauwendraat, Cornelis, Craig, David W., Narendra, Derek, Faghri, Faraz, Gibbs, J.Raphael, Hernandez, Dena G., Van Keuren-Jensen, Kendall, Shulman, Joshua M., Iwaki, Hirotaka, Leonard, Hampton L., Nalls, Mike A., Robak, Laurie, Bras, Jose, Guerreiro, Rita, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E., Lungu, Codrin, Singleton, Andrew B., Scholz, Sonja W., Reed, Xylena, Alcalay, Roy N., Gan-Or, Zin, Rouleau, Guy A., Krohn, Lynne, van Hilten, Jacobus J., Marinus, Johan, Adarmes-Gómez, A.D, Aguilar Barberà, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María Teresa, Buiza-Rueda, Dolores, Carrillo, Fátima, Carrión-Claro, M, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, Monica, Dols Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria Jose, Gonzalez-Aramburu, Isabel, Gorostidi Pagola, Ana, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose Luis, López de Munain Arregui, Adolfo, Macias, Daniel, Martínez Torres, Irene, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Méndez-del-Barrio, Carlota, Menéndez González, Manuel, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Mondragon Rezola, Elisabet, Muñoz, Esteban, Pagonabarraga Mora, Javier, Pastor, Pau, Perez Errazquin, Francisco, Periñán-Tocino, Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Sanchez Rodriguez, Antonio, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Majamaa, Kari, Siitonen, Ari, Okubadejo, Njideka U., Ojo, Oluwadamilola O., Shashkin, Chingiz, Zharkynbekova, Nazira, Akhmetzhanov, Vadim, Aitkulova, Akbota, Zholdybayeva, Elena, Zharmukhanov, Zharkyn, Kaishybayeva, Gulnaz, Karimova, Altynay, Sadykova, Dinara, Iacoviello, Licia, Gianfrancesco, F., Acampora, D., D'Esposito, M., Simeone, A., Ciullo, M., Esposito, T., and Universidad de Cantabria

Subjects
0301 basic medicine, Male, Aging, Candidate gene, Parkinson's disease, Neurodegenerative, Bioinformatics, 0302 clinical medicine, Late onset Parkinson’s disease, Novel candidate genes for Parkinson’s disease, Rare variant burden analysis, Whole exome sequencing, Adult, Age of Onset, Aged, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Parkinson Disease, Pedigree, Whole Exome Sequencing, 2.1 Biological and endogenous factors, Medicine, Novel candidate genes for Parkinson's disease, Aetiology, Exome, Exome sequencing, screening and diagnosis, education.field_of_study, Parkinson's Disease, LRRK2, International Parkinson’s Disease Genomics Consortium, Detection, Neurological, Late onset Parkinson's disease, 4.2 Evaluation of markers and technologies, Research Article, Clinical Sciences, Population, 03 medical and health sciences, Cellular and Molecular Neuroscience, Clinical Research, Exome Sequencing, Genetics, RC346-429, education, Molecular Biology, Neurology & Neurosurgery, business.industry, Genetic heterogeneity, Prevention, RC952-954.6, Neurosciences, PARK7, medicine.disease, Brain Disorders, 030104 developmental biology, Geriatrics, Neurology. Diseases of the nervous system, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

