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21 results on '"Hernández, Isabel"'

1. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

Author

Reus, Lianne M, Pasaniuc, Bogdan, Posthuma, Danielle, Boltz, Toni, Consortium, International FTD-Genomics, Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, Pietro, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, and Gu, Wei

Subjects
Biological Sciences, Genetics, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Aging, Dementia, Neurodegenerative, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Prevention, Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Neurological, Frontotemporal Dementia, Gene Expression, Humans, International FTD-Genomics Consortium, 17q21.31 inversion region, Dorsolateral prefrontal cortex, Expression quantitative trait loci, Frontotemporal dementia, SEC22B, Transcriptome-wide association study, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BackgroundThe etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach.MethodsFUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold.ResultsWe identified 73 significant gene-tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed.ConclusionsWe identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

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. 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, 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, Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, and van der Flier, Wiesje M

Subjects
Biomedical and Clinical Sciences, Neurosciences, Rare Diseases, Acquired Cognitive Impairment, Alzheimer's Disease, Neurodegenerative, Alzheimer's Disease Related Dementias (ADRD), Brain Disorders, Dementia, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Prevention, Aging, Genetics, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alleles, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Brain, Frontotemporal Dementia, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lewy Body Disease, Longevity, Microglia, Multiple Sclerosis, Mutation, Neuroimaging, Parkinson Disease, Phospholipase C gamma, Risk, Alzheimer's disease, Frontotemporal dementia, Dementia with Lewy bodies, Progressive supranuclear palsy, Parkinson's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, Neurodegenerative disease, PLCG2, Phospholipase C Gamma 2, 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, Parkinson’s disease, frontotemporal dementia, dementia with Lewy-bodies, progressive suprauclear palsy, Parkinson's Disease, amyotrophic lateral sclerosis, multiple sclerosis, neurodegenerative disease, longevity, Clinical Sciences, 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

4. 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

5. Frontotemporal dementia and its subtypes: a genome-wide association study

Author

Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, and Rossor, Martin N

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Alzheimer's Disease Related Dementias (ADRD), Genetics, Neurodegenerative, Dementia, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Aging, Human Genome, Clinical Research, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Aged, 80 and over, Female, Frontotemporal Dementia, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundFrontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.MethodsWe did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p

Published
2014

6. Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Author

Jansen, Iris, van der Lee, Sven J, Bellenguez, Céline, Ramakers, Inez, Rodriguez-Rodriguez, Eloy, Rujescu, Dan, Saltvedt, Ingvild, Sanchez-Juan, Pascual, Scheltens, Philip, Scherbaum, Norbert, Schmid, Matthias, Schneider, Anja, Selbæk, Geir, Kleineidam, Luca, Selnes, Per, Shadrin, Alexey, Skoog, Ingmar, Soininen, Hilkka, Tárraga, Lluís, Teipel, Stefan, group, GR@ACE study, Tijms, Betty, Tsolaki, Magda, Van Broeckhoven, Christine, Küçükali, Fahri, Van Dongen, Jasper, van Swieten, John C, Vandenberghe, Rik, Vidal, Jean-Sébastien, Visser, Pieter J, Vogelgsang, Jonathan, Waern, Margda, Wagner, Michael, Wiltfang, Jens, Wittens, Mandy M J, Sung, Yun Ju, Zetterberg, Henrik, Zulaica, Miren, van Duijn, Cornelia M, Bjerke, Maria, Engelborghs, Sebastiaan, Jessen, Frank, Teunissen, Charlotte E, Pastor, Pau, Hiltunen, Mikko, Ingelsson, Martin, Tesí, Niccolo, Andreassen, Ole A, Clarimón, Jordi, Sleegers, Kristel, Ruiz, Agustín, Ramirez, Alfredo, Cruchaga, Carlos, Lambert, Jean-Charles, van der Flier, Wiesje, Vromen, Ellen M, Wightman, Douglas P, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Gomez-Fonseca, Duber, Amouyel, Philippe, Athanasiu, Lavinia, Bahrami, Shahram, Bailly, Henri, Belbin, Olivia, Bergh, Sverre, Bertram, Lars, Biessels, Geert Jan, Blennow, Kaj, Blesa, Rafael, de Rojas, Itziar, Boada, Mercè, Boland, Anne, Bürger, Katharina, Carracedo, Ángel, Cervera-Carles, Laura, Chene, Geneviève, Claassen, Jurgen A H R, Debette, Stephanie, Deleuze, Jean-Francois, de Deyn, Peter Paul, Dalmasso, Maria Carolina, Diehl-Schmid, Janine, Djurovic, Srdjan, Dols-Icardo, Oriol, Dufouil, Carole, Duron, Emmanuelle, Düzel, Emrah, consortium, EADB, Fladby, Tormod, Fortea, Juan, Frölich, Lutz, Grenier-Boley, Benjamin, García-González, Pablo, Garcia-Martinez, Maria, Giegling, Ina, Goldhardt, Oliver, Gobom, Johan, Grimmer, Timo, Haapasalo, Annakaisa, Hampel, Harald, Hanon, Olivier, Hausner, Lucrezia, Zettergren, Anna, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael, Hernández, Isabel, Herukka, Sanna-Kaisa, Holstege, Henne, Jarholm, Jonas, Kern, Silke, Knapskog, Anne-Brita, Koivisto, Anne M, Mishra, Aniket, Kornhuber, Johannes, Kuulasmaa, Teemu, Lage, Carmen, Laske, Christoph, Leinonen, Ville, Lewczuk, Piotr, Lleó, Alberto, de Munain, Adolfo López, Lopez-Garcia, Sara, Maier, Wolfgang, Ali, Muhammad, Marquié, Marta, Mol, Merel O, Montrreal, Laura, Moreno, Fermin, Moreno-Grau, Sonia, Nicolas, Gael, Nöthen, Markus M, Orellana, Adelina, Pålhaugen, Lene, Papma, Janne M, Andrade, Victor, Pasquier, Florence, Perneczky, Robert, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Posthuma, Danielle, Pozueta, Ana, Priller, Josef, Puerta, Raquel, Quintela, Inés, Molecular Neuroscience and Ageing Research (MOLAR), Complex Trait Genetics, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Complex Trait Genetics, VU University medical center, Neurology, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Brain Imaging, Laboratory Medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, APH - Personalized Medicine, APH - Methodology, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychology 2, Psychology 6, Pathologic Biochemistry and Physiology, Clinical Biology, Clinical sciences, Neuroprotection & Neuromodulation, European Commission, Clinical genetics, Amsterdam Reproduction & Development, Clinical chemistry, Department of Neurosciences, Clinicum, Helsinki University Hospital Area, University of Helsinki, HUS Neurocenter, Neurologian yksikkö, Epidemiology, and Universidad de Cantabria

Subjects
Neurologi, LD SCORE REGRESSION, Medizin, Cell Cycle Proteins, cerebrospinal fluid [Amyloid beta-Peptides], 3124 Neurology and psychiatry, pathology [Alzheimer Disease], Pathology, GWAS, RISK, NEURODEGENERATION, ASSOCIATION, Alzheimer's disease, AMYLOID-BETA, Cerebrospinal fluid, Neurology, cerebrospinal fluid [Biomarkers], Amyloid-beta, Life Sciences & Biomedicine, Alzheimer’s disease, EXPRESSION, Neuroscience(all), Clinical Neurology, tau Proteins, DIAGNOSIS, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Apolipoproteins E, SDG 3 - Good Health and Well-being, Alzheimer Disease, Humans, ddc:610, cerebrospinal fluid [Peptide Fragments], Amyloid beta-Peptides, Science & Technology, MUTATIONS, neurology, 3112 Neurosciences, Neurosciences, GENE, Peptide Fragments, genetics [tau Proteins], cerebrospinal fluid [tau Proteins], TAU LEVELS, genetics [Apolipoproteins E], 3111 Biomedicine, Human medicine, Neurology (clinical), Neurosciences & Neurology, Tau, Biomarkers
Abstract

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

Published
2022

7. Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning: Dementia Praecox Revisited

Author

Koutsouleris, Nikolaos, Pantelis, Christos, Kambeitz, Joseph, Toivonen, Anna, Turtonen, Otto, Botterweck, Sonja, Kluthausen, Norman, Antoch, Gerald, Caspers, Julian, Wittsack, Hans-Jörg, Blasi, Giuseppe, Pergola, Giulio, Caforio, Grazia, Salokangas, Raimo K R, Fazio, Leonardo, Quarto, Tiziana, Gelao, Barbara, Romano, Raffaella, Andriola, Ileana, Falsetti, Andrea, Barone, Marina, Passiatore, Roberta, Sangiuliano, Marina, Surmann, Marian, Hietala, Jarmo, Bienek, Olga, Dannlowski, Udo, Solana, Ana Beatriz, Abraham, Manuela, Schirmer, Timo, Ferro, Adele, Re, Marta, Sberna, Maurizio, D'Agostino, Armando, Del Fabro, Lorenzo, Bertolino, Alessandro, Perna, Giampaolo, Nobile, Maria, Balestrieri, Matteo, Bonivento, Carolina, Cabras, Giuseppe, Fabbro, Franco, Delvecchio, Giuseppe, Maggioni, Eleonora, Squarcina, Letizia, Gritti, Davide, Brambilla, Paolo, Rossetti, Maria Gloria, Ferrari, Raffaele, Hernandez, Dena Michelle Godwin, Nalls, Michael, Rohrer, Jonathan, Ramasamy, Adaikalavan, Kwok, John, Dobson-Stone, Carol, Brooks, William, Schofield, Peter, Upthegrove, Rachel, Halliday, Glenda, Hodges, John, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Wood, Stephen J, Cruchaga, Carlos, Cairns, Nigel, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Lencer, Rebekka, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Landqvist Waldö, Maria, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging-Yuek, Mann, David, Borgwardt, Stefan, Grafman, Jordan, Morris, Christopher, Attems, Johannes, McKeith, Ian, Thomas, Alan, Pietrini, Pietro, Huey, Edward, Wassermann, Eric, Baborie, Atik, Jaros, Evelyn, Maj, Carlo, Tierney, Michael, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Velakoulis, Dennis, Nöthen, Markus M., Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James, Schlachetzki, Johannes, Uphill, James, Collinge, John, Degenhardt, Franziska, Mead, Simon, Van Deerlin, Vivianna, Marschhauser, Anke, Regenbrecht, Frank, Thoene-Otto, Angelika, Gordulla, Jannis, Ballarini, Tommaso, Engel, Annerose, Pino, Daniele, Leuthold, Dominique, Polyakova, Maryna, Naumann, Heike, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhofen, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Mueller, Karsten, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Villringer, Arno, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Danek, Adrian, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Fassbender, Klaus, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David S, Josephs, Keith A, Fliessbach, Klaus, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise Gp, Seelaar, Harro, Pijnenburg, Yolande Al, Jahn, Holger, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Kornhuber, Johannes, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, McGuire, Philip, Landwehrmeyer, Bernhard, Hardy, John, Momeni, Parastoo, Barthel, Henryk, Elisa, Semler, Jolina, Lombardi, Christine, von Arnim, Felix, Oberahauser, Kai, Schumacher, Jan, Lehmbeck, Juan-Manuel, Maler, Anderl-Straub, Sarah, Tanja, Richter-Schmidinger, Anke, Hammer-Kaspereit, Timo, Oberstein, Felix, Müller-Sarnowski, Carola, Roßmeier, Albert, Ludolph, Jan, Kassubek, Anja, Schneider, Johannes, Levin, Prudlo, Johannes, Synofzik, Matthis, Wiltfang, Jens, Riedl, Lina, Diehl-Schmid, Janine, Otto, Markus, Meisenzahl, Eva, Falkai, Peter, Dwyer, Dominic B, Schroeter, Matthias L, Consortium, the PRONIA, Haas, Shalaila, Hasan, Alkomiet, Hoff, Claudius, Khanyaree, Ifrah, Melo, Aylin, Muckenhuber-Sternbauer, Susanna, Köhler, Yanis, Urquijo-Castro, Maria-Fernanda, Öztürk, Ömer, Penzel, Nora, Rangnick, Adrian, von Saldern, Sebastian, Spangemacher, Moritz, Tupac, Ana, Weiske, Johanna, Wosgien, Antonia, Krämer, Camilla, Blume, Karsten, Paul, Riya, Hedderich, Dennis, Julkowski, Dominika, Kaiser, Nathalie, Lichtenstein, Thorsten, Milz, Ruth, Nikolaides, Alexandra, Pilgram, Tanja, Seves, Mauro, Wassen, Martina, Andreou, Christina, Dong, Sen, Egloff, Laura, Harrisberger, Fabienne, Heitz, Ulrike, Lenz, Claudia, Leanza, Letizia, Mackintosh, Amatya, Smieskova, Renata, Studerus, Erich, Walter, Anna, Widmayer, Sonja, Popovic, David, Day, Chris, Lowri Griffiths, Sian, Iqbal, Mariam, Pelton, Mirabel, Mallikarjun, Pavan, Stainton, Alexandra, Lin, Ashleigh, Lalousis, Paris, Denissoff, Alexander, Ellilä, Anu, Oeztuerk, Oemer, From, Tiina, Heinimaa, Markus, Ilonen, Tuula, Jalo, Päivi, Laurikainen, Heikki, Luutonen, Antti, Mäkela, Akseli, Paju, Janina, Pesonen, Henri, Säilä, Reetta-Liina, International FTD-Genetics Consortium (IFGC), German Frontotemporal Lobar Degeneration (FTLD) Consortium, PRONIA Consortium, and International FTD-Genetics Consortium Consortium

Subjects
Adult, Male, Medizin, genetics [Alzheimer Disease], genetics [Psychotic Disorders], Neuropsychological Tests, diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [Psychotic Disorders], Machine Learning, methods [Magnetic Resonance Imaging], Brain, Female, Humans, Magnetic Resonance Imaging, Alzheimer Disease, Frontotemporal Dementia, Psychotic Disorders, Schizophrenia, pathology [Brain], genetics [Schizophrenia], ddc:610, diagnostic imaging [Brain], genetics [Frontotemporal Dementia], Settore MED/25 - Psichiatria, Psychiatry and Mental health, diagnostic imaging [Schizophrenia], diagnostic imaging [Alzheimer Disease]
Abstract

Weitere Nicht-UDE Autoren sind nicht genannt. Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2= 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2= 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

Published
2022

8. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Author

Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlos, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexis, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Gasparoni, Gilles, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrios, Lah, James J., Levey, Allan I., Kondou, Shinichi, Geschwind, Daniel H., Int Frontotemporal Dementia Gen, Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlo, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johanne, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagioti, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, Jame, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexi, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthia, Mayhaus, Manuel, Gasparoni, Gille, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrio, Lah, James J., Levey, Allan I., Kondou, Shinichi, and Geschwind, Daniel H.