Published
2021

42. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores

Author

de Rojas, Itziar, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, Nancy L., Stringa, Najada, Zettergren, Anna, Hernández, Isabel, Montrreal, Laura, Antúnez, Carmen, Antonell, Anna, Tankard, Rick M., Bis, Joshua C., Sims, Rebecca, Bellenguez, Céline, Quintela, Inés, González-Perez, Antonio, Calero, Miguel, Franco-Macías, Emilio, Macías, Juan, Blesa, Rafael, Cervera-Carles, Laura, Menéndez-González, Manuel, Frank-García, Ana, Royo, Jose Luís, Moreno, Fermin, Huerto Vilas, Raquel, Baquero, Miquel, Diez-Fairen, Monica, Lage, Carmen, García-Madrona, Sebastián, García-González, Pablo, Alarcón-Martín, Emilio, Valero, Sergi, Sotolongo-Grau, Oscar, Ullgren, Abbe, Naj, Adam C., Lemstra, Afina W., Benaque, Alba, Pérez-Cordón, Alba, Benussi, Alberto, Rábano, Alberto, Padovani, Alessandro, Squassina, Alessio, de Mendonça, Alexandre, Arias Pastor, Alfonso, Kok, Almar A. L., Meggy, Alun, Pastor, Ana Belén, Espinosa, Ana, Corma-Gómez, Anaïs, Martín Montes, Angel, Sanabria, Ángela, DeStefano, Anita L., Schneider, Anja, Haapasalo, Annakaisa, Kinhult Ståhlbom, Anne, Tybjærg-Hansen, Anne, Hartmann, Annette M., Spottke, Annika, Corbatón-Anchuelo, Arturo, Rongve, Arvid, Borroni, Barbara, Arosio, Beatrice, Nacmias, Benedetta, Nordestgaard, Børge G., Kunkle, Brian W., Charbonnier, Camille, Abdelnour, Carla, Masullo, Carlo, Martínez Rodríguez, Carmen, Muñoz-Fernandez, Carmen, Dufouil, Carole, Graff, Caroline, Ferreira, Catarina B., Chillotti, Caterina, Reynolds, Chandra A., Fenoglio, Chiara, Van Broeckhoven, Christine, Clark, Christopher, Pisanu, Claudia, Satizabal, Claudia L., Holmes, Clive, Buiza-Rueda, Dolores, Aarsland, Dag, Rujescu, Dan, Alcolea, Daniel, Galimberti, Daniela, Wallon, David, Seripa, Davide, Grünblatt, Edna, Dardiotis, Efthimios, Düzel, Emrah, Scarpini, Elio, Conti, Elisa, Rubino, Elisa, Gelpi, Ellen, Rodriguez-Rodriguez, Eloy, Duron, Emmanuelle, Boerwinkle, Eric, Ferri, Evelyn, Tagliavini, Fabrizio, Küçükali, Fahri, Pasquier, Florence, Sanchez-Garcia, Florentino, Mangialasche, Francesca, Jessen, Frank, Nicolas, Gaël, Selbæk, Geir, Ortega, Gemma, Chêne, Geneviève, Hadjigeorgiou, Georgios, Rossi, Giacomina, Spalletta, Gianfranco, Giaccone, Giorgio, Grande, Giulia, Binetti, Giuliano, Papenberg, Goran, Hampel, Harald, Bailly, Henri, Zetterberg, Henrik, Soininen, Hilkka, Karlsson, Ida K., Alvarez, Ignacio, Appollonio, Ildebrando, Giegling, Ina, Skoog, Ingmar, Saltvedt, Ingvild, Rainero, Innocenzo, Rosas Allende, Irene, Hort, Jakub, Diehl-Schmid, Janine, Van Dongen, Jasper, Vidal, Jean-Sebastien, Lehtisalo, Jenni, Wiltfang, Jens, Thomassen, Jesper Qvist, Kornhuber, Johannes, Haines, Jonathan L., Vogelgsang, Jonathan, Pineda, Juan A., Fortea, Juan, Popp, Julius, Deckert, Jürgen, Buerger, Katharina, Morgan, Kevin, Fließbach, Klaus, Sleegers, Kristel, Molina-Porcel, Laura, Kilander, Lena, Weinhold, Leonie, Farrer, Lindsay A., Wang, Li-San, Kleineidam, Luca, Farotti, Lucia, Parnetti, Lucilla, Tremolizzo, Lucio, Hausner, Lucrezia, Benussi, Luisa, Froelich, Lutz, Ikram, M. Arfan, Deniz-Naranjo, M. Candida, Tsolaki, Magda, Rosende-Roca, Maitée, Löwenmark, Malin, Hulsman, Marc, Spallazzi, Marco, Pericak-Vance, Margaret A., Esiri, Margaret, Bernal Sánchez-Arjona, María, Dalmasso, Maria Carolina, Martínez-Larrad, María Teresa, Arcaro, Marina, Nöthen, Markus M., Fernández-Fuertes, Marta, Dichgans, Martin, Ingelsson, Martin, Herrmann, Martin J., Scherer, Martin, Vyhnalek, Martin, Kosmidis, Mary H., Yannakoulia, Mary, Schmid, Matthias, Ewers, Michael, Heneka, Michael T., Wagner, Michael, Scamosci, Michela, Kivipelto, Miia, Hiltunen, Mikko, Zulaica, Miren, Alegret, Montserrat, Fornage, Myriam, Roberto, Natalia, van Schoor, Natasja M., Seidu, Nazib M., Banaj, Nerisa, Armstrong, Nicola J., Scarmeas, Nikolaos, Scherbaum, Norbert, Goldhardt, Oliver, Hanon, Oliver, Peters, Oliver, Skrobot, Olivia Anna, Quenez, Olivier, Lerch, Ondrej, Bossù, Paola, Caffarra, Paolo, Dionigi Rossi, Paolo, Sakka, Paraskevi, Hoffmann, Per, Holmans, Peter A., Fischer, Peter, Riederer, Peter, Yang, Qiong, Marshall, Rachel, Kalaria, Rajesh N., Mayeux, Richard, Vandenberghe, Rik, Cecchetti, Roberta, Ghidoni, Roberta, Frikke-Schmidt, Ruth, Sorbi, Sandro, Hägg, Sara, Engelborghs, Sebastiaan, Helisalmi, Seppo, Botne Sando, Sigrid, Kern, Silke, Archetti, Silvana, Boschi, Silvia, Fostinelli, Silvia, Gil, Silvia, Mendoza, Silvia, Mead, Simon, Ciccone, Simona, Djurovic, Srdjan, Heilmann-Heimbach, Stefanie, Riedel-Heller, Steffi, Kuulasmaa, Teemu, del Ser, Teodoro, Lebouvier, Thibaud, Polak, Thomas, Ngandu, Tiia, Grimmer, Timo, Bessi, Valentina, Escott-Price, Valentina, Giedraitis, Vilmantas, Deramecourt, Vincent, Maier, Wolfgang, Jian, Xueqiu, Pijnenburg, Yolande A. L., Kehoe, Patrick Gavin, García-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Pérez-Tur, Jordi, Piñol-Ripoll, Gerard, Lopez de Munain, Adolfo, García-Alberca, Jose María, Bullido, María J., Álvarez, Victoria, Lleó, Alberto, Real, Luis M., Mir, Pablo, Medina, Miguel, Scheltens, Philip, Holstege, Henne, Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Amouyel, Philippe, Schellenberg, Gerard D., Williams, Julie, Seshadri, Sudha, van Duijn, Cornelia M., Mather, Karen A., Sánchez-Valle, Raquel, Serrano-Ríos, Manuel, Orellana, Adelina, Tárraga, Lluís, Blennow, Kaj, Huisman, Martijn, Andreassen, Ole A., Posthuma, Danielle, Clarimón, Jordi, Boada, Mercè, van der Flier, Wiesje M., Ramirez, Alfredo, Lambert, Jean-Charles, van der Lee, Sven J., Ruiz, Agustín, Universitat Autònoma de Barcelona, de Rojas, Itziar, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, Nancy L., Stringa, Najada, Zettergren, Anna, Hernández, Isabel, Montrreal, Laura, Antúnez, Carmen, Antonell, Anna, Tankard, Rick M., Bis, Joshua C., Sims, Rebecca, Bellenguez, Céline, Quintela, Inés, González-Perez, Antonio, Calero, Miguel, Franco-Macías, Emilio, Macías, Juan, Blesa, Rafael, Cervera-Carles, Laura, Menéndez-González, Manuel, Frank-García, Ana, Royo, Jose Luís, Moreno, Fermin, Huerto Vilas, Raquel, Baquero, Miquel, Diez-Fairen, Monica, Lage, Carmen, García-Madrona, Sebastián, García-González, Pablo, Alarcón-Martín, Emilio, Valero, Sergi, Sotolongo-Grau, Oscar, Ullgren, Abbe, Naj, Adam C., Lemstra, Afina W., Benaque, Alba, Pérez-Cordón, Alba, Benussi, Alberto, Rábano, Alberto, Padovani, Alessandro, Squassina, Alessio, de Mendonça, Alexandre, Arias Pastor, Alfonso, Kok, Almar A. L., Meggy, Alun, Pastor, Ana Belén, Espinosa, Ana, Corma-Gómez, Anaïs, Martín Montes, Angel, Sanabria, Ángela, DeStefano, Anita L., Schneider, Anja, Haapasalo, Annakaisa, Kinhult Ståhlbom, Anne, Tybjærg-Hansen, Anne, Hartmann, Annette M., Spottke, Annika, Corbatón-Anchuelo, Arturo, Rongve, Arvid, Borroni, Barbara, Arosio, Beatrice, Nacmias, Benedetta, Nordestgaard, Børge G., Kunkle, Brian W., Charbonnier, Camille, Abdelnour, Carla, Masullo, Carlo, Martínez Rodríguez, Carmen, Muñoz-Fernandez, Carmen, Dufouil, Carole, Graff, Caroline, Ferreira, Catarina B., Chillotti, Caterina, Reynolds, Chandra A., Fenoglio, Chiara, Van Broeckhoven, Christine, Clark, Christopher, Pisanu, Claudia, Satizabal, Claudia L., Holmes, Clive, Buiza-Rueda, Dolores, Aarsland, Dag, Rujescu, Dan, Alcolea, Daniel, Galimberti, Daniela, Wallon, David, Seripa, Davide, Grünblatt, Edna, Dardiotis, Efthimios, Düzel, Emrah, Scarpini, Elio, Conti, Elisa, Rubino, Elisa, Gelpi, Ellen, Rodriguez-Rodriguez, Eloy, Duron, Emmanuelle, Boerwinkle, Eric, Ferri, Evelyn, Tagliavini, Fabrizio, Küçükali, Fahri, Pasquier, Florence, Sanchez-Garcia, Florentino, Mangialasche, Francesca, Jessen, Frank, Nicolas, Gaël, Selbæk, Geir, Ortega, Gemma, Chêne, Geneviève, Hadjigeorgiou, Georgios, Rossi, Giacomina, Spalletta, Gianfranco, Giaccone, Giorgio, Grande, Giulia, Binetti, Giuliano, Papenberg, Goran, Hampel, Harald, Bailly, Henri, Zetterberg, Henrik, Soininen, Hilkka, Karlsson, Ida K., Alvarez, Ignacio, Appollonio, Ildebrando, Giegling, Ina, Skoog, Ingmar, Saltvedt, Ingvild, Rainero, Innocenzo, Rosas Allende, Irene, Hort, Jakub, Diehl-Schmid, Janine, Van Dongen, Jasper, Vidal, Jean-Sebastien, Lehtisalo, Jenni, Wiltfang, Jens, Thomassen, Jesper Qvist, Kornhuber, Johannes, Haines, Jonathan L., Vogelgsang, Jonathan, Pineda, Juan A., Fortea, Juan, Popp, Julius, Deckert, Jürgen, Buerger, Katharina, Morgan, Kevin, Fließbach, Klaus, Sleegers, Kristel, Molina-Porcel, Laura, Kilander, Lena, Weinhold, Leonie, Farrer, Lindsay A., Wang, Li-San, Kleineidam, Luca, Farotti, Lucia, Parnetti, Lucilla, Tremolizzo, Lucio, Hausner, Lucrezia, Benussi, Luisa, Froelich, Lutz, Ikram, M. Arfan, Deniz-Naranjo, M. Candida, Tsolaki, Magda, Rosende-Roca, Maitée, Löwenmark, Malin, Hulsman, Marc, Spallazzi, Marco, Pericak-Vance, Margaret A., Esiri, Margaret, Bernal Sánchez-Arjona, María, Dalmasso, Maria Carolina, Martínez-Larrad, María Teresa, Arcaro, Marina, Nöthen, Markus M., Fernández-Fuertes, Marta, Dichgans, Martin, Ingelsson, Martin, Herrmann, Martin J., Scherer, Martin, Vyhnalek, Martin, Kosmidis, Mary H., Yannakoulia, Mary, Schmid, Matthias, Ewers, Michael, Heneka, Michael T., Wagner, Michael, Scamosci, Michela, Kivipelto, Miia, Hiltunen, Mikko, Zulaica, Miren, Alegret, Montserrat, Fornage, Myriam, Roberto, Natalia, van Schoor, Natasja M., Seidu, Nazib M., Banaj, Nerisa, Armstrong, Nicola J., Scarmeas, Nikolaos, Scherbaum, Norbert, Goldhardt, Oliver, Hanon, Oliver, Peters, Oliver, Skrobot, Olivia Anna, Quenez, Olivier, Lerch, Ondrej, Bossù, Paola, Caffarra, Paolo, Dionigi Rossi, Paolo, Sakka, Paraskevi, Hoffmann, Per, Holmans, Peter A., Fischer, Peter, Riederer, Peter, Yang, Qiong, Marshall, Rachel, Kalaria, Rajesh N., Mayeux, Richard, Vandenberghe, Rik, Cecchetti, Roberta, Ghidoni, Roberta, Frikke-Schmidt, Ruth, Sorbi, Sandro, Hägg, Sara, Engelborghs, Sebastiaan, Helisalmi, Seppo, Botne Sando, Sigrid, Kern, Silke, Archetti, Silvana, Boschi, Silvia, Fostinelli, Silvia, Gil, Silvia, Mendoza, Silvia, Mead, Simon, Ciccone, Simona, Djurovic, Srdjan, Heilmann-Heimbach, Stefanie, Riedel-Heller, Steffi, Kuulasmaa, Teemu, del Ser, Teodoro, Lebouvier, Thibaud, Polak, Thomas, Ngandu, Tiia, Grimmer, Timo, Bessi, Valentina, Escott-Price, Valentina, Giedraitis, Vilmantas, Deramecourt, Vincent, Maier, Wolfgang, Jian, Xueqiu, Pijnenburg, Yolande A. L., Kehoe, Patrick Gavin, García-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Pérez-Tur, Jordi, Piñol-Ripoll, Gerard, Lopez de Munain, Adolfo, García-Alberca, Jose María, Bullido, María J., Álvarez, Victoria, Lleó, Alberto, Real, Luis M., Mir, Pablo, Medina, Miguel, Scheltens, Philip, Holstege, Henne, Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Amouyel, Philippe, Schellenberg, Gerard D., Williams, Julie, Seshadri, Sudha, van Duijn, Cornelia M., Mather, Karen A., Sánchez-Valle, Raquel, Serrano-Ríos, Manuel, Orellana, Adelina, Tárraga, Lluís, Blennow, Kaj, Huisman, Martijn, Andreassen, Ole A., Posthuma, Danielle, Clarimón, Jordi, Boada, Mercè, van der Flier, Wiesje M., Ramirez, Alfredo, Lambert, Jean-Charles, van der Lee, Sven J., Ruiz, Agustín, and Universitat Autònoma de Barcelona