Subjects
Proteomics, Genetics and Molecular Biology (all), 0301 basic medicine, Messenger, Gene regulatory network, Inbred C57BL, Biochemistry, Transgenic, Mice, 0302 clinical medicine, Gene Regulatory Networks, Regulation of gene expression, Cell Death, Drug discovery, Neurodegeneration, Neurodegenerative Diseases, General Medicine, Chemistry, Frontotemporal Dementia, 030220 oncology & carcinogenesis, Frontotemporal dementia, Evolution, Systems biology, Genetic Vectors, Animals, Dementia, Disease Models, Animal, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, RNA, Messenger, Reproducibility of Results, Transcriptome, tau Proteins, Evolution, Molecular, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, microRNA, medicine, Biochemistry, Genetics and Molecular Biology (all), Animal, Molecular, medicine.disease, 030104 developmental biology, Disease Models, RNA, Human medicine
Abstract

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

Published
2018

9. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

Author

KLEINEIDAM, Luca, Chouraki, Vincent, Próchnicki, Tomasz, van der Lee, Sven, Madrid‑Márquez, Laura, Wagner-Thelen, Holger, Karaca, Ilker, WEINHOLD, Leonie, Wolfsgruber, Steffen, Boland, Anne, Martino Adami, Pamela, Lewczuk, Piotr, POPP, Julius, Brosseron, Frederic, Jansen, Iris, HULSMAN, Marc, Kornhuber, Johannes, Peters, Oliver, Berr, Claudine, Heun, Reinhard, Frölich, Lutz, Tzourio, Christophe, Dartigues, Jean-François, Hüll, Michael, Espinosa, Ana, Hernández, Isabel, de Rojas, Itziar, ORELLANA, Adelina, VALERO, Sergi, STRINGA, Najada, Van Schoor, Natasja, Huisman, Martijn, Scheltens, Philip, For The Alzheimer'S Disease Neuroimaging Initiative, (ADNI), Rüther, Eckart, Deleuze, Jean-François, Wiltfang, Jens, Tarraga, Lluis, Schmid, Matthias, Scherer, Martin, Riedel-Heller, Steffi, Heneka, Michael, Amouyel, Philippe, Jessen, Frank, Boada, Merce, Maier, Wolfgang, Schneider, Anja, González‑Pérez, Antonio, van der Flier, Wiesje, Wagner, Michael, Lambert, Jean-Charles, Holstege, Henne, Saez, Mª Eugenia, Latz, Eicke, Ruiz, Agustin, Ramirez, Alfredo, University Hospital Bonn, Universität zu Köln, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Epidémiologie et de Santé Publique [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Amsterdam UMC, Vrije Universiteit Amsterdam [Amsterdam] (VU), Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] (CAEBi), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universitätsklinikum Erlangen [Erlangen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University of Bialystok, Lausanne University Hospital, University hospital of Zurich [Zurich], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Heidelberg [Heidelberg], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Albert-Ludwigs-Universität Freiburg, Universitat Internacional de Catalunya [Barcelona] (UIC), Instituto de Salud Carlos III [Madrid] (ISC), University Medical Center Göttingen (UMG), Universidade de Aveiro, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Universität Leipzig [Leipzig], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Open Access funding provided by Projekt DEAL. This publication was funded in part by the German Federal Ministry of Education and Research (BMBF) (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434, grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project 'Diet-Body-Brain: from epidemiology to evidence-based communication'. Part of the work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Part of the analysis was funded by the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case–control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica, Inc., Biogen, Bristol-Myers Squibb Company, CereSpir, Inc., Cogstate, Eisai Inc., ElanPharmaceuticals, Inc., Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc., Fujirebio, GE Healthcare, IXICO Ltd., Janssen Alzheimer Immunotherapy Research and Development, LLC., Johnson and Johnson Pharmaceutical Research and Development LLC., Lumosity, Lundbeck, Merck and Co., Inc., Meso Scale Diagnostics, LLC., NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc., Piramal Imaging, Servier, Takeda Pharmaceutical Company, and transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The Three-City Study genotyping and analysis was funded by the GENMED Labex, the Joint Programming Initiative on Neurodegenerative Diseases Research (JPND, PERADES project), the Institute Pasteur de Lille, the University of Lille, and the Nord-Pas de Calais Regional Council. This work also benefited from the Lille Métropole Communauté Urbaine Council, the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer’s disease). In addition, the Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. Additional funding for the 3C Study was also obtained from the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM 'Cohortes et collections de données biologiques' programme. Lille Génopôle received an unconditional grant from Eisai. Fundacio ACE cohort receives support from the Innovative Medicines Initiative 2 Joint Undertaking which receives support from the European Union’s Horizon 2020 research and innovation programme (ADAPTED Grant No. 115975). A. Ruiz’s research is also supported by Instituto de Salud Carlos III (ISCIII) grants PI13/02434, PI16/01861, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de Hacer Europa'), by Fundación bancaria 'La Caixa' and Grifols SA (GR@ACE project). For the Longitudinal Aging Study Amsterdam (LASA) supports was largely obtained from a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The data collection in 2012–2013 was financially supported by the Netherlands Organization for Scientific Research (NWO) in the framework of the project 'New Cohorts of young old in the twenty-first century' (File Number 480-10-014). Genotyping using Axiom-NL array was financially supported by EMGO+ Research Institute. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. JW is supported by an Ilídio Pinho professorship and iBiMED (UID/BIM/04501/2013), at the University of Aveiro, Portugal. JP was supported by a grant from the Swiss National Science Foundation (320030L_141179)., Universität zu Köln = University of Cologne, Amsterdam UMC - Amsterdam University Medical Center, Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Leipzig, Alzheimer's Disease Neuroimaging Initiative (ADNI), Kleineidam, L., Karaca, I., Heneka, M.T., Maier, W., Schneider, A., Wagner, M., Chouraki, V., Amouyel, P., Lambert, J.C., Próchnicki, T., Latz, E., van der Lee, S.J., Jansen, I.E., Hulsman, M., Scheltens, P., van der Flier, W.M., Holstege, H., Madrid-Márquez, L., González-Pérez, A., Sáez, M.E., Wagner-Thelen, H., Martino Adami, P.V., Jessen, F., Ramirez, A., Weinhold, L., Schmid, M., Wolfsgruber, S., Brosseron, F., Boland, A., Deleuze, J.F., Lewczuk, P., Kornhuber, J., Popp, J., Peters, O., Berr, C., Heun, R., Frölich, L., Tzourio, C., Dartigues, J.F., Hüll, M., Espinosa, A., Hernández, I., de Rojas, I., Orellana, A., Valero, S., Ruiz, A., Tarraga, L., Boada, M., Stringa, N., van Schoor, N.M., Huisman, M., Rüther, E., Wiltfang, J., Scherer, M., Riedel-Heller, S., Neurology, Human genetics, Epidemiology and Data Science, APH - Aging & Later Life, APH - Societal Participation & Health, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, APH - Methodology, Sociology, and The Social Context of Aging (SoCA)

Subjects
Apolipoprotein E, Male, pathology [Cognitive Dysfunction], Cognitive decline, genetics [Alzheimer Disease], Disease, SEPIA, pathology [Alzheimer Disease], 0302 clinical medicine, Cognition, genetics [Amyloid beta-Peptides], Medicine, Aged, 80 and over, 0303 health sciences, education.field_of_study, Microglia, physiology [Cognition], Middle Aged, medicine.anatomical_structure, Disease Progression, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], analysis [Biomarkers], Alzheimer’s disease, Amyloid, Phospholipase C gamma 2, Population, tau Proteins, Pathology and Forensic Medicine, PLCG2, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, Humans, Cognitive Dysfunction, ddc:610, education, Mild cognitive impairment, HEALTHY, 030304 developmental biology, Aged, metabolism [Phospholipase C gamma], Original Paper, Amyloid beta-Peptides, TREM2, business.industry, Phospholipase C gamma, genetics [Cognitive Dysfunction], metabolism [tau Proteins], cerebrospinal fluid [tau Proteins], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers
Abstract

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Published
2020

10. 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, Zettergren, Anna, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Mead, S., Synofzik, M., Andlauer, Till F 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., Diez-Fairen, Monica, Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Simon-Sanchez, Javier, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Lleó, Alberto, 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., Zetterberg, Henrik, 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., Nygaard, Marianne, Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Blauwendraat, Cornelis, 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., Savage, Jeanne E, van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Mengel-From, Jonas, Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Jansen, Iris, Moreno-Grau, Sonia, 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., Wagner, Michael, Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Fortea, Juan, 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., Keogh, Michael J, Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Blennow, Kaj, Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Coppola, G., Skoog, Ingmar, Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Friese, Manuel A, Geschwind, D. H., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, Carrasquillo, Minerva M, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Kleineidam, Luca, 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, van den Akker, Erik, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Bank, Netherlands Brain, Boeve, Bradley F, Hernández, Isabel, 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, van Eijk, Kristel R, 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, Stringa, Najada, 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, Chen, Jason A, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT, and Clarimón, Jordi

Subjects
0301 basic medicine, Dementia with Lewy bodies, Disease, Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, Missense mutation, media_common, 2. Zero hunger, Longevity, Brain, Parkinson Disease, Phospholipase C Gamma 2, Biobank, 3. Good health, ddc, Frontotemporal Dementia, Microglia, Alzheimer's disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, Multiple Sclerosis, media_common.quotation_subject, education, Neuroimaging, Genomics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Phospholipase C gamma, business.industry, Amyotrophic Lateral Sclerosis, Correction, medicine.disease, 030104 developmental biology, Mutation, Dementia, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
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. 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

11. Cognitive Composites Domain Scores Related to Neuroimaging Biomarkers within Probable-Amnestic Mild Cognitive Impairment-Storage Subtype

Author

Espinosa, Ana, Alegret, Montserrat, Pesini, Pedro, Valero Ventura, Sergi, Lafuente, Asunción, Buendía, Mar, San José, Itziar, Ibarria, Marta, Tejero, Miguel Ángel, Giménez Ruiz, Joan, Ruiz, Susana, Hernández, Isabel, Pujadas, Francesc, Martínez Lage, Pablo, Munuera, Josep, Arbizu, Javier, Tárraga, Lluís, Hendrix, Suzanne B., Ruiz, Agustín, Becker, James T., Landau, Susan M., Sotolongo Grau, Oscar, Sarasa, Manuel, Boada, Mercè, and Universitat Autònoma de Barcelona

Subjects
0301 basic medicine, cognition, Male, positron emission tomography, hippocampus, Neuropsychological Tests, Hippocampus, memory, Cognition, 0302 clinical medicine, Hippocampus (mythology), magnetic resonance imaging, Neuropsychological assessment, Composite material, Aged, 80 and over, Aniline Compounds, medicine.diagnostic_test, General Neuroscience, amyloid, Brain, General Medicine, Organ Size, Alzheimer's disease, 3. Good health, Psychiatry and Mental health, Clinical Psychology, Female, Psychology, Alzheimer’s disease, Research Article, Amyloid, Positron emission tomography, Prodromal Symptoms, Neuroimaging, 03 medical and health sciences, amnestic mild cognitive impairment, Magnetic resonance imaging, Memory, Alzheimer Disease, Fluorodeoxyglucose F18, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, Survival analysis, Aged, medicine.disease, Survival Analysis, Thiazoles, 030104 developmental biology, Positron-Emission Tomography, Mental Recall, Amnestic mild cognitive impairment, Geriatrics and Gerontology, Radiopharmaceuticals, 030217 neurology & neurosurgery
Abstract

The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p -value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the "MCI due to AD" with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.

Published
2017

12. 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
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13. Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

Author

Bonham, L.W., Steele, N.Z.R., Karch, C.M., Broce, I., Geier, E.G., Wen, N.L., Momeni, P., Hardy, J., Miller, Z.A., Gorno-Tempini, M.L., Hess, C.P., Lewis, P., Miller, B.L., Seeley, W.W., Manzoni, C., Desikan, R.S., Baranzini, S.E., Ferrari, R., Yokoyama, J.S., 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., Haan, E., Hernández, Isabel, Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N.J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, Diego, Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, Alberto, 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., Pastor, Pau, 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., Mead, S., Danek, A., Van Deerlin, V.M., Grossman, M., Trojanowski, J.Q., van der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S.F., Leber, I., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, Sandro, 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., Heutink, 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., Rademakers, R., Baker, M., Dickson, Dennis W., Graff-Radford, N.R., Petersen, R.C., Knopman, D., Josephs, K.A., Boeve, B.F., Parisi, J.E., Karydas, A.M., Rosen, H., van Swieten, J.C., Dopper, E.G.P., Seelaar, H., Pijnenburg, Y.A.L., Scheltens, Philip, 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., Universitat Autònoma de Barcelona, Broce, Iris [0000-0003-4932-1430], Miller, Zachary A. [0000-0002-5991-3053], Lewis, Patrick [0000-0003-4537-0489], Baranzini, Sergio E. [0000-0003-0067-194X], Apollo - University of Cambridge Repository, Int FTD-Genomics Consortium, Neurology, Amsterdam Neuroscience - Neurodegeneration, Divisions, and CCA - Imaging and biomarkers

Subjects
0301 basic medicine, Aging, Transcription, Genetic, Gene regulatory network, lcsh:Medicine, Genome-wide association study, Apoptosis, Neurodegenerative, Primary progressive aphasia, Cohort Studies, 0302 clinical medicine, 692/617/375/132, Risk Factors, Databases, Genetic, 2.1 Biological and endogenous factors, Gene Regulatory Networks, Protein Interaction Maps, Aetiology, lcsh:Science, Multidisciplinary, Neurodegeneration, Neurodegenerative diseases, article, Frontotemporal lobar degeneration, 631/208/205, Single Nucleotide, Phenotype, ddc, 3. Good health, DNA-Binding Proteins, Frontotemporal Dementia (FTD), 692/617/375/365, Neurological, Medical genetics, 38/39, Engineering sciences. Technology, Transcription, Biotechnology, medicine.medical_specialty, Computational biology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Databases, Rare Diseases, Genetic, medicine, Aphasia, Acquired Cognitive Impairment, Genetics, Humans, Primary Progressive Nonfluent Aphasia, Polymorphism, Gene, Genetic association study, International FTD-Genomics Consortium, lcsh:R, Human Genome, Neurosciences, medicine.disease, Brain Disorders, 631/208/199, 030104 developmental biology, Gene Expression Regulation, RNA, lcsh:Q, Dementia, Gene expression, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.

Published
2019

14. Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin

Author

Cuberas-Borrós, Gemma, Roca Bielsa, María Isabel, Boada, Mercè, Tárraga, Lluís, Hernández, Isabel, Buendia, Mar, Rubio, Lourdes, Torres, Gustavo, Bittini, Ángel, Guzmán-de-Villoria, Juan A., Pujadas, Francesc, Torres, Mireia, Núñez, Laura, Castell Conesa, Joan, Páez, Antonio, and Universitat Autònoma de Barcelona

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Pathology, Time Factors, Perfusion scanning, Neuroimaging, Serum Albumin, Human, Statistical parametric mapping, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Internal medicine, medicine, Humans, Longitudinal Studies, Cerebral perfusion pressure, Aged, Aged, 80 and over, Tomography, Emission-Computed, Single-Photon, medicine.diagnostic_test, Plasma Exchange, business.industry, single-photon emission computed tomography, General Neuroscience, Albumin, Magnetic resonance imaging, General Medicine, Alzheimer's disease, Middle Aged, Magnetic Resonance Imaging, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Treatment Outcome, Brain size, Cardiology, Female, Geriatrics and Gerontology, business, Perfusion, Alzheimer’s disease, 030217 neurology & neurosurgery, Brodmann area, Research Article
Abstract

Altres ajuts: This study was funded by Grifols. [...] James T. Becker (Department of Psychiatry, Neurology and Psychology. University of Pittsburgh, Pittsburgh PA, USA) read and commented on an earlier draft of the manuscript. Jordi Bozzo PhD, CMPP (Grifols) is acknowledged for medical writing and editorial assistance in the preparation of the manuscript. Recently, modifications of Aβ levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. Patients received between 3 and 18 PE with albumin (Albutein ® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam ®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.

Published
2018

15. MAPT H1 haplotype is associated with late-onset Alzheimer's disease risk in APOE ε 4 noncarriers: Results from the dementia genetics Spanish consortium

Author

Pastor, Pau, Moreno, Fermín, Antonell, Anna, Elcoroaristizabal, Xabier, Lleó, Alberto, Blesa, Rafael, Fortea, Juan, Belbin, Olivia, Alcolea, Daniel, Carmona-Iragui, María, Sánchez-Saudinós, M Belén, Sala, Isabel, Anton-Aguirre, Sofía, Coto, Eliecer, Morenas, Estrella, Ribosa, Roser, Colom-Cadena, Martí, Cervera, Laura, Muñoz, Laia, Dols-Icardo, Oriol, Clarimón, Jordi, Ortega-Cubero, Sara, Hernandez, Isabel, Tárraga, Lluís, Boada, Mercè, Kulisevsky, Jaime, Vázquez-Higuera, José Luis, Infante, Jon, Rábano, Alberto, Fernández-Blázquez, Miguel Ángel, Valentí, Meritxell, Indakoetxea, Begoña, Barandiarán, Myriam, Gorostidi, Ana, Frank-García, Ana, Sastre, Isabel, Lorenzo, Elena, Ruiz, Agustín, Pastor, María A, Lennarz, Martina, Maier, Wolfgang, Rámirez, Alfredo, Serrano-Ríos, Manuel, Lee, Suzee E, Sánchez-Juan, Pascual, Consortium, Dementia Genetic Spanish, Combarros, Onofre, Lorenzo-Betancor, Oswaldo, Pastor, Maria A, Hernández, Isabel, Lafuente, Asunción, Rosende-Roca, Maitée, Mauleón, Ana, Vargas, Liliana, Rodríguez, Octavio, Calero, Miguel, Abdelnour, Carla, Alegret, Montserrat, Espinosa, Ana, Ortega, Gemma, Sanabria, Ángela, Ibarria, Marta, Diego, Susana, Canyabate, Pilar, Moreno, Mariola, Buendía, Mar, López de Munain, Adolfo, Pancho, Ana, Palacio, María Eugenia, Ruiz, Susana, Tantinya, Natalia, Tarragona, Marina, Morera, América, Guitart, Marina, Sotolongo Grau, Oscar, Martín, Elvira, Fernández, Victòria, Bullido, Maria J, Sánchez-Valle, Raquel, Molinuevo, José Luis, Lladó, Albert, Rami, Lorena, Alvarez, Victoria, de Pancorbo, Marian M, Pozueta, Ana, González Suarez, Andrea, Carro, Eva, Rodriguez-Rodriguez, Eloy, Mateo, Ignacio, Berciano, José, Bullido, María J, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Universidad Pública de Navarra, Universidad del País Vasco, Universidad Autónoma de Madrid, Fundació ACE. Institut Català de Neurociències Aplicades, University of Bonn, University of California, Universitat de Barcelona, Universitat Autònoma de Barcelona, and Universitat Oberta de Catalunya (UOC)

Subjects
Gerontology, Male, associació genètica, genetic association, Apolipoprotein E4, A152T, enfermedad de Alzheimer, genetics [Alzheimer Disease], frontotemporal dementia, MAPT, Alzheimer, Enfermedad de, genetics [Genetic Predisposition to Disease], genetics [Frontotemporal Dementia], genetics [Apolipoprotein E4], Aged, 80 and over, General Neuroscience, General Medicine, demencia frontotemporal, Middle Aged, Alzheimer's disease, Psychiatry and Mental health, Clinical Psychology, demència frontotemporal, genetics [Polymorphism, Single Nucleotide], Christian ministry, Female, Alzheimer’s disease, Frontotemporal dementia, Late onset, MAPT protein, human, tau Proteins, Polymorphism, Single Nucleotide, asociación genética, Alzheimer Disease, malaltia d'Alzheimer, mental disorders, medicine, Dementia, Humans, Genetic Predisposition to Disease, ddc:610, Genetic association, Aged, business.industry, Haplotype, medicine.disease, nervous system diseases, H1H2, genetics [tau Proteins], Alzheimer, Malaltia d', Logistic Models, Haplotypes, Spain, Disease risk, Geriatrics and Gerontology, business
Abstract

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR)=2.03; p=0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR=1.12; p=0.0005). Stratification analysis showed that this association was mainly driven by APOE ε4 noncarriers (OR=1.14; p=0.0025). MAPT H1 was also associated with risk for PD (OR=1.30; p=0.0003) and PSP (OR=3.18; p=8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ε4 AD., Spanish Ministry of Science and Innovation SAF 2006-10126 (2006–2009) and SAF2010-22329-C02-01 (2011–2013) to P.P and by the UTE project FIMA to P.P. Grants from the Ministry of Science (SAF2010-15558) and CIBERNED. Agust´ın Ruiz is supported by grant PI13/02434 (Acción Estratégica en Salud. Instituto de Salud Carlos III. Ministerio de Economía y Competitividad, Spain). Grant: Consolider (CSD2010-00045).

Published
2015

16. ATP5H/KCTD2 locus is associated with Alzheimer's disease risk

Author

Boada, Mercè, Antúnez, Carmen, Ramírez Lorca, Repo, DeStefano, Anita L., González Pérez, A., Gayán, Javier, López Arrieta, Jesús, Ikram, M. Arfan, Hernández, Isabel, Marín, J., Galán, José Jorge, Bis, Joshua C., Mauleón, Ana, Rosende-Roca, Maitée, Moreno Rey, Concha, Gudnason, Vilmundur, Morón, Francisco Jesús, Velasco, Juan, Carrasco, José Miguel, Alegret, Montserrat, Espinosa, Ana, Vinyes, Georgina, Lafuente, Asunción, Vargas, Liliana, Fitzpatrick, Annette L., Launer, Lenore Joy, Sáez, María Eugenia, Vázquez, Enrique, Becker, James T., López, Oscar L., Serrano Ríos, Manuel, Tárraga, Lluís, van Duijn, Cornelia M., Real, Luis M., Seshadri, Sudha, Ruiz, Agustín, Universitat Autònoma de Barcelona, Radiology & Nuclear Medicine, and Epidemiology

Subjects
Male, Genotyping Techniques, SNP, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, molecular epidemiology, Cohort Studies, Cellular and Molecular Neuroscience, Alzheimer Disease, medicine, genomics, Humans, GWAS, Computer Simulation, Genetic Predisposition to Disease, Molecular Biology, Genotyping, Genetic association, Genetics, Aged, 80 and over, Odds ratio, Genomics, Middle Aged, Alzheimer's disease, medicine.disease, 3. Good health, Psychiatry and Mental health, Genetic Loci, Molecular epidemiology, Female, Original Article, Mitochondrial ADP, ATP Translocases, Genome-Wide Association Study
Abstract

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P

Published
2014

17. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Author

Escott-Price, Valentina, Bellenguez, Céline, DeStefano, Anita L, Galimberti, Daniela, Scarpini, Elio, Bonuccelli, Ubaldo, Mancuso, Michelangelo, Siciliano, Gabriele, Moebus, Susanne, Mecocci, Patrizia, Zompo, Maria Del, Maier, Wolfgang, Hampel, Harald, Lambert, Jean-Charles, Pilotto, Alberto, Frank-García, Ana, Panza, Francesco, Solfrizzi, Vincenzo, Caffarra, Paolo, Nacmias, Benedetta, Perry, William, Mayhaus, Manuel, Lannfelt, Lars, Hakonarson, Hakon, Ibrahim-Verbaas, Carla A, Pichler, Sabrina, Carrasquillo, Minerva M, Ingelsson, Martin, Beekly, Duane, Alvarez, Victoria, Zou, Fanggeng, Valladares, Otto, Younkin, Steven G, Coto, Eliecer, Hamilton-Nelson, Kara L, Naj, Adam C, Gu, Wei, Razquin, Cristina, Pastor, Pau, Mateo, Ignacio, Owen, Michael J, Faber, Kelley M, Jonsson, Palmi V, Combarros, Onofre, O'Donovan, Michael C, Cantwell, Laura B, Sims, Rebecca, Soininen, Hilkka, Blacker, Deborah, Mead, Simon, Mosley, Thomas H, Bennett, David A, Harris, Tamara B, Fratiglioni, Laura, Holmes, Clive, de Bruijn, Renee F A G, Passmore, Peter, Jun, Gyungah, Montine, Thomas J, Bettens, Karolien, Rotter, Jerome I, Brice, Alexis, Morgan, Kevin, Foroud, Tatiana M, Kukull, Walter A, Hannequin, Didier, Powell, John F, Nalls, Michael A, Bis, Joshua C, Ritchie, Karen, Lunetta, Kathryn L, Kauwe, John S K, Boerwinkle, Eric, Riemenschneider, Matthias, Boada, Mercè, Hiltunen, Mikko, Martin, Eden R, Schmidt, Reinhold, Rujescu, Dan, Beecham, Gary W, Dartigues, Jean-François, Mayeux, Richard, Tzourio, Christophe, Hofman, Albert, Nöthen, Markus M, Graff, Caroline, Psaty, Bruce M, Haines, Jonathan L, Lathrop, Mark, Pericak-Vance, Margaret A, Grenier-Boley, Benjamin, Launer, Lenore J, Van Broeckhoven, Christine, Farrer, Lindsay A, van Duijn, Cornelia M, Ramirez, Alfredo, Seshadri, Sudha, Schellenberg, Gerard D, Amouyel, Philippe, Williams, Julie, Study, Cardiovascular Health, Russo, Giancarlo, Olson, Jean, Kronmal, Richard, Arnold, Alice M, Robbins, John, Carlson, Michelle, Burke, Gregory, Kuller, Lewis H, Tracy, Russell, Gottdiener, John, Prineas, Ronald, Wang, Li-San, Thornton-Wells, Tricia A, Becker, James T, Enright, Paul, Klein, Ronald, O'Leary, Daniel H, Denning, Nicola, Smith, Albert V, Chouraki, Vincent, Thomas, Charlene, Ikram, M Arfan, Zelenika, Diana, Vardarajan, Badri N, Kamatani, Yoichiro, Lin, Chiao-Feng, Choi, Seung-Hoan, Schmidt, Helena, Kunkle, Brian, Dunstan, Melanie L, Vronskaya, Maria, Consortium, United Kingdom Brain Expression, Johnson, Andrew D, Ruiz, Agustin, Bihoreau, Marie-Thérèse, Reitz, Christiane, Pasquier, Florence, Harold, Denise, Hollingworth, Paul, Hanon, Olivier, Fitzpatrick, Annette L, Buxbaum, Joseph D, Campion, Dominique, Crane, Paul K, Baldwin, Clinton, Becker, Tim, Gudnason, Vilmundur, Cruchaga, Carlos, Jones, Lesley, Craig, David, Amin, Najaf, Berr, Claudine, Lopez, Oscar L, De Jager, Philip L, Deramecourt, Vincent, Johnston, Janet A, Evans, Denis, Lovestone, Simon, Letenneur, Luc, Holmans, Peter, Hernández, Isabel, Rubinsztein, David C, Eiriksdottir, Gudny, Sleegers, Kristel, Goate, Alison M, Fiévet, Nathalie, Huentelman, Matthew J, Gill, Michael, Brown, Kristelle, Kamboh, M Ilyas, Gerrish, Amy, Keller, Lina, Barberger-Gateau, Pascale, McGuinness, Bernadette, Larson, Eric B, Myers, Amanda J, Dufouil, Carole, Todd, Stephen, Wallon, David, Love, Seth, Rogaeva, Ekaterina, Vedernikov, Alexey, Gallacher, John, George-Hyslop, Peter St, Clarimon, Jordi, Lleo, Alberto, Bayer, Anthony, Tsuang, Debby W, Yu, Lei, Tsolaki, Magda, Bossù, Paola, Spalletta, Gianfranco, Richards, Alexander, Proitsi, Petra, Collinge, John, Sorbi, Sandro, Garcia, Florentino Sanchez, Fox, Nick C, Hardy, John, Naranjo, Maria Candida Deniz, Bosco, Paolo, Clarke, Robert, Brayne, Carol, Neurology, Radiology & Nuclear Medicine, Epidemiology, UAM. Departamento de Medicina, Universidad de Cantabria, and United Kingdom Brain Expression

Subjects
Genetics and Molecular Biology (all), Alzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell, Agricultural and Biological Sciences (all), Biochemistry, Genetics and Molecular Biology (all), Medicine (all), genotype, Medizin, lcsh:Medicine, genetics [Alzheimer Disease], Genome-wide association study, Genomics--Data processing, Disease, genetics [Carrier Proteins], Biochemistry, Alzheimer's disease, 0302 clinical medicine, genetics [Heat-Shock Proteins], genetics [Receptors, Antigen, B-Cell], Disease susceptibility--Genetic aspects, Receptors, Pathology, Medicine and Health Sciences, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, pathogenesis, Genomics, Single Nucleotide, Neurology, Antigen, Physical Sciences, protein degradation, Alzheimer disease, Engineering sciences. Technology, Statistics (Mathematics), Research Article, medicine.medical_specialty, Medicina, Geriatrik, Late onset, Biostatistics, Biology, Medical sciences, 03 medical and health sciences, Molecular genetics, Mental Health and Psychiatry, Genome-Wide Association Studies, medicine, chromosome 8, Dementia, ddc:610, Polymorphism, QH426, Genetic Association Studies, 030304 developmental biology, TP53INP1 protein, human, lcsh:R, Case-control study, B-Cell, Biology and Life Sciences, Computational Biology, Human Genetics, Genome Analysis, medicine.disease, R1, Human genetics, immune system, Geriatrics, FOS: Biological sciences, Alzheimer's disease--Genetic aspects, RC0321, lcsh:Q, Mathematics, 030217 neurology & neurosurgery
Abstract