Abstract

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease. Known genetic loci account for only a fraction of the genetic contribution to Alzheimer's disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer's disease polygenic risk score.

Published
2021

43. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], Chia, Ruth, Sabir, Marya S., Bandres-Ciga, Sara, Saez-Atienzar, Sara, Reynolds, Regina H., Gustavsson, Emil, Walton, Ronald L., Ahmed, Sarah, Viollet, Coralie, Ding, Jinhui, Makarious, Mary B., Diez-Fairen, Monica, Portley, Makayla K., Shah, Zalak, Abramzon, Yevgeniya, Hernandez, Dena G., Blauwendraat, Cornelis, Stone, David J., Eicher, John, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S., Marder, Karen, Lemstra, Afina, St George-Hyslop, Peter, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T., Jaunmuktane, Zane, Galasko, Douglas, Santana, Isabel, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Cairns, Nigel J., Morris, John C., Halliday, Glenda M., Van Deerlin, Vivianna M., Trojanowski, John Q., Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C., Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T., Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David S., Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Sotis, Anthony R., Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa Mcgrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Kaufmann, Horacio, Shakkottai, Vikram G., Perkins, Matthew, Newell, Kathy L., Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Kim, Ronald C., Caraway, Chad A., Monuki, Edwin S., Brunetti, Maura, Dawson, Ted M., Rosenthal, Liana S., Albert, Marilyn S., Pletnikova, Olga, Troncoso, Juan C., Flanagan, Margaret E., Mao, Qinwen, Bigio, Eileen H., Rodríguez-Rodríguez, Eloy, Infante, Jon, Lage, Carmen, González-Aramburu, Isabel, Sanchez-Juan, Pascual, Ghetti, Bernardino, Keith, Julia, Black, Sandra E., Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J., Tilley, Bension S., Gentleman, Steve, Logroscino, Giancarlo, Serrano, Geidy E., Beach, Thomas G., McKeith, Ian G., Thomas, Alan J., Attems, Johannes, Morris, Christopher M., Palmer, Laura, Love, Seth, Troakes, Claire, Al-Sarraj, Safa, Hodges, Angela K., Aarsland, Dag, Klein, Gregory, Kaiser, Scott M., Woltjer, Randy, Pastor, Pau, Bekris, Lynn M., Leverenz, James B., Besser, Lilah M., Kuzma, Amanda, Renton, Alan E., Goate, Alison, Bennett, David A., Scherzer, Clemens R., Morris, Huw R., Ferrari, Raffaele, Albani, Diego, Pickering-Brown, Stuart, Faber, Kelley, Kukull, Walter A., Morenas-Rodriguez, Estrella, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Clarimon, Jordi, Nalls, Mike A., Ferrucci, Luigi, Resnick, Susan M., Tanaka, Toshiko, Foroud, Tatiana M., Graff-Radford, Neill R., Wszolek, Zbigniew K., Ferman, Tanis, Boeve, Bradley F., Hardy, John A., Topol, Eric J., Torkamani, Ali, Singleton, Andrew B., Ryten, Mina, Dickson, Dennis W., Chiò, Adriano, Ross, Owen A., Gibbs, J. Raphael, Dalgard, Clifton L., Traynor, Bryan J., Scholz, Sonja W., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Fonds National de la Recherche - FnR [sponsor], Chia, Ruth, Sabir, Marya S., Bandres-Ciga, Sara, Saez-Atienzar, Sara, Reynolds, Regina H., Gustavsson, Emil, Walton, Ronald L., Ahmed, Sarah, Viollet, Coralie, Ding, Jinhui, Makarious, Mary B., Diez-Fairen, Monica, Portley, Makayla K., Shah, Zalak, Abramzon, Yevgeniya, Hernandez, Dena G., Blauwendraat, Cornelis, Stone, David J., Eicher, John, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S., Marder, Karen, Lemstra, Afina, St George-Hyslop, Peter, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T., Jaunmuktane, Zane, Galasko, Douglas, Santana, Isabel, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Cairns, Nigel J., Morris, John C., Halliday, Glenda M., Van Deerlin, Vivianna M., Trojanowski, John Q., Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C., Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T., Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David S., Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Sotis, Anthony R., Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa Mcgrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Kaufmann, Horacio, Shakkottai, Vikram G., Perkins, Matthew, Newell, Kathy L., Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Kim, Ronald C., Caraway, Chad A., Monuki, Edwin S., Brunetti, Maura, Dawson, Ted M., Rosenthal, Liana S., Albert, Marilyn S., Pletnikova, Olga, Troncoso, Juan C., Flanagan, Margaret E., Mao, Qinwen, Bigio, Eileen H., Rodríguez-Rodríguez, Eloy, Infante, Jon, Lage, Carmen, González-Aramburu, Isabel, Sanchez-Juan, Pascual, Ghetti, Bernardino, Keith, Julia, Black, Sandra E., Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J., Tilley, Bension S., Gentleman, Steve, Logroscino, Giancarlo, Serrano, Geidy E., Beach, Thomas G., McKeith, Ian G., Thomas, Alan J., Attems, Johannes, Morris, Christopher M., Palmer, Laura, Love, Seth, Troakes, Claire, Al-Sarraj, Safa, Hodges, Angela K., Aarsland, Dag, Klein, Gregory, Kaiser, Scott M., Woltjer, Randy, Pastor, Pau, Bekris, Lynn M., Leverenz, James B., Besser, Lilah M., Kuzma, Amanda, Renton, Alan E., Goate, Alison, Bennett, David A., Scherzer, Clemens R., Morris, Huw R., Ferrari, Raffaele, Albani, Diego, Pickering-Brown, Stuart, Faber, Kelley, Kukull, Walter A., Morenas-Rodriguez, Estrella, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Clarimon, Jordi, Nalls, Mike A., Ferrucci, Luigi, Resnick, Susan M., Tanaka, Toshiko, Foroud, Tatiana M., Graff-Radford, Neill R., Wszolek, Zbigniew K., Ferman, Tanis, Boeve, Bradley F., Hardy, John A., Topol, Eric J., Torkamani, Ali, Singleton, Andrew B., Ryten, Mina, Dickson, Dennis W., Chiò, Adriano, Ross, Owen A., Gibbs, J. Raphael, Dalgard, Clifton L., Traynor, Bryan J., and Scholz, Sonja W.

Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Published
2021

44. Exome-wide rare variant analysis in familial essential tremor

Author

Diez-Fairen, Monica, Houle, Gabrielle, Ortega-Cubero, Sara, Bandres-Ciga, Sara, Alvarez, Ignacio, Carcel, Maria, Ibañez, Laura, Fernandez, Maria Victoria, Budde, John P, Trotta, Jean-Rémi, Tonda, Raúl, Chong, Jessica X, Bamshad, Michael J, Nickerson, Deborah A, University of Washington Center for Mendelian Genomics (UWCMG), Aguilar, Miquel, Tartari, Juan P, Gironell, Alexandre, García-Martín, Elena, Agundez, Jose Ag, Alonso-Navarro, Hortensia, Jimenez-Jimenez, Felix Javier, Fernandez, Manel, Valldeoriola, Francesc, Marti, Maria Jose, Tolosa, Eduard, Coria, Francisco, Pastor, Maria A, Vilariño-Güell, Carles, Rajput, Alex, Dion, Patrick A, Cruchaga, Carlos, Rouleau, Guy A, and Pastor, Pau

Subjects
0301 basic medicine, Adult, Male, Candidate gene, Movement disorders, Essential Tremor, Disease, Biology, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Matrix Metalloproteinase 10, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Gene, Exome, Exome sequencing, Aged, Genetics, Genetic risk, Aged, 80 and over, Essential tremor, MMP10, Rare variants, Heritability, Middle Aged, medicine.disease, Pedigree, 030104 developmental biology, Neurology, WES, Female, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, 030217 neurology & neurosurgery
Abstract

Introduction Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing. Methods We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes. Results Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders. Conclusions We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.

Published
2020

45. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

Author

Zhang, Ming, Ferrari, Raffaele, Tartaglia, Maria Carmela, Keith, Julia, Surace, Ezequiel I, Wolf, Uri, Sato, Christine, Grinberg, Mark, Liang, Yan, Xi, Zhengrui, Dupont, Kyle, McGoldrick, Philip, Weichert, Anna, McKeever, Paul M, Schneider, Raphael, McCorkindale, Michael D, Manzoni, Claudia, Rademakers, Rosa, Graff-Radford, Neill R, Dickson, Dennis W, Parisi, Joseph E, Boeve, Bradley F, Petersen, Ronald C, Miller, Bruce L, Seeley, William W, Van Swieten, John C, Van Rooij, Jeroen, Pijnenburg, Yolande, Van Der Zee, Julie, Van Broeckhoven, Christine, Le Ber, Isabelle, Van Deerlin, Vivianna, Suh, EunRan, Rohrer, Jonathan D, Mead, Simon, Graff, Caroline, Öijerstedt, Linn, Pickering-Brown, Stuart, Rollinson, Sara, Rossi, Giacomina, Tagliavini, Fabrizio, Brooks, William S, Dobson-Stone, Carol, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Binetti, Giuliano, Benussi, Luisa, Ghidoni, Roberta, Nacmias, Benedetta, Sorbi, Sandro, Bruni, Amalia C, Galimberti, Daniela, Scarpini, Elio, Rainero, Innocenzo, Rubino, Elisa, Clarimon, Jordi, Lleó, Alberto, Ruiz, Agustin, Hernández, Isabel, Pastor, Pau, Diez-Fairen, Monica, Borroni, Barbara, Pasquier, Florence, Deramecourt, Vincent, Lebouvier, Thibaud, Perneczky, Robert, Diehl-Schmid, Janine, Grafman, Jordan, Huey, Edward D, Mayeux, Richard, Nalls, Michael A, Hernandez, Dena, Singleton, Andrew, Momeni, Parastoo, Zeng, Zhen, Hardy, John, Robertson, Janice, Zinman, Lorne, Rogaeva, Ekaterina, International FTD-Genomics Consortium (IFGC), Schneider, Raphael [0000-0003-1776-2418], Manzoni, Claudia [0000-0001-5367-4023], Diez-Fairen, Monica [0000-0003-1882-0309], and Apollo - University of Cambridge Repository

Subjects
Male, Aging, amyotrophic lateral sclerosis, Heterozygote, genetic association, Genotype, Neurodegenerative, Medical and Health Sciences, frontotemporal dementia, Polymorphism, Single Nucleotide, Rare Diseases, age of onset, Clinical Research, C9orf72, Acquired Cognitive Impairment, Genetics, 2.1 Biological and endogenous factors, Humans, Polymorphism, Aetiology, Age of Onset, Aged, Neurology & Neurosurgery, C9orf72 Protein, International FTD-Genomics Consortium, Human Genome, Psychology and Cognitive Sciences, Amyotrophic Lateral Sclerosis, Neurosciences, Single Nucleotide, DNA Methylation, Middle Aged, Brain Disorders, Gene Expression Regulation, Frontotemporal Dementia, Neurological, Dementia, CpG Islands, Female, ALS, Biotechnology
Abstract

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Published
2019
Full Text
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48. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author