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease, The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. The French National Fondation on Alzheimer's disease and related disorders supported several I-GAP meetings and communications. Data management involved the Centre National de Génotypage,and was supported by the Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) and by the LABEX GENMED grant (Medical Genomics). The French National Foundation on Alzheimer's disease and related disorders and the Alzheimer's Association (Chicago, Illinois) grant supported IGAP in-person meetings, communication and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses. EADI The authors thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM «Cohortes et collections de données biologiques» programme. Lille Génopôle received an unconditional grant from Eisai. The Three-city biological bank was developed and maintained by the laboratory for genomic analysis LAG-BRC - Institut Pasteur de Lille. Belgium sample collection: The patients were clinically and pathological characterized by the neurologists Sebastiaan Engelborghs, Rik Vandenberghe and Peter P. De Deyn, and in part genetically by Caroline Van Cauwenberghe, Karolien Bettens and Kristel Sleegers. Research at the Antwerp site is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Foundation Alzheimer Research (SAO-FRA), the Flemish Government initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund, Belgium. Karolien Bettens is a postdoctoral fellow of the FWO. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and the University Hospitals Leuven. Finish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Centre of Excellence in Neurodegeneration. Italian sample collections: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by grant RF-2010-2319722, grant from the the Cassa di Risparmio di Pistoia e Pescia (Grant 2012) and the Cassa di Risparmio di Firenze (Grant 2012). The Milan site was supported by a grant from the «fondazione Monzino». The authors thank the expert contribution of Mr. Carmelo Romano. The Roma site received financial support from Italian Ministry of Health, Grant RF07-08 and RC08-09-10-11-12. The Pisa site is grateful to Dr. Annalisa LoGerfo for her technical assistance in the DNA purification studies. Spanish sample collection: the Madrid site (MB) was supported by grants of the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III), and an institutional grant of the Fundación Ramón Areces to the CBMSO. The authors thank I. Sastre and Dr. A. Martínez-García for the preparation and control of the DNA collection, and Drs. P. Gil and P. Coria for their cooperation in the cases/controls recruitment. The authors are grateful to the Asociación de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help. Swedish sample collection: Financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), the King Gustaf V and Queen Victoria's Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation and the Swedish Alzheimer Foundation. CHARGE AGES: The AGES-Reykjavik Study is funded by National Institutes of Health (NIH) contract N01-AG-12100 (National Institute on Aging (NIA) with contributions from the National Eye Institute, National Institute on Deafness and Other Communication Disorders and National Heart, Lung, and Blood Institute (NHLBI)), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). ASPS/PRODEM: The Austrian Stroke Prevention Study and The Prospective Dementia Register of the Austrian Alzheimer Society was supported by The Austrian Science Fond (FWF) grant number P20545-P05 (H. Schmidt) and P13180; The Austrian Alzheimer Society; The Medical University of Graz. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and HHSN268200960009C; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629, AG15928, AG20098, AG027058 and AG033193 (Seshadri) from the NIA. A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with A_ymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study as also supported by grants from the National Institute on Aging: AG08122 and AG033193 (Seshadri). Drs. Seshadri and DeStefano were also supported by additional grants from the National Institute on Aging: (R01 AG16495; AG031287, AG033040), the National Institute of Neurological Disorders and Stroke (R01 NS17950), and the National Heart, Lung and Blood Institute (U01 HL096917, HL093029 and K24HL038444, RC2-HL102419 and UC2 HL103010. Fundació ACE would like to thank patients and controls who participated in this project. This work has been funded by the Fundación Alzheimur (Murcia), the Ministerio de Educación y Ciencia (PCT-010000-2007-18), (DEX-580000-2008-4), (Gobierno de España), Corporación Tecnológica de Andalucía (08/211) and Agencia IDEA (841318) (Consejería de Innovación, Junta de Andalucía). The authors thank to Ms. Trinitat Port-Carbó and her family for their generous support of Fundació ACE research programs. The Rotterdam Study: The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission;and the Municipality of Rotterdam; by grants from the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), Internationale Stichting Alzheimer Onderzoek, Hersenstichting Nederland, the Netherlands Genomics Initiative–Netherlands Organization for Scientific Research (Center for Medical Systems Biology and the Netherlands Consortium for Healthy Aging), the Seventh Framework Program (FP7/2007-2013), the ENGAGE project (grant agreement HEALTH-F4-2007-201413), MRACE-grant from the Erasmus Medical Center, the Netherlands Organization for Health Research and Development (ZonMW Veni-grant no. 916.13.054). ARIC: The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01- HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grants R01-HL087641, RC2-HL102419 (Boerwinkle, CHARGE-S), UC2 HL103010, U01-HL096917 (Mosley) and R01-HL093029; NHGRI contract U01- HG004402; and NIH contract HHSN268200625226C and NIA: R01 AG033193 (Seshadri). Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. GERAD Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer's Research United Kingdom (ARUK) and the Welsh Government. ARUK supported sample collections at the Kings College London, the South West Dementia Bank, Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer's Society, Ulster Garden Villages, N. Ireland R & D Office and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group. DCR is a Wellcome Trust Principal Research fellow. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer's Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and their work was supported by the NIHR Queen Square Dementia BRU. LASER-AD was funded by Lundbeck SA. The Bonn group would like to thank Dr. Heike Koelsch for her scientific support. The Bonn group was funded by the German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant number 01GI0102, 01GI0711, 01GI0420. The AgeCoDe study group was supported by the German Federal Ministry for Education and Research grants 01 GI 0710, 01 GI 0712, 01 GI 0713, 01 GI 0714, 01 GI 0715, 01 GI 0716, 01 GI 0717. The Homburg group was funded by the German Federal Ministry of Education and Research (BMBF): German National Genome Research Network (NGFN); Alzheimer's disease Integrated Genome Research Network; AD-IG: 01GS0465. Genotyping of the Bonn case-control sample was funded by the German centre for Neurodegenerative Diseases (DZNE), Germany. The GERAD Consortium also used samples ascertained by the NIMH AD Genetics Initiative. Harald Hampel was supported by a grant of the Katharina-Hardt-Foundation, Bad Homburg vor der Höhe, Germany. The KORA F4 studies were financed by Helmholtz Zentrum München; German Research Center for Environmental Health; BMBF; German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr. Jur. G.Schmidt, Chairman) and BMBF. Coriell Cell Repositories is supported by NINDS and the Intramural Research Program of the National Institute on Aging. The authors acknowledge use of genotype data from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Nottingham Group (KM) are supported by the Big Lottery. MRC CFAS is part of the consortium and data will be included in future analyses. ADGC The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, R01 AG041797; MIRAGE R01 AG025259; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD., Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Glaxo-SmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. The authors thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-o_cio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the United States Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. Peter St George-Hyslop is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health

Published
2014

18. 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, Mónica, 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 AL, 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, Mecocci, Patrizia, 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 AL, EADB Contributors, GR@ACE Study Group, DEGESCO Consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ Consortia, Kehoe, Patrick Gavin, Garcia-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, and Ruiz, Agustín

Subjects
Aged, 80 and over, Male, Heterozygote, Multifactorial Inheritance, Datasets as Topic, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, 3. Good health, Cohort Studies, Amyloid beta-Protein Precursor, Apolipoproteins E, Alzheimer Disease, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Age of Onset, Aged, Follow-Up Studies, Genome-Wide Association Study
Abstract

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061, 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.

19. 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, Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, Van Der Flier, Wiesje M, and Holstege, Henne

Subjects
Lewy Body Disease, Risk, Multiple Sclerosis, Dementia with Lewy bodies, Longevity, Neuroimaging, Neurodegenerative disease, PLCG2, Alzheimer Disease, Humans, Genetic Predisposition to Disease, Alleles, Phospholipase C gamma, Progressive supranuclear palsy, Amyotrophic Lateral Sclerosis, Brain, Parkinson Disease, Phospholipase C Gamma 2, 3. Good health, Frontotemporal Dementia, Mutation, Parkinson’s disease, Dementia, Microglia, Alzheimer’s disease, Genome-Wide Association Study
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.

20. 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, 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, Ferrari, Raffaele, and International FTD-Genetics Consortium

Subjects
Aged, 80 and over, Male, Principal Component Analysis, DNA Repeat Expansion, C9orf72 Protein, Geography, Mediterranean Region, Syndrome, Middle Aged, Scandinavian and Nordic Countries, Cohort Studies, Europe, Aphasia, Primary Progressive, Frontotemporal Dementia, Humans, Female, Age of Onset, Frontotemporal Lobar Degeneration, 10. No inequality, Aged
Abstract

OBJECTIVE: We 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: Our 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.

21. Mapping the human genetic architecture of COVID-19

Author

Niemi, MEK, Karjalainen, J, Liao, RG, Neale, BM, Daly, M, Ganna, A, Pathak, GA, Andrews, SJ, Kanai, M, Veerapen, K, Fernandez-Cadenas, I, Schulte, EC, Striano, P, Marttila, M, Minica, C, Marouli, E, Karim, MA, Wendt, FR, Savage, J, Sloofman, L, Butler-Laporte, G, Kim, H-N, Kanoni, S, Okada, Y, Byun, J, Han, Y, Uddin, MJ, Smith, GD, Willer, CJ, Buxbaum, JD, Mehtonen, J, Finucane, H, Cordioli, M, Martin, AR, Zhou, W, Pasaniuc, B, Julienne, H, Aschard, H, Shi, H, Yengo, L, Polimanti, R, Ghoussaini, M, Schwartzentruber, J, Dunham, I, Chwialkowska, K, Francescatto, M, Trankiem, A, Balaconis, MK, Davis, L, Lee, S, Priest, J, Renieri, A, Sankaran, VG, van Heel, D, Deelen, P, Richards, JB, Nakanishi, T, Biesecker, L, Kerchberger, VE, Kenneth, J, Mari, F, Bernasconi, A, Ceri, S, Canakoglu, A, Wolford, B, Faucon, A, Dutta, AK, Schurmann, C, Harry, E, Birney, E, Nguyen, H, Nasir, J, Kaunisto, M, Solomonson, M, Dueker, N, Vadgama, N, Limou, S, Rahmouni, S, Mbarek, H, Darwish, D, Uddin, MM, Albertos, R, Perez-Tur, J, Li, R, Folkersen, L, Moltke, I, Koelling, N, Teumer, A, Kousathanas, A, Utrilla, A, Verdugo, RA, Zarate, R, Medina-Gomez, C, Gomez-Cabrero, D, Carnero-Montoro, E, Cadilla, CL, Moreno-Estrada, A, Garmendia, A, Moya, L, Sedaghati-Khayat, B, Boua, PR, Fave, M-J, Francioli, L, Lemacon, A, Migeotte, I, Patel, S, Varnai, R, Szentpeteri, JL, Sipeky, C, Colombo, F, von Hohenstaufen, K, Lio, P, Vallerga, C, Wang, Q, Tanigawa, Y, Im, H, Han, C, Song, H, Lim, J, Lee, Y, Kim, S, Im, S, Atanasovska, B, Ahmad, HF, Boer, C, Jansen, P, Franke, L, Kaja, E, Pasko, D, Kennis-Szilagyi, I, Kornilov, SA, Prijatelj, V, Prokic, I, Sivanadhan, I, Perumal, S, Esmaeeli, S, Pearson, NM, Auton, A, Shelton, JF, Shastri, AJ, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, O'Connell, J, Ye, C, Weldon, CH, Perera, M, O'Leary, K, Tuck, M, O'Brien, T, Meltzer, D, O'Donnell, P, Nutescu, E, Yang, G, Alarcon, C, Herrmann, S, Mazurek, S, Banagan, J, Hamidi, Z, Barbour, A, Raffat, N, Moreno, D, Friedman, P, Ferwerda, B, van de Beek, D, Brouwer, MC, Vlaar, APJ, Wiersinga, WJ, Posthuma, D, Tissink, E, Zwinderman, AHK, Uffelmann, E, van Agtmael, M, Algera, AG, van Baarle, F, Bax, D, Beudel, M, Bogaard, HJ, Bomers, M, Bonta, PI, Bos, L, Botta, M, de Brabander, J, de Bree, G, de Bruin, S, Bugiani, M, Bulle, E, Chouchane, O, Cloherty, A, Dongelmans, D, Elbers, P, Fleuren, L, Geerlings, S, Geerts, B, Geijtenbeek, T, Girbes, A, Goorhuis, B, Grobusch, MP, Hafkamp, F, Hagens, L, Hamann, J, Harris, V, Hemke, R, Hermans, SM, Heunks, L, Hollmann, M, Horn, J, Hovius, JW, de Jong, MD, Koning, R, van Mourik, N, Nellen, J, Nossent, EJ, Paulus, F, Peters, E, van der Poll, T, Preckel, B, Prins, JM, Raasveld, J, Reijnders, T, Schinkel, M, Schultz, MJ, Schuurman, A, Sigaloff, K, Smit, M, Stijnis, CS, Stilma, W, Teunissen, C, Thoral, P, Tsonas, A, van der Valk, M, Veelo, D, de Vries, H, van Vugt, M, Wouters, D, Minnaar, RP, Kromhout, A, van Uffelen, KWJ, Wolterman, RA, Roberts, G, Park, D, Ball, CA, Coignet, M, McCurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Hong, EL, Rand, K, Girshick, A, Guturu, H, Baltzell, AH, Guntz, J, Beguin, Y, Pigazzini, S, Nkambule, L, Bouysran, Y, Busson, A, Peyrassol, X, Wilkin, F, Pichon, B, Smits, G, Vandernoot, I, Goffard, J-C, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Jadot, L, Azarzar, S, Dellot, P, Gofflot, S, Claassen, S, Bertrand, A, Parzibut, G, Clarinval, M, Moermans, C, Malaise, O, El Kandoussi, K, Thonon, R, Huynen, P, Mesdagh, A, Melo, S, Jacques, N, Di Valentin, E, Giroule, F, Collignon, A, Radermecker, C, Lebrun, M, Peree, H, Latour, S, Barada, O, Sanchez, J, Josse, C, Boujemla, B, Meunier, M, Mariavelle, E, Anania, S, Gazon, H, Juszczak, D, Fadeur, M, Camby, S, Meuris, C, Thys, M, Jacques, J, Henket, M, Leonard, P, Frippiat, F, Giot, J-B, Sauvage, A-S, Von Frenckell, C, Mni, M, Wery, M, Staderoli, A, Belhaj, Y, Lambermont, B, Morrison, DR, Mooser, V, Forgetta, V, Ghosh, B, Laurent, L, Belisle, A, Henry, D, Abdullah, T, Adeleye, O, Mamlouk, N, Kimchi, N, Afrasiabi, Z, Rezk, N, Vulesevic, B, Bouab, M, Guzman, C, Petitjean, L, Tselios, C, Xue, X, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Brassard, N, Durand, M, Schurr, E, Lepage, P, Ragoussis, J, Auld, D, Chasse, M, Kaufmann, DE, Lathrop, GM, Adra, D, Davis, LK, Cox, NJ, Below, JE, Sealock, JM, Faucon, AB, Shuey, MM, Polikowsky, HG, Petty, LE, Shaw, DM, Chen, H-H, Zhu, W, Ludwig, KU, Schroeder, J, Maj, C, Rolker, S, Noethen, MM, Fazaal, J, Keitel, V, Jensen, B-EO, Feldt, T, Kurth, I, Marx, N, Dreher, M, Pink, I, Cornberg, M, Illig, T, Lehmann, C, Schommers, P, Augustin, M, Rybniker, J, Knopp, L, Eggermann, T, Volland, S, Altmueller, J, Berger, MM, Brenner, T, Hinney, A, Witzke, O, Bals, R, Herr, C, Ludwig, N, Walter, J, Fuchsberger, C, Pattaro, C, De Grandi, A, Pramstaller, P, Emmert, D, Melotti, R, Foco, L, Mascalzoni, D, Gogele, M, Domingues, F, Hicks, A, Gignoux, CR, Wicks, SJ, Crooks, K, Barnes, KC, Daya, M, Shortt, J, Rafaels, N, Chavan, S, Goldstein, DB, Kiryluk, K, Sengupta, S, Chung, W, Reilly, MP, Khan, A, Wang, C, Povysil, G, Bhardwaj, N, Gharavi, AG, Ionita-Laza, I, Shang, N, O'Byrne, SM, Nandakumar, R, Menon, A, So, YS, Hod, E, Pendrick, D, Park, S-K, Kim, H-L, Kang, CK, Lee, H-J, Song, K-H, Yoon, KJ, Paik, N-J, Seok, W, Yoon, H, Joo, E-J, Chang, Y, Ryu, S, Park, WB, Park, JS, Park, KU, Ham, SY, Jung, J, Kim, ES, Kim, HB, Ellinghaus, D, Degenhardt, F, Caceres, M, Juzenas, S, Lenz, TL, Albillos, A, Julia, A, Heidecker, B, Garcia, F, Kurth, F, Tran, F, Hanses, F, Zoller, H, Holter, JC, Fernandez, J, Sander, LE, Rosenstiel, P, Koehler, P, de Cid, R, Asselta, R, Schreiber, S, Hehr, U, Prati, D, Baselli, G, Valenti, L, Bujanda, L, Banales, JM, Duga, S, D'Amato, M, Romero-Gomez, M, Buti, M, Invernizzi, P, Franke, A, Hov, JR, Karlsen, TH, Folseraas, T, Maya-Miles, D, Teles, A, Azuure, C, Wacker, EM, Uellendahl-Werth, F, Elabd, H, Arora, J, Lerga-Jaso, J, Wienbrandt, L, Ruehlemann, MC, Wendorff, M, Vadla, MS, Lenning, OB, Oezer, O, Myhre, R, Raychaudhuri, S, Tanck, A, Gassner, C, Hemmrich-Stanisak, G, Kaessens, J, Basso, MEF, Schulzky, M, Wittig, M, Braun, N, Wesse, T, Albrecht, W, Yi, X, Ortiz, AB, Garrido Chercoles, A, Ruiz, A, Mantovani, A, Holten, AR, Mayer, A, Cherubini, A, Protti, A, Aghemo, A, Gerussi, A, Ramirez, A, Braun, A, Barreira, A, Lleo, A, Kildal, AB, Glueck, A, Carreras Nolla, A, Latiano, A, Dyrhol-Riise, AM, Muscatello, A, Voza, A, Rando-Segura, A, Solier, A, Karina, B, Cortes, B, Mateos, B, Nafria-Jimenez, B, Schaefer, B, Bellinghausen, C, Ferrando, C, Quereda, C, Skurk, C, Thibeault, C, Spinner, CD, Lange, C, Hu, C, Cappadona, C, Bianco, C, Sancho, C, Hoff, DAL, Galimberti, D, Jimenez, D, Pestana, D, Toapanta, D, Azzolini, E, Scarpini, E, Helbig, ET, Urrechaga, E, Paraboschi, EM, Pontali, E, Reverter, E, Navas, E, Arana, E, Garcia Sanchez, F, Ceriotti, F, Malvestiti, F, Mesonero, F, Pezzoli, G, Lamorte, G, Neb, H, My, I, Hernandez, I, de Rojas, I, Galvan-Femenia, I, Heyckendorf, J, Badia, JR, Schneider, J, Goikoetxea, J, Kraft, J, Mueller, KE, Gaede, KI, Garcia-Etxebarria, K, Tonby, K, Heggelund, L, Izquierdo-Sanchez, L, Sumoy, L, Lippert, LJ, Terranova, L, Garbarino, L, Tellez, L, Roade, L, Ostadreza, M, Intxausti, M, Kogevinas, M, Gutierrez-Stampa, MA, Vehreschild, MJGT, Marquie, M, Castoldi, M, Cecconi, M, Boada, M, Seilmaier, MJ, Mazzocco, M, Rodriguez-Gandia, M, Imaz Ayo, N, Blay, N, Martinez, N, Cornely, OA, Palmieri, O, Tentorio, P, Rodrigues, PM, Espana, PP, Hoffmann, P, Bacher, P, Suwalski, P, de Pablo, R, Nieto, R, Badalamenti, S, Ciesek, S, Bombace, S, Wilfling, S, Brunak, S, Heilmann-Heimbach, S, Ripke, S, Bahmer, T, Landmesser, U, Protzer, U, Rimoldi, V, Skogen, V, Andrade, V, Moreno, V, Poller, W, Farre, X, Wang, X, Khodamoradi, Y, Karadeniz, Z, de Salazar, A, Palom, A, Garcia-Fernandez, A-E, Blanco-Grau, A, Zanella, A, Bandera, A, Nebel, A, Biondi, A, Caba Llero-Garralda, A, Gori, A, Lind, A, Fracanzani, AL, Peschuck, A, Pesenti, A, De la Horra, C, Milani, C, Paccapelo, C, Angelini, C, Cea, C, Muniz-Diaz, E, Sandoval, E, Calderon, EJ, Solligard, E, Aziz, F, Martinelli-Boneschi, F, Peyvandi, F, Blasi, F, Medrano, FJ, Rodriguez-Frias, F, Mueller, F, Grasselli, G, Costantino, G, Cardamone, G, Foti, G, Matullo, G, Kurihara, H, Afset, JE, Damas, JK, Ampuero, J, Martin, J, Erdmann, J, Bergan, J, Goerg, S, Ferrusquia-Acosta, J, Hernandez Quero, J, Delgado, J, Guerrero, JM, Risnes, K, Bettini, LR, Moreira, L, Gustad, LT, Santoro, L, Scudeller, L, Riveiro-Barciela, M, Schaefer, M, Carrabba, M, Valsecchi, MG, Hernandez-Tejero, M, Acosta-Herrera, M, D'Angio, M, Baldini, M, Cazzaniga, M, Ciccarelli, M, Bocciolone, M, Miozzo, M, Chueca, N, Montano, N, Faverio, P, Preatoni, P, Bonfanti, P, Omodei, P, Castro, P, Ferrer, R, Gualtierotti, R, Gallego-Duran, R, Morilla, R, Haider, S, Marsal, S, Aneli, S, Pelusi, S, 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Huang, Qin Qin, Martin, Hilary C., Mason, Dan, Trivedi, Bhavi, Wright, John, Finer, Sarah, Griffiths, Christopher J., Akhtar, Shaheen, Anwar, Mohammad, Arciero, Elena, Ashraf, Samina, Breen, Gerome, Chung, Raymond, Curtis, Charles J., Chowdhury, Maharun, Colligan, Grainne, Deloukas, Pano, Durham, Ceri, Griffiths, Chri, Hurles, Matt, Hussain, Shapna, Islam, Kamrul, Khan, Ahsan, Khan, Amara, Lavery, Cath, Lee, Sang Hyuck, Lerner, Robin, Macarthur, Daniel, Maclaughlin, Bev, Martin, Hilary, Miah, Shefa, Newman, Bill, Safa, Nishat, Tahmasebi, Farah, Smith, Albert V., Boughton, Andrew P., Li, Kevin W., Lefaive, Jonathon, Annis, Aubrey, Jannes, Cinthia E., Krieger, Jose E., Pereira, Alexandre C., Velho, Mariliza, Marques, Emanuelle, Lima, Isabella Ramo, Tada, Mauricio Teruo, Valino, Karina, Mccarthy, Mark, Rosenberger, Carrie, Lee, Jong Eun, Chang, Diana, Hammer, Christian, Hunkapiller, Julie, Mahajan, Anubha, Pendergrass, Sarah, Sucheston-Campbell, Lara, Yaspan, Brian, Lee, Hyun Soo, Shin, Eunsoon, Jang, Hye Yoon, Kim, Sunmie, Kym, Sungmin, Kim, Yeon-Sook, Jeong, Hyeongseok, Kwon, Ki Tae, Kim, Shin-Woo, Kim, Jin Yong, Jang, Young Rock, Kim, Hyun ah, Lee, Ji Yeon, Lee, Jeong Eun, Lee, Shinwon, Choe, Kang-Won, Kang, Yu Min, Jee, Sun Ha, Jung, Keum Ji, Parikh, Victoria, Ashley, Euan, Wheeler, Matthew, Rivas, Manuel, Bustamante, Carlo, Pinksy, Benjamin, Febbo, Phillip, Farh, Kyle, Schroth, Gary P., Desouza, Franci, Dalton, Karen, Christle, Jeff, Deboever, Christopher, Szalma, Sándor, Rubinacci, Simone, Delaneau, Olivier, Gorzynski, John, de Jong, Hannah, Sutton, Shirley, Youlton, Nathan, Joshi, Ruchi, Jimenez-Morales, David, Hughes, Christopher, Amar, David, Ioannidis, Alex, Hershman, Steve, Kirillova, Anna, Seo, Kinya, Huang, Yong, Shoura, Massa, Hammond, Nathan, Watson, Nathaniel, Raja, Archana, Huang, Chunhong, Sahoo, Malaya, Wang, Hannah, Zhen, Jimmy, Rakitko, Alexander, Ilinsky, Valery, Yermakovich, Danat, Popov, Iaroslav, Chernitsov, Alexander, Kovalenko, Elena, Krasnenko, Anna, Plotnikov, Nikolay, Stetsenko, Ivan, Kim, Anna, Cirulli, Elizabeth T., Schiabor Barrett, Kelly M., Bolze, Alexandre, White, Simon, Washington, Nicole L., Lu, James T., Riffle, Stephen, Tanudjaja, Francisco, Wang, Xueqing, Ramirez, Jimmy M., Leonetti, Nicole, Sandoval, Efren, Neveux, Iva, Dabe, Shaun, Grzymski, Joseph J., Esteban Miñano, Juan Ignacio, Aguirre, Luis A., López-Collazo, Eduardo, de la Mata Pazos, Manuel, Cerrato, Luciano, Lozano-Rodríguez, Roberto, Avendaño-Ortiz, José, Arcos, Verónica Terrón, Montalbán-Hernández, Karla Marina, Quiroga, Jaime