Dewan, Ramita, primary, Chia, Ruth, additional, Ding, Jinhui, additional, Hickman, Richard A., additional, Stein, Thor D., additional, Abramzon, Yevgeniya, additional, Ahmed, Sarah, additional, Sabir, Marya S., additional, Portley, Makayla K., additional, Tucci, Arianna, additional, Ibáñez, Kristina, additional, Shankaracharya, F.N.U., additional, Keagle, Pamela, additional, Rossi, Giacomina, additional, Caroppo, Paola, additional, Tagliavini, Fabrizio, additional, Waldo, Maria L., additional, Johansson, Per M., additional, Nilsson, Christer F., additional, Rowe, James B., additional, Benussi, Luisa, additional, Binetti, Giuliano, additional, Ghidoni, Roberta, additional, Jabbari, Edwin, additional, Viollet, Coralie, additional, Glass, Jonathan D., additional, Singleton, Andrew B., additional, Silani, Vincenzo, additional, Ross, Owen A., additional, Ryten, Mina, additional, Torkamani, Ali, additional, Tanaka, Toshiko, additional, Ferrucci, Luigi, additional, Resnick, Susan M., additional, Pickering-Brown, Stuart, additional, Brady, Christopher B., additional, Kowal, Neil, additional, Hardy, John A., additional, Van Deerlin, Vivianna, additional, Vonsattel, Jean Paul, additional, Harms, Matthew B., additional, Morris, Huw R., additional, Ferrari, Raffaele, additional, Landers, John E., additional, Chiò, Adriano, additional, Gibbs, J. Raphael, additional, Dalgard, Clifton L., additional, Scholz, Sonja W., additional, Traynor, Bryan J., additional, Adeleye, Adelani, additional, Alba, Camille, additional, Bacikova, Dagmar, additional, Hupalo, Daniel N., additional, Martinez, Elisa McGrath, additional, Pollard, Harvey B., additional, Sukumar, Gauthaman, additional, Soltis, Anthony R., additional, Tuck, Meila, additional, Zhang, Xijun, additional, Wilkerson, Matthew D., additional, Smith, Bradley N., additional, Ticozzi, Nicola, additional, Fallini, Claudia, additional, Gkazi, Athina Soragia, additional, Topp, Simon D., additional, Kost, Jason, additional, Scotter, Emma L., additional, Kenna, Kevin P., additional, Miller, Jack W., additional, Tiloca, Cinzia, additional, Vance, Caroline, additional, Danielson, Eric W., additional, Troakes, Claire, additional, Colombrita, Claudia, additional, Al-Sarraj, Safa, additional, Lewis, Elizabeth A., additional, King, Andrew, additional, Calini, Daniela, additional, Pensato, Viviana, additional, Castellotti, Barbara, additional, de Belleroche, Jacqueline, additional, Baas, Frank, additional, ten Asbroek, Anneloor L.M.A., additional, Sapp, Peter C., additional, McKenna-Yasek, Diane, additional, McLaughlin, Russell L., additional, Polak, Meraida, additional, Asress, Seneshaw, additional, Esteban-Pérez, Jesús, additional, Muñoz-Blanco, José Luis, additional, Stevic, Zorica, additional, D’Alfonso, Sandra, additional, Mazzini, Letizia, additional, Comi, Giacomo P., additional, Del Bo, Roberto, additional, Ceroni, Mauro, additional, Gagliardi, Stella, additional, Querin, Giorgia, additional, Bertolin, Cinzia, additional, van Rheenen, Wouter, additional, Diekstra, Frank P., additional, Rademakers, Rosa, additional, van Blitterswijk, Marka, additional, Boylan, Kevin B., additional, Lauria, Giuseppe, additional, Duga, Stefano, additional, Corti, Stefania, additional, Cereda, Cristina, additional, Corrado, Lucia, additional, Sorarù, Gianni, additional, Williams, Kelly L., additional, Nicholson, Garth A., additional, Blair, Ian P., additional, Leblond-Manry, Claire, additional, Rouleau, Guy A., additional, Hardiman, Orla, additional, Morrison, Karen E., additional, Veldink, Jan H., additional, van den Berg, Leonard H., additional, Al-Chalabi, Ammar, additional, Pall, Hardev, additional, Shaw, Pamela J., additional, Turner, Martin R., additional, Talbot, Kevin, additional, Taroni, Franco, additional, García-Redondo, Alberto, additional, Wu, Zheyang, additional, Gellera, Cinzia, additional, Ratti, Antonia, additional, Brown, Robert H., additional, Shaw, Christopher E., additional, Ambrose, John C., additional, Arumugam, Prabhu, additional, Baple, Emma L., additional, Bleda, Marta, additional, Boardman-Pretty, Freya, additional, Boissiere, Jeanne M., additional, Boustred, Christopher R., additional, Brittain, H., additional, Caulfield, Mark J., additional, Chan, Georgia C., additional, Craig, Clare E.H., additional, Daugherty, Louise C., additional, de Burca, Anna, additional, Devereau, Andrew, additional, Elgar, Greg, additional, Foulger, Rebecca E., additional, Fowler, Tom, additional, Furió-Tarí, Pedro, additional, Hackett, Joanne M., additional, Halai, Dina, additional, Hamblin, Angela, additional, Henderson, Shirley, additional, Holman, James E., additional, Hubbard, Tim J.P., additional, Jackson, Rob, additional, Jones, Louise J., additional, Kasperaviciute, Dalia, additional, Kayikci, Melis, additional, Lahnstein, Lea, additional, Lawson, Kay, additional, Leigh, Sarah E.A., additional, Leong, Ivonne U.S., additional, Lopez, Javier F., additional, Maleady-Crowe, Fiona, additional, Mason, Joanne, additional, McDonagh, Ellen M., additional, Moutsianas, Loukas, additional, Mueller, Michael, additional, Murugaesu, Nirupa, additional, Need, Anna C., additional, Odhams, Chris A., additional, Patch, Christine, additional, Perez-Gil, Daniel, additional, Polychronopoulos, Dimitris, additional, Pullinger, John, additional, Rahim, Tahrima, additional, Rendon, Augusto, additional, Riesgo-Ferreiro, Pablo, additional, Rogers, Tim, additional, Savage, Kevin, additional, Sawant, Kushmita, additional, Scott, Richard H., additional, Siddiq, Afshan, additional, Sieghart, Alexander, additional, Smedley, Damian, additional, Smith, Katherine R., additional, Sosinsky, Alona, additional, Spooner, William, additional, Stevens, Helen E., additional, Stuckey, Alexander, additional, Sultana, Razvan, additional, Thomas, Ellen R.A., additional, Thompson, Simon R., additional, Tregidgo, Carolyn, additional, Walsh, Emma, additional, Watters, Sarah A., additional, Welland, Matthew J., additional, Williams, Eleanor, additional, Witkowska, Katarzyna, additional, Wood, Suzanne M., additional, Zarowiecki, Magdalena, additional, Arepalli, Sampath, additional, Auluck, Pavan, additional, Baloh, Robert H., additional, Bowser, Robert, additional, Brice, Alexis, additional, Broach, James, additional, Camu, William, additional, Cooper-Knock, John, additional, Corcia, Philippe, additional, Drepper, Carsten, additional, Drory, Vivian E., additional, Dunckley, Travis L., additional, Faghri, Faraz, additional, Farren, Jennifer, additional, Feldman, Eva, additional, Floeter, Mary Kay, additional, Fratta, Pietro, additional, Gerhard, Glenn, additional, Gibson, Summer B., additional, Goutman, Stephen A., additional, Heiman-Patterson, Terry