Valentín, Pascual-Iglesias, Alejandro, Maroun-Eid, Charbel, Martín-Quirós, Alejandro, Namkoong, Ho, Imoto, Seiya, Katayama, Kazuhiko, Fukunaga, Koichi, Kitagawa, Yuko, Sato, Toshiro, Hasegawa, Naoki, Kumanogoh, Atsushi, Kimura, Akinori, Ai, Masumi, Tokunaga, Katsushi, Kanai, Takanori, Miyano, Satoru, Ogawa, Seishi, Edahiro, Ryuya, Sonehara, Kyuto, Shirai, Yuya, Ishii, Makoto, Kabata, Hiroki, Masaki, Katsunori, Kamata, Hirofumi, Ikemura, Shinnosuke, Chubachi, Shotaro, Okamori, Satoshi, Terai, Hideki, Tanaka, Hiromu, Morita, Atsuho, Lee, Ho, Asakura, Takanori, Sasaki, Junichi, Morisaki, Hiroshi, Uwamino, Yoshifumi, Nanki, Kosaku, Mikami, Yohei, Tomono, Kazunori, Kato, Kazuto, Matsuda, Fumihiko, Takahashi, Meiko, Hizawa, Nobuyuki, Takeda, Yoshito, Hirata, Haruhiko, Shiroyama, Takayuki, Miyawaki, Satoru, Suzuki, Ken, Maeda, Yuichi, Nii, Takuro, Noda, Yoshimi, Niitsu, Takayuki, Adachi, Yuichi, Enomoto, Takatoshi, Amiya, Saori, Hara, Reina, Takahashi, Kunihiko, Anzai, Tatsuhiko, Hasegawa, Takanori, Ito, Satoshi, Koike, Ryuji, Endo, Akifumi, Uchimura, Yuji, Miyazaki, Yasunari, Honda, Takayuki, Tateishi, Tomoya, Tohda, Shuji, Ichimura, Naoya, Sonobe, Kazunari, Sassa, Chihiro, Nakajima, Jun, Nannya, Yasuhito, Omae, Yosuke, Takahashi, Kazuhisa, Harada, Norihiro, Hiki, Makoto, Takagi, Haruhi, Nakamura, Ai, Tagaya, Etsuko, Kawana, Masatoshi, Arimura, Ken, Ishiguro, Takashi, Takayanagi, Noboru, Isono, Taisuke, Takaku, Yotaro, Takano, Kenji, Anan, Ryusuke, Nakajima, Yukiko, Nakano, Yasushi, Nishio, Kazumi, Ueda, Soichiro, Hayashi, Reina, Tateno, Hiroki, Hase, Isano, Yoshida, Shuichi, Suzuki, Shoji, Mitamura, Keiko, Saito, Fumitake, Ueda, Tetsuya, Azuma, Masanori, Nagasaki, Tadao, Yasui, Yoshinori, Hasegawa, Yoshinori, Mutoh, Yoshikazu, Yoshiyama, Takashi, Shoko, Tomohisa, Kojima, Mitsuaki, Adachi, Tomohiro, Ishikawa, Motonao, Takahashi, Kenichiro, Watanabe, Kazuyoshi, Manabe, Tadashi, Ito, Fumimaro, Fukui, Takahiro, Funatsu, Yohei, Koh, Hidefumi, Hirai, Yoshihiro, Kawashima, Hidetoshi, Narita, Atsuya, Niwa, Kazuki, Sekikawa, Yoshiyuki, Saito, Fukuki, Yoshiya, Kazuhisa, Yoshihara, Tomoyuki, Suzuki, Yusuke, Nakayama, Sohei, Masuzawa, Keita, Nishi, Koichi, Nishitsuji, Masaru, Tani, Maiko, Inoue, Takashi, Hirano, Toshiyuki, Kobayashi, Keigo, Miyazawa, Naoki, Kimura, Yasuhiro, Sado, Reiko, Ogura, Takashi, Kitamura, Hideya, Murohashi, Kota, Nakachi, Ichiro, Baba, Rie, Arai, Daisuke, Fuke, Satoshi, Saito, Hiroshi, Kuwahara, Naota, Fujiwara, Akiko, Okada, Takenori, Baba, Tomoya, Noda, Junya, Mashimo, Shuko, Yagi, Kazuma, Shiomi, Tetsuya, Hashiguchi, Mizuha, Odani, Toshio, Mochimaru, Takao, Oyamada, Yoshitaka, Mori, Nobuaki, Izumi, Namiki, Nagata, Kaoru, Taki, Reiko, Murakami, Koji, Yamada, Mitsuhiro, Sugiura, Hisatoshi, Hayashi, Kentaro, Shimizu, Tetsuo, Gon, Yasuhiro, Fujitani, Shigeki, Tsuchida, Tomoya, Yoshida, Toru, Kagaya, Takashi, Kita, Toshiyuki, Sakagami, Satoru, Kimizuka, Yoshifumi, Kawana, Akihiko, Nakamura, Yoshihiko, Ishikura, Hiroyasu, Takata, Tohru, Kikuchi, Takahide, Taniyama, Daisuke, Nakamura, Morio, Kodama, Nobuhiro, Kaneyama, Yasunari, Maeda, Shunsuke, Nagasaki, Yoji, Okamoto, Masaki, Ishihara, Sayoko, Ito, Akihiro, Chihara, Yusuke, Takeuchi, Mayumi, Onoi, Keisuke, Hashimoto, Naozumi, Wakahara, Keiko, Ando, Akira, Masuda, Makoto, Wakabayashi, Aya, Watanabe, Hiroki, Sageshima, Hisako, Nakada, Taka-Aki, Abe, Ryuzo, Shimada, Tadanaga, Kawamura, Kodai, Ichikado, Kazuya, Nishiyama, Kenta, Yamasaki, Masaki, Hashimoto, Satoru, Kusaka, Yu, Ohba, Takehiko, Isogai, Susumu, Takada, Minoru, Kanda, Hidenori, Komase, Yuko, Sano, Fumiaki, Asano, Koichiro, Oguma, Tsuyoshi, Harada, Masahiro, Takahashi, Takeshi, Shibusawa, Takayuki, Abe, Shinji, Kono, Yuta, Togashi, Yuki, Izumo, Takehiro, Inomata, Minoru, Awano, Nobuyasu, Ogawa, Shinichi, Ogata, Tomouki, Ishihara, Shoichiro, Kanehiro, Arihiko, Ozaki, Shinji, Fuchimoto, Yasuko, Kitagawa, Yuichiro, Yoshida, Shozo, Ogura, Shinji, Nishiyama, Kei, Yoshida, Kousuke, Beppu, Satoru, Fukuyama, Satoru, Eriguchi, Yoshihiro, Yonekawa, Akiko, Inoue, Yoshiaki, Yamagata, Kunihiro, Chiba, Shigeru, Narumoto, Osamu, Nagai, Hideaki, Ooshima, Nobuharu, Motegi, Mitsuru, Sagara, Hironori, Tanaka, Akihiko, Ohta, Shin, Shibata, Yoko, Tanino, Yoshinori, Sato, Yuki, Yamada, Yuichiro, Hashino, Takuya, Shinoki, Masato, Iwagoe, Hajime, Imamura, Tomonori, Umeda, Akira, Shimada, Hisato, Endo, Mayu, Hayashi, Shinichi, Takahashi, Mai, Nakano, Shigefumi, Yatomi, Masakiyo, Maeno, Toshitaka, Ishii, Tomoo, Utsugi, Mitsuyoshi, Ono, Akihiro, Kanaoka, Kensuke, Ihara, Shoichi, Komuta, Kiyoshi, Boezen, Marike, Claringbould, Annique, Lopera, Esteban, Warmerdam, Robert, Vonk, Judith. M., van Blokland, Irene, Lanting, Pauline, Ori, Anil P. S., Obeidat, Ma’En, Hernández Cordero, Ana I., Sin, Don D., Bossé, Yohan, Joubert, Philippe, Hao, Ke, Nickle, David, Timens, Wim, van den Berge, Maarten, Feng, Yen-Chen Anne, Mercader, Josep, Weiss, Scott T., Karlson, Elizabeth W., Smoller, Jordan W., Murphy, Shawn N., Meigs, James B., Woolley, Ann E., Green, Robert C., Perez, Emma F., Zöllner, Sebastian, Wang, Jiongming, Beck, Andrew, Sloofman, Laura G., Ascolillo, Steven, Sebra, Robert P., Collins, Brett L., Levy, Te, Sealfon, Stuart C., Jordan, Daniel M., Thompson, Ryan C., Gettler, Kyle, Chaudhary, Kumardeep, Belbin, Gillian M., Preuss, Michael, Hoggart, Clive, Choi, Sam, Underwood, Slayton J., Salib, Irene, Britvan, Bari, Keller, Katherine, Tang, Lara, Peruggia, Michael, Hiester, Liam L., Niblo, Kristi, Aksentijevich, Alexandra, Labkowsky, Alexander, Karp, Avromie, Zlatopolsky, Menachem, Zyndorf, Marissa, Charney, Alexander W., Beckmann, Noam D., Schadt, Eric E., Abul-Husn, Noura S., Cho, Judy H., Itan, Yuval, Kenny, Eimear E., Loos, Ruth J. F., Nadkarni, Girish N., Do, Ron, O’Reilly, Paul, Huckins, Laura M., Ferreira, Manuel A. R., Abecasis, Goncalo R., Leader, Joseph B., Cantor, Michael N., Justice, Anne E., Carey, Dave J., Chittoor, Geetha, Josyula, Navya Shilpa, Kosmicki, Jack A., Horowitz, Julie E., Baras, Ari, Gass, Matthew C., Yadav, Ashish, Mirshahi, Tooraj, Jan Hottenga, Jouke, Bartels, Meike, de Geus, Eco J. C., Nivard, Michel G., Verma, Anurag, Ritchie, Marylyn D., Rader, Daniel, Li, Binglan, Verma, Shefali S., Lucas, Anastasia, Bradford, Yuki, Zara, Federico, Salpietro, Vincenzo, Scala, Marcello, Iacomino, Michele, Scudieri, Paolo, Bocciardi, Renata, Minetti, Carlo, Riva, Antonella, Vari, Maria Stella, Rahier, Jean-Françoi, Giorgio, Elisa, Carli, Diana, Louis, Edouad, Bulik, Cynthia M., Landén, Mikael, Brusco, Alfredo, Ferrero, Giovanni Battista, Madia, Francesca, Fundín, Bengt, Ismail, Said I., Saad, Chadi, Al-Sarraj, Yaser, Badji, Radja Messai, Al-Muftah, Wadha, Al Thani, Asma, Afifi, Nahla, Klovins, Jani, Rovite, Vita, Rescenko, Raimond, Peculis, Raiti, Ustinova, Monta, Zeberg, Hugo, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklo, Johnson, Ruth, Geschwind, Daniel H., Freimer, Nelson, Butte, Manish J., Ding, Yi, Chiu, Alec, Chang, Timothy S., Boutros, Paul, Moutsianas, Louka, Caulfield, Mark J., Scott, Richard H., Walker, Susan, Stuckey, Alex, Odhams, Christopher A., Rhodes, Daniel, Fowler, Tom, Rendon, Augusto, Chan, Georgia, Arumugam, Prabhu, Karczewski, Konrad J., Wilson, Daniel J., Spencer, Chris A., Crook, Derrick W., Wyllie, David H., O’Connell, Anne Marie, Atkinson, Elizabeth G., Tsuo, Kristin, Baya, Nikola, Turley, Patrick, Gupta, Rahul, Walters, Raymond K., Palmer, Duncan S., Sarma, Gopal, Cheng, Nathan, Lu, Wenhan, Churchhouse, Claire, Goldstein, Jacqueline I., King, Daniel, Seed, Cotton, Daly, Mark J., Bryant, Sam, Satterstrom, F. Kyle, Band, Gavin, Earle, Sarah G., Lin, Shang-Kuan, Arning, Nicola, Armstrong, Jacob, Rudkin, Justine K., Callier, Shawneequa, Cusick, Caroline, Soranzo, Nicole, Zhao, Jing Hua, Danesh, John, Di Angelantonio, Emanuele, Butterworth, Adam S., Sun, Yan V., Huffman, Jennifer E., Cho, Kelly, O’Donnell, Christopher J., Tsao, Phil, Gaziano, J. Michael, Peloso, Gina, Ho, Yuk-Lam, Mian, Michael, Scaggiante, Federica, Chang, Xiao, Glessner, Joseph R., Hakonarson, Hakon, Mcguigan, Peter J., Prockter Moore, Luke Stephen, Vizcaychipi, Marcela Paola, Hall, Kathryn, Campbell, Andy, Nichol, Ailstair, Ward, Geraldine, Page, Valerie Joan, Semple, Malcolm G., Adeniji, Kayode, Agranoff, Daniel, Agwuh, Ken, Ail, Dhiraj, Aldera, Erin L., Alegria, Ana, Angus, Brian, Ashish, Abdul, Atkinson, Dougal, Bari, Shahedal, Barlow, Gavin, Barnass, Stella, Barrett, Nichola, Bassford, Christopher, Basude, Sneha, Baxter, David, Beadsworth, Michael, Bernatoniene, Jolanta, Berridge, John, Best, Nicola, Bothma, Pieter, Chadwick, David, Brittain-Long, Robin, Bulteel, Naomi, Burden, Tom, Burtenshaw, Andrew, Caruth, Vikki, Chambler, Duncan, Chee, Nigel, Child, Jenny, Chukkambotla, Srikanth, Clark, Tom, Collini, Paul, Cosgrove, Catherine, Cupitt, Jason, Cutino-Moguel, Maria-Teresa, Dark, Paul, Dawson, Chri, Dervisevic, Samir, Donnison, Phil, Douthwaite, Sam, Drummond, Andrew, Durand, Ingrid, Dushianthan, Ahilanadan, Dyer, Tristan, Evans, Cariad, Eziefula, Chi, Fegan, Christopher, Finn, Adam, Fullerton, Duncan, Garg, Sanjeev, Garg, Atul, Gkrania-Klotsas, Effrossyni, Godden, Jo, Goldsmith, Arthur, Graham, Clive, Hardy, Elaine, Hartshorn, Stuart, Harvey, Daniel, Havalda, Peter, Hawcutt, Daniel B., Hobrok, Maria, Hodgson, Luke, Hormis, Anil, Jacobs, Michael, Jain, Susan, Jennings, Paul, Kaliappan, Agilan, Kasipandian, Vidya, Kegg, Stephen, Kelsey, Michael, Kendall, Jason, Kerrison, Caroline, Kerslake, Ian, Koch, Oliver, Koduri, Gouri, Koshy, George, Laha, Shondipon, Laird, Steven, Larkin, Susan, Leiner, Tama, Lillie, Patrick, Limb, Jame, Linnett, Vanessa, Little, Jeff, Lyttle, Mark, Macmahon, Michael, Macnaughton, Emily, Mankregod, Ravish, Masson, Huw, Matovu, Elijah, Mccullough, Katherine, Mcewen, Ruth, Meda, Manjula, Mills, Gary H., Minton, Jane, Ward, Karl, Mirfenderesky, Mariyam, Mohandas, Kavya, Mok, Quen, Moon, Jame, Moore, Elinoor, Morgan, Patrick, Morris, Craig, Mortimore, Katherine, Moses, Samuel, Mpenge, Mbiye, Mulla, Rohinton, Murphy, Michael, Nagel, Megan, Nagarajan, Thapa, Nelson, Mark, O’Shea, Matthew K., Otahal, Igor, Ostermann, Marlie, Pais, Mark, Panchatsharam, Selva, Papakonstantinou, Danai, Paraiso, Hassan, Patel, Brij, Pattison, Natalie, Pepperell, Justin, Peters, Mark, Phull, Mandeep, Pintus, Stefania, Pooni, Jagtur Singh, Post, Frank, Price, David, Prout, Rachel, Rae, Nikola, Reschreiter, Henrik, Reynolds, Tim, Richardson, Neil, Roberts, Mark, Roberts, Devender, Rose, Alistair, Rousseau, Guy, Ryan, Brendan, Saluja, Taranprit, Shah, Aarti, Shanmuga, Prad, Sharma, Anil, Shawcross, Anna, Sizer, Jeremy, Shankar-Hari, Manu, Smith, Richard, Snelson, Catherine, Spittle, Nick, Staines, Nikki, Stambach, Tom, Stewart, Richard, Subudhi, Pradeep, Szakmany, Tama, Tatham, Kate, Thomas, Jo, Thompson, Chri, Thompson, Robert, Tridente, Ascanio, Tupper-Carey, Darell, Twagira, Mary, Ustianowski, Andrew, Vallotton, Nick, Vincent-Smith, Lisa, Visuvanathan, Shico, Vuylsteke, Alan, Waddy, Sam, Wake, Rachel, Walden, Andrew, Welters, Ingeborg, Whitehouse, Tony, Whittaker, Paul, Whittington, Ashley, Papineni, Padmasayee, Wijesinghe, Meme, Williams, Martin, Wilson, Lawrence, Cole, Sarah, Winchester, Stephen, Wiselka, Martin, Wolverson, Adam, Wooton, Daniel G., Workman, Andrew, Yates, Bryan, Young, Peter, Beale, Rupert, Bretherick, Andrew D., Clohisey, Sara, Fourman, Max Head, Furniss, Jame, Gountouna, Elvina, Grimes, Graeme, Haley, Chri, Harrison, David, Hayward, Caroline, Keating, Sean, Klaric, Lucija, Klenerman, Paul, Law, Andy, Meynert, Alison M., Millar, Jonathan, Pairo-Castineira, Erola, Parkinson, Nichola, Ponting, Chris P., Porteous, David J., Rawlik, Konrad, Richmond, Anne, Rowan, Kathy, Russell, Clark D., Shen, Xia, Shih, Barbara, Tenesa, Albert, Vitart, Veronique, Wang, Bo, Wilson, James F., Wu, Yang, Yang, Jian, Yang, Zhijian, Zechner, Marie, Zhai, Ranran, Zheng, Chenqing, Norman, Lisa, Pius, Riinu, Drake, Thomas M., Fairfield, Cameron J., Knight, Stephen R., Mclean, Kenneth A., Murphy, Derek, Shaw, Catherine A., Dalton, Jo, Girvan, Michelle, Saviciute, Egle, Roberts, Stephanie, Harrison, Janet, Marsh, Laura, Connor, Marie, Halpin, Sophie, Jackson, Clare, Gamble, Carrol, Leeming, Gary, Law, Andrew, Wham, Murray, Hendry, Ro, Scott-Brown, Jame, Begg, Colin, Hinds, Charle, Wai Ho, Antonia Ying, Horby, Peter W., Knight, Julian, Ling, Lowell, Maslove, David, Mcauley, Danny, Montgomery, Hugh, Nichol, Alistair, Openshaw, Peter J. M., Summers, Charlotte, Walsh, Timothy, Armstrong, Lisa, Bates, Hayley, Dooks, Emma, Farquhar, Fiona, Hairsine, Brigid, Mcparland, C., Packham, Sophie, Alldis, Zoe, Astin-Chamberlain, Raine, Bibi, Fatima, Biddle, Jack, Blow, Sarah, Bolton, Matthew, Borra, Catherine, Bowles, Ruth, Burton, Maudrian, Choudhury, Yasmin, Collier, David, Cox, Amber, Easthope, Amy, Ebano, Patrizia, Fotiadis, Stavro, Gurasashvili, Jana, Halls, Rosslyn, Hartridge, Pippa, Kallon, Delordson, Kassam, Jamila, Lancoma-Malcolm, Ivone, Matharu, Maninderpal, May, Peter, Mitchelmore, Oliver, Newman, Tabitha, Patel, Mital, Pheby, Jane, Pinzuti, Irene, Prime, Zoe, Prysyazhna, Oleksandra, Shiel, Julian, Taylor, Melanie, Tierney, Carey, Wood, Suzanne, Zak, Anne, Zongo, Olivier, Forsey, Miranda, Nicholson, Anne, Riches, Joanne, Vertue, Mark, Wasson, Christopher, Finn, Stephanie, Green, Jackie, Collins, Erin, King, Bernadette, Grauslyte, Lina, Hussain, Musarat, Pogreban, Tatiana, Rosaroso, Lace, Salciute, Erika, Franke, George, Wong, Joanna, George, Aparna, Akeroyd, Louise, Bano, Shereen, Bromley, Matt, Gurr, Lucy, Lawton, Tom, Morgan, Jame, Sellick, Kirsten, Warren, Deborah, Wilkinson, Brian, Mcgowan, Janet, Ledgard, Camilla, Stacey, Amelia, Pye, Kate, Bellwood, Ruth, Bentley, Michael, Loosley, Ronda, Mcguinness, Heather, Tench, Helen, Wolf-Roberts, Rebecca, Gibson, Sian, Lyle, Amanda, Mcneela, Fiona, Radhakrishnan, Jayachandran, Hughes, Alistair, Ali, Asifa, Brady, Megan, Dale, Sam, Dance, Annalisa, Gledhill, Lisa, Greig, Jill, Hanson, Kathryn, Holdroyd, Kelly, Home, Marie, Kelly, Diane, Kitson, Ro, Matapure, Lear, Melia, Deborah, Mellor, Samantha, Nortcliffe, Tonicha, Pinnell, Jez, Robinson, Matthew, Shaw, Lisa, Shaw, Ryan, Thomis, Lesley, Wilson, Alison, Wood, Tracy, Bayo, Lee-Ann, Merwaha, Ekta, Ishaq, Tahira, Hanley, Sarah, Antcliffe, David, Banach, Dorota, Brett, Stephen, Coghlan, Phoebe, Fernandez, Ziortza, Gordon, Anthony, Rojo, Roceld, Arias, Sonia Sousa, Templeton, Maie, Jha, Rajeev, Krishnamurthy, Vinodh, Lim, Lai, Bi, Rehana, Scholefield, Barney, Ashton, Lydia, Williams, Alison, Cheyne, Claire, Saunderson, Anne, Allan, Angela, Anderson, Felicity, Kaye, Callum, Liew, Jade, Medhora, Jasmine, Scott, Teresa, Trumper, Erin, Botello, Adriana, Polgarova, Petra, Stroud, Katerina, Meaney, Eoghan, Jones, Megan, Ng, Anthony, Agrawal, Shruti, Pathan, Nazima, White, Deborah, Daubney, Esther, Elston, Kay, Parker, Robert, Reddy, Amie, Turner-Bone, Ian, Wilding, Laura, Harding, Peter, Jacob, Reni, Jones, Cathy, Denmade, Craig, Croft, Maria, White, Ian, Lim, Li, Griffin, Denise, Muchenje, Nycola, Mupudzi, Mcdonald, Partridge, Richard, Conyngham, Jo-Anna, Thomas, Rachel, Wright, Mary, Corral, Maria Alvarez, Bastion, Victoria, Clarke, Daphene, David, Beena, Kent, Harriet, Lorusso, Rachel, Lubimbi, Gamu, Murdoch, Sophie, Penacerrada, Melchizedek, Thomas, Alastair, Valentine, Jennifer, Vochin, Ana, Wulandari, Retno, Djeugam, Brice, Dawson, Joy, Garrioch, Sweyn, Tolson, Melanie, Aldridge, Jonathan, de Almeida Martins, Laura Gome, Carungcong, Jaime, Beavis, Sarah, Dale, Katie, Gascoyne, Rachel, Hawes, Joanne, Pritchard, Kelly, Stevenson, Lesley, Whileman, Amanda, Cowley, Anne, Highgate, Judith, Crawley, Rikki, Crew, Abigail, Cunningham, Mishell, Daniels, Allison, Harrison, Laura, Hope, Susan, Inweregbu, Ken, Jones, Sian, Lancaster, Nicola, Matthews, Jamie, Nicholson, Alice, Wray, Gemma, Benham, Leonie, Bradshaw, Zena, Brown, Joanna, Caswell, Melanie, Melling, Sarah, Preston, Stephen, Slawson, Nicola, Stoddard, Emma, Warden, Scott, Combes, Edward, Joefield, Teishel, Monnery, Sonja, Beech, Valerie, Trotman, Sallyanne, Hopkins, Bridget, Scriven, Jame, Thrasyvoulou, Laura, Willis, Heather, Anderson, Susan, Birch, Janine, Collins, Emma, Hammerton, Kate, O’Leary, Ryan, Abernathy, Caroline, Foster, Louise, Gratrix, Andrew, Martinson, Vicky, Parkinson, Priyai, Stones, Elizabeth, Carbral-Ortega, Llucia, Kapoor, Ritoo, Loader, David, Castle, Karen, Brandwood, Craig, Smith, Lara, Clark, Richard, Birchall, Katie, Kolakaluri, Laurel, Baines, Deborah, Sukumaran, Anila, Mapfunde, Isheunesu, Meredith, Megan, Morris, Lucy, Ryan, Lucy, Clark, Amy, Sampson, Julia, Peters, Cecilia, Dent, Martin, Langley, Margaret, Ashraf, Saima, Wei, Shuying, Andrew, Angela, Chablani, Manish, Kirkby, Amy, Netherton, Kimberley, Bates, Michelle, Dasgin, Jo, Gill, Jaspret, Nilsson, Annette, Apetri, Elena, Basikolo, Cathrine, Blackledge, Bethan, Catlow, Laura, Charles, Bethan, Doonan, Reece, Harris, Jade, Harvey, Alice, Horner, Daniel, Knowles, Karen, Lee, Stephanie, Lomas, Diane, Lyons, Chloe, Marsden, Tracy, Mclaughlan, Danielle, Mcmorrow, Liam, Pendlebury, Jessica, Perez, Jane, Poulaka, Maria, Proudfoot, Nicola, Slaughter, Melanie, Slevin, Kathryn, Thomas, Vicky, Walker, Danielle, Michael, Angiy, Collis, Matthew, Clark, Martyn, Coulding, Martina, Jude, Edward, Mccormick, Jacqueline, Mercer, Oliver, Potla, Darsh, Rehman, Hafiz, Savill, Heather, Turner, Victoria, Davey, Miriam, Golden, David, Seaman, Rebecca, Hunt, Jodie, Dearden, Joy, Dobson, Emma, Mulcahy, Michelle, Munt, Sheila, O’Connor, Grainne, Philbin, Jennifer, Rishton, Chloe, Tully, Redmond, Winnard, Sarah, Cagova, Lenka, Fofano, Adama, Garner, Lucie, Holcombe, Helen, Mepham, Sue, Mitchell, Alice Michael, Mwaura, Lucy, Praman, K., Vuylsteke, Alain, Zamikula, Julie, Bercades, Georgia, Brealey, David, Hass, Ingrid, Maccallum, Niall, Martir, Glady, Raith, Eamon, Reyes, Anna, Smyth, Deborah, Taylor, Abigail, Hughes, Rachel Anne, Thomas, Helen, Rees, Alun, Duskova, Michaela, Phipps, Janet, Brooks, Suzanne, Edwards, Michelle, Alexander, Peter, Allen, Schvearn, Bradley-Potts, Joanne, Brantwood, Craig, Egan, Jasmine, Felton, Timothy, Padden, Grace, Ward, Luke, Moss, Stuart, Glasgow, Susannah, Beesley, Kate, Board, Sarah, Kubisz-Pudelko, Agnieszka, Lewis, Alison, Perry, Je, Pippard, Lucy, Wood, Di, Buckley, Clare, Brown, Alison, Gregory, Jane, O’Connell, Susan, Smith, Tim, Belagodu, Zakaula, Fuller, Bridget, Gherman, Anca, Olufuwa, Olumide, Paramsothy, Remi, Stuart, Carmel, Oakley, Naomi, Kamundi, Charlotte, Tyl, David, Collins, Katy, Silva, Pedro, Taylor, June, King, Laura, Coates, Charlotte, Crowley, Maria, Wakefield, Phillipa, Beadle, Jane, Johnson, Laura, Sargeant, Janet, Anderson, Madeleine, Jardine, Catherine, Williams, Dewi, Parris, Victoria, Quaid, Sheena, Watson, Ekaterina, Melville, Julie, Naisbitt, Jay, Joseph, Rosane, Lazo, Maria, Walton, Olivia, Neal, Alan, Hill, Michaela, Kannan, Thogulava, Wild, Laura, Allan, Elizabeth, Darlington, Kate, Davies, Ffyon, Easton, Jack, Kumar, Sumit, Lean, Richard, Menzies, Daniel, Pugh, Richard, Qiu, Xinyi, Davies, Llino, Williams, Hannah, Scanlon, Jeremy, Davies, Gwyneth, Mackay, Callum, Lewis, Joannne, Rees, Stephanie, Coetzee, Samantha, Gales, Alistair, Raj, Meena, Sell, Craig, Langton, Helen, Watters, Malcolm, Novis, Catherine, Arbane, Gill, Bociek, Aneta, Campos, Sara, Grau, Neu, Jones, Tim Owen, Lim, Rosario, Marotti, Martina, Whitton, Christopher, Barron, Anthony, Collins, Ciara, Kaul, Sundeep, Passmore, Heather, Prendergast, Claire, Reed, Anna, Rogers, Paula, Shokkar, Rajvinder, Woodruff, Meriel, Middleton, Hayley, Polgar, Oliver, Nolan, Claire, Thwaites, Vicky, Mahay, Kanta, Sri-Chandana, Chunda, Scherewode, Joslan, Stephenson, Lorraine, Marsh, Sarah, Bancroft, Hollie, Bellamy, Mary, Carmody, Margaret, Daglish, Jacqueline, Moore, Faye, Rhodes, Joanne, Sangombe, Mirriam, Kadiri, Salma, Ayers, Amanda, Harrison, Wendy, North, Julie, Cavazza, Anna, Cockrell, Maeve, Corcoran, Eleanor, Depante, Maria, Finney, Clare, Jerome, Ellen, Mcphail, Mark, Nayak, Monalisa, Noble, Harriet, O’Reilly, Kevin, Pappa, Evita, Saha, Rohit, Saha, Sian, Smith, John, Knighton, Abigail, Gill, Mandy, Paul, Paul, Ratnam, Valli, Shelton, Sarah, Wynter, Inez, Baptista, David, Crowe, Rebecca, Fernandes, Rita, Herdman-Grant, Rosaleen, Joseph, Anna, Loveridge, Adam, Mckenley, India, Morino, Eriko, Naranjo, Andre, Simms, Richard, Sollesta, Kathryn, Swain, Andrew, Venkatesh, Harish, Khera, Jacyntha, Fox, Jonathan, Barber, Russell, Hewitt, Claire, Hilldrith, Annette, Jackson-Lawrence, Karen, Shepardson, Sarah, Wills, Maryanne, Butler, Susan, Tavares, Silvia, Cunningham, Amy, Hindale, Julia, Arif, Sarwat, George, Linsha, Twiss, Sophie, Wright, David, Holland, Maureen, Keenan, Natalie, Lyons, Marc, Wassall, Helen, Marsh, Chri, Mahenthran, Mervin, Carter, Emma, Kong, Thoma, Adanini, Oluronke, Bhatia, Nikhil, Msiska, Maine, Mew, Louise, Mwaura, Esther, Williams, Felicity, Wren, Lynn, Sutherland, Sara-Beth, Battle, Ceri, Brinkworth, Elaine, Harford, Rachel, Murphy, Carl, Newey, Luke, Rees, Tabitha, Williams, Marie, Arnold, Sophie, Hardy, John, Houlden, Henry, Moncur, Eleanor, Tariq, Ambreen, Tucci, Arianna, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Keshet-Price, Jocelyn, Randell, Georgina, Stammers, Katie, Abdelrazik, Marwa, Bakthavatsalam, Dhanalakshmi, Elhassan, Munzir, Ganesan, Arunkumar, Haldeos, Anne, Moreno-Cuesta, Jeronimo, Purohit, Dharam, Vincent, Rachel, Xavier, Kugan, Rohit, Kumar, Alasdair, Frater, Saleem, Malik, David, Carter, Jenkins, Samuel, Lamond, Zoe, Wall, Alanna, Reynolds, Jessica, Campbell, Helen, Thompsom, Maria, Dodds, Steve, Duffy, Stacey, Butcher, Deborah, O’Sullivan, Susie, Butterworth-Cowin, Nicola, Deacon, Bethan, Hibbert, Meg, Pothecary, Carla, Tetla, Dariusz, Woodford, Christopher, Durga, Latha, Kennard-Holden, Gareth, de Gordoa, Laura Ortiz-Ruiz, Peasgood, Emily, Phillips, Claire, Skinner, Denise, Gaylard, Jane, Mullan, Dee, Newman, Julie, Davies, Ellie, Roche, Lisa, Sathe, Sonia, Brimfield, Lutece, Daly, Zoe, Pogson, David, Rose, Steve, Collins, Amy, Khaliq, Waqa, Gude, Estefania Treu, Allen, Louise, Beranova, Eva, Crisp, Nikki, Deery, Joanne, Hazelton, Tracy, Knight, Alicia, Price, Carly, Tilbey, Sorrell, Turki, Salah, Turney, Sharon, Giles, Julian, Booth, Simon, Bell, Gillian, English, Katy, Katary, Amro, Wilcox, Louise, Campbell, Rachael, Clarke, Noreen, Whiteside, Jonathan, Mascarenhas, Mairi, Donaldson, Avril, Matheson, Joanna, Barrett, Fiona, O’Hara, Marianne, O’Keefe, Laura, Bradley, Clare, Collier, Dawn, Walker, Rachel, Maynard, Victoria, Patel, Tahera, Smith, Matthew, Kazi, Aayesha, Hartley, Janice, Dykes, Joseph, Hijazi, Muhammad, Keith, Sarah, Khan, Meherunnisa, Ryan-Smith, Janet, Springle, Philippa, Thomas, Jacqueline, Truman, Nick, Saad, Samuel, Coleman, Dabheoc, Fine, Christopher, Matt, Roseanna, Gay, Bethan, Dalziel, Jack, Ali, Syamlan, Goodchild, Drew, Harling, Rhiannan, Bhatterjee, Ravi, Goddard, Wendy, Davison, Chloe, Duberly, Stephen, Hargreaves, Jeanette, Bolton, Rachel, Verlander, Mark, Williams, Alexandra, Blackman, Helen, Creagh-Brown, Ben, Donlon, Sinead, Michalak-Glinska, Natalia, Mtuwa, Sheila, Pristopan, Veronika, Salberg, Armorel, Smith, Eleanor, Stone, Sarah, Piercy, Charle, Verula, Jerik, Burda, Dorota, Montaser, Rugia, Harden, Lesley, Mayangao, Irving, Marriott, Cheryl, Bradley, Paul, Harris, Celia, Cooper, Joshua, Finch, Cheryl, Liderth, Sarah, Quinn, Alison, Waddington, Natalia, Fidler, Katy, Tagliavini, Emma, Donnelly, Kevin, Abel, Lynn, Brett, Michael, Digby, Brian, Gemmell, Lisa, Hornsby, Jame, Macgoey, Patrick, O’Neil, Pauline, Price, Richard, Rodden, Natalie, Rooney, Kevin, Sundaram, Radha, Thomson, Nicola, Flanagan, Rebecca, Hughes, Gareth, Latham, Scott, Mckenna, Emma, Anderson, Jennifer, Hull, Robert, Rhead, Kat, Branney, Debbie, Frankham, Jordan, Pitts, Sally, White, Nigel, Cristiano, Daniele, Dormand, Natalie, Farzad, Zohreh, Gummadi, Mahitha, Liyanage, Kamal, Patel, Brijesh