D., additional, Hernandez, Dena G., additional, Hoover, Ben, additional, Jansson, Lilja, additional, Kamel, Freya, additional, Kirby, Janine, additional, Kowall, Neil W., additional, Laaksovirta, Hannu, additional, Landi, Francesco, additional, Le Ber, Isabelle, additional, Lumbroso, Serge, additional, MacGowan, Daniel JL., additional, Maragakis, Nicholas J., additional, Mora, Gabriele, additional, Mouzat, Kevin, additional, Myllykangas, Liisa, additional, Nalls, Mike A., additional, Orrell, Richard W., additional, Ostrow, Lyle W., additional, Pamphlett, Roger, additional, Pioro, Erik, additional, Pulst, Stefan M., additional, Ravits, John M., additional, Renton, Alan E., additional, Robberecht, Wim, additional, Robey, Ian, additional, Rogaeva, Ekaterina, additional, Rothstein, Jeffrey D., additional, Sendtner, Michael, additional, Sidle, Katie C., additional, Simmons, Zachary, additional, Stone, David J., additional, Tienari, Pentti J., additional, Trojanowski, John Q., additional, Troncoso, Juan C., additional, Valori, Miko, additional, Van Damme, Philip, additional, Van Den Bosch, Ludo, additional, Zinman, Lorne, additional, Albani, Diego, additional, Borroni, Barbara, additional, Padovani, Alessandro, additional, Bruni, Amalia, additional, Clarimon, Jordi, additional, Dols-Icardo, Oriol, additional, Illán-Gala, Ignacio, additional, Lleó, Alberto, additional, Danek, Adrian, additional, Galimberti, Daniela, additional, Scarpini, Elio, additional, Serpente, Maria, additional, Graff, Caroline, additional, Chiang, Huei-Hsin, additional, Khoshnood, Behzad, additional, Öijerstedt, Linn, additional, Morris, Christopher M., additional, Nacmias, Benedetta, additional, Sorbi, Sandro, additional, Nielsen, Jorgen E., additional, Hjermind, Lynne E., additional, Novelli, Valeria, additional, Puca, Annibale A., additional, Pastor, Pau, additional, Alvarez, Ignacio, additional, Diez-Fairen, Monica, additional, Aguilar, Miquel, additional, Perneczky, Robert, additional, Diehl-Schimd, Janine, additional, Rossi, Mina, additional, Ruiz, Agustin, additional, Boada, Mercè, additional, Hernández, Isabel, additional, Moreno-Grau, Sonia, additional, Schlachetzki, Johannes C., additional, Aarsland, Dag, additional, Albert, Marilyn S., additional, Attems, Johannes, additional, Barrett, Matthew J., additional, Beach, Thomas G., additional, Bekris, Lynn M., additional, Bennett, David A., additional, Besser, Lilah M., additional, Bigio, Eileen H., additional, Black, Sandra E., additional, Boeve, Bradley F., additional, Bohannan, Ryan C., additional, Brett, Francesca, additional, Brunetti, Maura, additional, Caraway, Chad A., additional, Palma, Jose-Alberto, additional, Calvo, Andrea, additional, Canosa, Antonio, additional, Dickson, Dennis, additional, Duyckaerts, Charles, additional, Faber, Kelley, additional, Ferman, Tanis, additional, Flanagan, Margaret E., additional, Floris, Gianluca, additional, Foroud, Tatiana M., additional, Fortea, Juan, additional, Gan-Or, Ziv, additional, Gentleman, Steve, additional, Ghetti, Bernardino, additional, Gibbs, Jesse Raphael, additional, Goate, Alison, additional, Goldstein, David, additional, González-Aramburu, Isabel, additional, Graff-Radford, Neill R., additional, Hodges, Angela K., additional, Hu, Heng-Chen, additional, Hupalo, Daniel, additional, Infante, Jon, additional, Iranzo, Alex, additional, Kaiser, Scott M., additional, Kaufmann, Horacio, additional, Keith, Julia, additional, Kim, Ronald C., additional, Klein, Gregory, additional, Krüger, Rejko, additional, Kukull, Walter, additional, Kuzma, Amanda, additional, Lage, Carmen, additional, Lesage, Suzanne, additional, Leverenz, James B., additional, Logroscino, Giancarlo, additional, Lopez, Grisel, additional, Love, Seth, additional, Mao, Qinwen, additional, Marti, Maria Jose, additional, Martinez-McGrath, Elisa, additional, Masellis, Mario, additional, Masliah, Eliezer, additional, May, Patrick, additional, McKeith, Ian, additional, Mesulam, Marek-Marsel, additional, Monuki, Edwin S., additional, Newell, Kathy L., additional, Norcliffe-Kaufmann, Lucy, additional, Palmer, Laura, additional, Perkins, Matthew, additional, Pletnikova, Olga, additional, Molina-Porcel, Laura, additional, Reynolds, Regina H., additional, Rodríguez-Rodríguez, Eloy, additional, Rohrer, Jonathan D., additional, Sanchez-Juan, Pascual, additional, Scherzer, Clemens R., additional, Serrano, Geidy E., additional, Shakkottai, Vikram, additional, Sidransky, Ellen, additional, Tayebi, Nahid, additional, Thomas, Alan J., additional, Tilley, Bension S., additional, Walton, Ronald L., additional, Woltjer, Randy, additional, Wszolek, Zbigniew K., additional, Xiromerisiou, Georgia, additional, Zecca, Chiara, additional, Phatnani, Hemali, additional, Kwan, Justin, additional, Sareen, Dhruv, additional, Broach, James R., additional, Arcila-Londono, Ximena, additional, Lee, Edward B., additional, Shneider, Neil A., additional, Fraenkel, Ernest, additional, Zaitlen, Noah, additional, Berry, James D., additional, Malaspina, Andrea, additional, Cox, Gregory A., additional, Thompson, Leslie M., additional, Finkbeiner, Steve, additional, Dardiotis, Efthimios, additional, Miller, Timothy M., additional, Chandran, Siddharthan, additional, Pal, Suvankar, additional, Hornstein, Eran, additional, MacGowan, Daniel J., additional, Heiman-Patterson, Terry, additional, Hammell, Molly G., additional, Patsopoulos, Nikolaos.A., additional, Butovsky, Oleg, additional, Dubnau, Joshua, additional, Nath, Avindra, additional, Harms, Matt, additional, Aronica, Eleonora, additional, Poss, Mary, additional, Phillips-Cremins, Jennifer, additional, Crary, John, additional, Atassi, Nazem, additional, Lange, Dale J., additional, Adams, Darius J., additional, Stefanis, Leonidas, additional, Gotkine, Marc, additional, Babu, Suma, additional, Raj, Towfique, additional, Paganoni, Sabrina, additional, Shalem, Ophir, additional, Smith, Colin, additional, Zhang, Bin, additional, Harris, Brent, additional, Broce, Iris, additional, Drory, Vivian, additional, Ravits, John, additional, McMillan, Corey, additional, Menon, Vilas, additional, Wu, Lani, additional, Altschuler, Steven, additional, Amar, Khaled, additional, Archibald, Neil, additional, Bandmann, Oliver, additional, Capps, Erica, additional, Church, Alistair, additional, Coebergh, Jan, additional, Costantini, Alyssa, additional, Critchley, Peter, additional, Ghosh, Boyd CP., additional, Hu, Michele T.M., additional, Kobylecki, Christopher, additional, Leigh, P. Nigel, additional, Mann, Carl, additional, Massey, Luke A., additional, Nath, Uma, additional, Pavese, Nicola, additional, Paviour, Dominic, additional, Sharma, Jagdish, additional, and Vaughan, Jenny, additional

Published
2021
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49. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture

Author

Chia, Ruth, Sabir, Marya S., Bandres-Ciga, Sara, Saez-Atienzar, Sara, Reynolds, Regina H., Gustavsson, Emil, Walton, Ronald L., Ahmed, Sarah, Viollet, Coralie, Ding, Jinhui, Makarious, Mary B., Diez-Fairen, Monica, Portley, Makayla K., Shah, Zalak, Abramzon, Yevgeniya, Hernandez, Dena G., Blauwendraat, Cornelis, Stone, David J., Eicher, John, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S., Marder, Karen, Lemstra, Afina, George-Hyslop, Peter St, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T., Jaunmuktane, Zane, Galasko, Douglas, Santana, Isabel, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Cairns, Nigel J., Morris, John C., Halliday, Glenda M., Van Deerlin, Vivianna M., Trojanowski, John Q., Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C., Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T., Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David, Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Palma, Jose-Alberto, Kaufmann, Horacio, Shakkottai, Vikram, Perkins, Matthew, Newell, Kathy L., Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Kim, Ronald C., Caraway, Chad A., Monuki, Ed, Brunetti, Maura, Dawson, Ted M., Rosenthal, Liana S., Albert, Marilyn S., Pletnikova, Olga, Troncoso, Juan C., Flanagan, Margaret E., Mao, Qinwen, Bigio, Eileen H., Rodríguez-Rodríguez, Eloy, Infante, Jon, Lage, Carmen, González-Aramburu, Isabel, Sanchez-Juan, Pascual, Ghetti, Bernardino, Keith, Julia, Black, Sandra E., Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J., Tilley, Bension S., Gentleman, Steve, Logroscino, Giancarlo, Serrano, Geidy E., Beach, Thomas G., McKeith, Ian G., Thomas, Alan J., Attems, Johannes, Morris, Christopher M., Palmer, Laura, Love, Seth, Troakes, Claire, Al-Sarraj, Safa, Hodges, Angela K., Aarsland, Dag, Klein, Gregory, Kaiser, Scott M., Woltjer, Randy, Pastor, Pau, Bekris, Lynn M., Leverenz, James, Besser, Lilah M., Kuzma, Amanda, Renton, Alan E., Goate, Alison, Bennett, David A., Scherzer, Clemens R., Morris, Huw R., Ferrari, Raffaele, Albani, Diego, Brown, Stuart Pickering, Faber, Kelley, Kukull, Walter, Morenas-Rodriguez, Estrella, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Clarimon, Jordi, Nalls, Michael A., Ferrucci, Luigi, Resnick, Susan M., Tanaka, Toshiko, Foroud, Tatiana M., Graff-Radford, Neill R., Wszolek, Zbigniew K., Ferman, Tanis, Boeve, Bradley F., Hardy, John A., Topol, Eric, Torkamani, Ali, Singleton, Andrew B., Ryten, Mina, Dickson, Dennis, Chiò, Adriano, Ross, Owen A., Gibbs, J. Raphael, Dalgard, Clifton L., Traynor, Bryan J., and Scholz, Sonja W.

Subjects
whole-genome sequencing, GBA, Lewy body dementia, Biochemistry, biophysics & molecular biology [F05] [Life sciences], Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant]
Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.Competing Interest StatementThomas G. Beach is a consultant for Prothena, Vivid Genomics and Avid Radiopharmaceuticals. He is a scientific advisory board member for Vivid Genomics. John A. Hardy, Huw R. Morris, Stuart Pickering-Brown, Andrew B. Singleton, and Bryan J. Traynor hold US, EU and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Michael A. Nalls is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA; as a possible conflict of interest Dr. Nalls also consults for Neuron23 Inc., Lysosomal Therapeutics Inc., Illumina Inc., the Michael J. Fox Foundation and Vivid Genomics among others. Jose A. Palma is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. Bradley F. Boeve, James Leverenz, and Sonja W. Scholz serve on the Scientific Advisory Council of the Lewy Body Dementia Association. Sonja W. Scholz is an editorial board member for the Journal of Parkinson's Disease. Bryan J. Traynor is an editorial board member for JAMA Neurology; Journal of Neurology, Neurosurgery, and Psychiatry; Brain; and Neurobiology of Aging. Zbigniew K. Wszolek serves as a principal investigator or co-principal investigator on Abbvie, Inc. (M15-562 and M15-563), Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301). Zbigniew K. Wszolek serves as the principal investigator of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as co-principal investigator of the Mayo Clinic APDA Center for Advanced Research. All other authors report no competing interests.

Published
2020

50. Correction to:A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity (Acta Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)

Author

van der Lee, Sven J., Conway, Olivia J., Jansen, Iris, Carrasquillo, Minerva M., Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R., Stringa, Najada, Chen, Jason A., Zettergren, Anna, Andlauer, Till F.M., Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E., Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J., Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M., Indakoetxea, Begoña, Collij, Lyduine E., Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W., van Berckel, Bart N.M., Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L., Pastor, Pau, Rodríguez Rodríguez, Eloy, Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B.J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Nilsson, K., Nilsson, C., Mackenzie, I. R.A., Hsiung, G. Y.R., Mann, D. M.A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C.M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G.P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J.T., Uitti, Ryan J., Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K., van Schoor, Natasja M., Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K., Ross, Owen A., Dickson, Dennis W., Graff-Radford, Neill R., Knopman, David, Rademakers, Rosa, Lemstra, Afina W., Pijnenburg, Yolande A.L., Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F., Hemmer, Bernhard, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A., Sørensen, Thorkild I.A., Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Geschwind, D. H., Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W., Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M., and Holstege, Henne

Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

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