V., Salmi, Sara, Sloane, Geraldine, Varghese, Mathew, Zborowski, Anelise C., Bean, Sarah, Burt, Karen, Spivey, Michael, Eastgate-Jackson, Christine, Filipe, Helder, Martin, Daniel, Maharajh, Amitaa, Garcia, Sara Mingo, De Neef, Mark, Lynch, Ceri, Howe, Gwenllian Sera, Singh, Jayaprakash, Turner, Keri, Ellis, Hannah, Stroud, Natalie, Cherian, Shiney, Cutler, Sean, Heron, Anne Emma, Roynon-Reed, Anna, Williams, Gemma, Richards, Owen, Cheema, Yusuf, Ahmad, Norfaizan, Barker, Joann, Bauchmuller, Kri, Bird, Sarah, Cawthron, Kay, Harrington, Kate, Jackson, Yvonne, Kibutu, Faith, Lenagh, Becky, Masuko, Shamiso, Raithatha, Ajay, Wiles, Matthew, Willson, Jayne, Newell, Helen, Lye, Alison, Nwafor, Lorenza, Jarman, Claire, Rowland-Jones, Sarah, Foote, David, Cole, Joby, Thompson, Roger, Watson, Jame, Hesseldon, Lisa, Macharia, Irene, Chetam, Luke, Smith, Jacqui, Ford, Amber, Anderson, Samantha, Birchall, Kathryn, Housley, Kay, Walker, Sara, Milner, Leanne, Hanratty, Helena, Trower, Helen, Phillips, Patrick, Oxspring, Simon, Donne, Ben, Bevan, Emily, Martin, Jane, Trodd, Dawn, Watson, Geoff, Brown, Caroline Wrey, Bunni, Lara, Jennings, Claire, Latif, Monica, Marshall, Rebecca, Subramanian, Gayathri, Bandla, Nageswar, Gellamucho, Minnie, Davies, Michelle, Thompson, Christopher, Trim, Fiona, Eapen, Beena, Ahmed, Cecilia, Baines, Balvinder, Clamp, Sarah, Colley, Julie, Haq, Risna, Hayes, Anne, Hulme, Jonathan, Hussain, Samia, Joseph, Sibet, Kumar, Rita, Maqsood, Zahira, Purewal, Manjit, Chandler, Ben, Elliott, Kerry, Mallinson, Janine, Turnbull, Alison, Dent, Kathy, Horsley, Elizabeth, Akhtar, Muhmmad Nauman, Pearson, Sandra, Potoczna, Dorota, Spencer, Sue, Blakemore, Hayley, Borislavova, Borislava, Faulkner, Beverley, Gendall, Emma, Goff, Elizabeth, Hayes, Kati, Thomas, Matt, Worner, Ruth, Smith, Kerry, Stephens, Deanna, Delgado, Carlos Castro, Dawson, Deborah, Ding, Lijun, Durrant, Georgia, Ezeobu, Obiageri, Farnell-Ward, Sarah, Harrison, Abiola, Kanu, Rebecca, Leaver, Susannah, Maccacari, Elena, Manna, Soumendu, Saluzzio, Romina Peperman, Queiroz, Joana, Samakomva, Tinashe, Sicat, Christine, Texeira, Joana, Da Gloria, Edna Fernande, Lisboa, Ana, Rawlins, John, Mathew, Jisha, Kinch, Ashley, Hurt, William Jame, Shah, Nirav, Clark, Victoria, Thanasi, Maria, Yun, Nikki, Patel, Kamal, Crickmore, Vikki, Debreceni, Gabor, Wilkins, Joy, Nicol, Liz, Burn, Iona, Hambrook, Geraldine, Manso, Katarina, Penn, Ruth, Shanmugasundaram, Pradeep, Tebbutt, Julie, Thornton, Danielle, Rostron, Anthony, Roy, Alistair, Woods, Lindsey, Cornell, Sarah, Wakinshaw, Fiona, Rogerson, Kimberley, Jarmain, Jordan, Anderson, Peter, Archer, Katie, Austin, Karen, Davis, Caroline, Durie, Alison, Kelsall, Olivia, Thrush, Jessica, Vigurs, Charlie, Wood, Hannah-Louise, Tranter, Helen, Harrison, Alison, Cowley, Nichola, Mcalindon, Michael, Digby, Stephen, Low, Emma, Morgan, Aled, Cother, Naiara, Rankin, Tobia, Clayton, Sarah, Mccurdy, Alex, Allibone, Suzanne, Mary-Genetu, Roman, Patel, Amit, Mac, Ainhi, Murphy, Anthony, Mahjoob, Parisa, Nazari, Roonak, Worsley, Lucy, Fagan, Andrew, Mohamed Ali, Inthakab Ali, Beaumont, Karen, Blunt, Mark, Coton, Zoe, Curgenven, Hollie, Elsaadany, Mohamed, Fernandes, Kay, Ally, Sameena Mohamed, Rangarajan, Harini, Sarathy, Varun, Selvanayagam, Sivarupan, Vedage, Dave, White, Matthew, Fernandez-Roman, Jaime, Hamilton, David O., Johnson, Emily, Johnston, Brian, Martinez, Maria Lopez, Mulla, Suleman, Shaw, David, Waite, Alicia A. C., Waugh, Victoria, Welters, Ingeborg D., Williams, Karen, Bemand, Thoma, Black, Ethel, Rosa, Arnold Dela, Howle, Ryan, Jhanji, Shaman, Baikady, Ravishankar Rao, Tatham, Kate Colette, Thomas, Benjamin, Halkes, Matthew, Mercer, Pauline, Thornton, Lorraine, West, Joe, Baird, Tracy, Ruddy, Jim, Reece-Anthony, Rosie, Birt, Mark, Cowton, Amanda, Kay, Andrea, Kent, Melanie, Potts, Kathryn, Wilkinson, Ami, Naylor, Suzanne, Brown, Ellen, Clark, Michele, Purvis, Sarah, Cole, Jade, Davies, Rhy, Duffin, Donna, Hill, Helen, Player, Ben, Thomas, Emma, Williams, Angharad, Beith, Claire Marie, Black, Karen, Clements, Suzanne, Morrison, Alan, Strachan, Dominic, Taylor, Margaret, Clarkson, Michelle, D’Sylva, Stuart, Norman, Kathryn, Coventry, Tina, Fowler, Susan, Mcgregor, Amanda, Brady, Ailbhe, Chan, Rebekah, Mcivor, Shane, Prady, Helena, Whittle, Helen, Mathew, Bijoy, Clapham, Melanie, Harper, Rosemary, Poultney, Una, Rice, Polly, Mutch, Rachel, Baird, Yolanda, Butler, Aaron, Chadbourn, Indra, Folkes, Linda, Fox, Heather, Gardner, Amy, Gomez, Raquel, Hobden, Gillian, King, Kirsten, Margarson, Michael, Martindale, Tim, Meadows, Emma, Raynard, Dana, Thirlwall, Yvette, Helm, David, Margalef, Jordi, Greer, Sandra, Shuker, Karen, Smuts, Sara, Duffield, Joseph, Smith, Oliver, Mallon, Lewi, Claire, Watkin, Birkinshaw, Isobel, Carter, Joseph, Howard, Kate, Ingham, Joanne, Joy, Rosie, Pearson, Harriet, Roche, Samantha, Scott, Zoe, Knights, Ellen, Price, Alicia, Thomas, Alice, Thorpe, Chri, Abraheem, Azmerelda, Bamford, Peter, Cawley, Kathryn, Dunmore, Charlie, Faulkner, Maria, Girach, Rumanah, Jeffrey, Helen, Jones, Rhianna, London, Emily, Nagra, Imrun, Nasir, Farah, Sainsbury, Hannah, Smedley, Clare, Khade, Reena, Sundar, Ashok, Tsinaslanidis, George, Behan, Teresa, Burnett, Caroline, Hatton, Jonathan, Heeney, Elaine, Mitra, Atideb, Newton, Maria, Pollard, Rachel, Stead, Rachael, Birch, Jenny, Bough, Laura, Goodsell, Josie, Tutton, Rebecca, Williams, Patricia, Williams, Sarah, Winter-Goodwin, Barbara, Auld, Fiona, Donnachie, Joanne, Edmond, Ian, Prentice, Lynn, Runciman, Nikole, Salutous, Dario, Symon, Lesley, Todd, Anne, Turner, Patricia, Short, Abigail, Sweeney, Laura, Murdoch, Euan, Senaratne, Dhaneesha, Burns, Karen, Higham, Andrew, Anderson, Taya, Hawcutt, Dan, O’Malley, Laura, Rad, Laura, Rogers, Naomi, Saunderson, Paula, Allison, Kathryn Sian, Afolabi, Deborah, Whitbread, Jennifer, Jones, Dawn, Dore, Rachael, Lankester, Liana, Nikitas, Nikita, Wells, Colin, Stowe, Bethan, Spencer, Kayleigh, Cathcart, Susanne, Duffy, Katharine, Puxty, Alex, Puxty, Kathryn, Turner, Lynne, Ireland, Jane, Semple, Gary, Barry, Peter, Hilltout, Paula, Evitts, Jayne, Tyler, Amanda, Waldron, Joanne, Irvine, Val, Shelley, Benjamin, Akinkugbe, Olugbenga, Bamford, Alasdair, Beech, Emily, Belfield, Holly, Bell, Michael, Davies, Charlene, Jones, Gareth A. L., Mchugh, Tara, Meghari, Hamza, O’Neill, Lauran, Peters, Mark J., Ray, Samiran, Tomas, Ana Luisa, Gorman, Claire, Gupta, Abhinav, Timlick, Elizabeth, Brady, Rebecca, Bonner, Stephen, Hugill, Keith, Jones, Jessica, Liggett, Steven, Bashyal, Archana, Davidson, Neil, Hutton, Paula, Mckechnie, Stuart, Wilson, Jean, Flint, Neil, Rekha, Patel, Hales, Dawn, Cruz, Carina, Gopal, Shameer, Harris, Nichola, Lake, Victoria, Metherell, Stella, Radford, Elizabeth, Clement, Ian, Patel, Bijal, Gulati, A., Hays, Carole, Webster, K., Hudson, Anne, Webster, Andrea, Stephenson, Elaine, Mccormack, Louise, Slater, Victoria, Nixon, Rachel, Hanson, Helen, Fearby, Maggie, Kelly, Sinead, Bridgett, Victoria, Robinson, Philip, Almaden-Boyle, Christine, Austin, Pauline, Cabrelli, Louise, Cole, Stephen, Casey, Matt, Chapman, Susan, Whyte, Clare, Brayne, Adam, Fisher, Emma, Hunt, Jane, Jackson, Peter, Kaye, Duncan, Love, Nichola, Parkin, Juliet, Tuckey, Victoria, van Koutrik, Lynne, Carter, Sasha, Andrew, Benedict, Findlay, Louise, Adams, Katie, Bruce, Michelle, Connolly, Karen, Duncan, Tracy, T. -Michael, Helen, Lindergard, Gabriella, Hey, Samuel, Fox, Claire, Alfonso, Jordan, Durrans, Laura Jayne, Guerin, Jacinta, Hruska, Martin, Eltayeb, Ayaa, Lamb, Thoma, Hodgkiss, Tracey, Cooper, Lisa, Rothwell, Joanne, Dennis, Catherine, Mcgregor, Alastair, Srikaran, Sinduya, Sukha, Anisha, Davies, Kim, O’Brien, Linda, Omar, Zohra, Perkins, Emma, Lewis, Tracy, Sutherland, Isobel, Brooke, Hollie, Buckley, Sarah, Suarez, Jose Cebrian, Charlesworth, Ruth, Hansson, Karen, Norris, John, Poole, Alice, Rose, Alastair, Sandhu, Rajdeep, Sloan, Brendan, Smithson, Elizabeth, Thirumaran, Muthu, Wagstaff, Veronica, Metcalfe, Alexandra, Camsooksai, Julie, Humphrey, Charlotte, Jenkins, Sarah, Wadams, Beverley, Death, Yasmin, Adams, Colene, Agasou, Anita, Arden, Tracie, Bowes, Amy, Boyle, Pauline, Beekes, Mandy, Button, Heather, Capps, Nigel, Carnahan, Mandy, Carter, Anne, Childs, Danielle, Donaldson, Denise, Hard, Kelly, Hurford, Fran, Hussain, Yasmin, Javaid, Ayesha, Jones, Jame, Jose, Sanal, Leigh, Michael, Martin, Terry, Millward, Helen, Motherwell, Nichola, Rikunenko, Rachel, Stickley, Jo, Summers, Julie, Ting, Louise, Tivenan, Helen, Tonks, Louise, Wilcox, Rebecca, Bokhari, Maria, Lucas, Rachael, Mccormick, Wendy, Ritzema, Jenny, Sanderson, Amanda, Wild, Helen, Baxter, Nicola, Henderson, Steven, Kennedy-Hay, Sophie, Mcparland, Christopher, Rooney, Laura, Sim, Malcolm, Mccreath, Gordan, Brunton, Mark, Caterson, Je, Coles, Holly, Frise, Matthew, Rai, Sabi Gurung, Keating, Liza, Tilney, Emma, Bartley, Shauna, Bhuie, Parminder, Downes, Charlotte, Holding, Kathleen, Riches, Katie, Hilton, Mary, Hayman, Mel, Subramanian, Deepak, Daniel, Priya, Zitter, Letizia, Benyon, Sarah, Marriott, Suzie, Park, Linda, Keenan, Samantha, Gordon, Elizabeth, Quinn, Helen, Baines, Kizzy, Andrew, Gillian, Barclay, Lucy, Callaghan, Marie, Clark, Sarah, Hope, Dave, Marshall, Lucy, Mcculloch, Corrienne, Briton, Kate, Singleton, Jo, Birch, Sophie, Simpson, Kerry, Craig, Jayne, Demetriou, Carrie, Eckbad, Charlotte, Hierons, Sarah, Howie, Lucy, Mitchard, Sarah, Ramos, Lidia, Serrano-Ruiz, Alfredo, White, Katie, Kelly, Fiona, Amin, Vishal, Anastasescu, Elena, Anumakonda, Vikram, Karthik, Komala, Kausar, Rizwana, Reid, Karen, Smith, Jacqueline, Imeson-Wood, Janet, Bellini, Arianna, Bryant, Jade, Mayer, Anton, Pickard, Amy, Roe, Nichola, Sowter, Jason, Howlett, Alex, Criste, Kristine, Cusack, Rebecca, Golder, Kim, Golding, Hannah, Jones, Oliver, Leggett, Samantha, Male, Michelle, Marani, Martyna, Prager, Kirsty, Williams, Toran, Roberts, Belinda, Salmon, Karen, Gondo, Prisca, Hadebe, B., Kayani, Abdul, Masunda, Bridgett, Ahmed, Ashar, Morris, Anna, Jakkula, Sriniva, Long, Kate, Whiteley, Simon, Wilby, Elizabeth, Ogg, Bethan, Moultrie, Sam, Odam, M., Bewley, Jeremy, Garland, Zoe, Grimmer, Lisa, Gumbrill, Bethany, Johnson, Rebekah, Sweet, Katie, Webster, Denise, Efford, Georgia, Bennett, Sara, Goodwin, Emma, Jackson, Matthew, Kent, Alissa, Tibke, Clare, Woodyatt, Wiesia, Zaki, Ahmed, Daniel, Amelia, Finn, Joanne, Saha, Rajnish, Bremmer, Pamela, Allan, J., Geary, T., Houston, Gordon, Meikle, A., O’Brien, P., Bell, Dina, Boyle, Rosalind, Douglas, Katie, Glass, Lynn, Lee, Emma, Lennon, Liz, Rattray, Austin, Charnock, Rob, Mcfarland, Denise, Cosgrove, Denise, Attwood, Ben, Parsons, Penny, Carmody, Siobhain, Oblak, Metod, Popescu, Monica, Thankachen, Mini, Baruah, Rosie, Morris, Sheila, Ferguson, Susie, Shepherd, Amy, Altabaibeh, Abdelhakim, Alvaro, Ana, Gilbert, Kayleigh, Ma, Louise, Mostoles, Loreta, Parmar, Chetan, Simpson, Kathryn, Jetha, Champa, Booker, Lauren, Pratley, Anezka, Cosier, Tracey, Millen, Gemma, Schumacher, Natasha, Weston, Heather, Rand, Jame, Alex, Beatrice, Bach, Benjamin, Barclay, Wendy S., Bogaert, Debby, Chand, Meera, Cooke, Graham S., Docherty, Annemarie B., Dunning, Jake, da Silva Filipe, Ana, Fletcher, Tom, Green, Christoper A., Harrison, Ewen M., Hiscox, Julian A., Ijaz, Samreen, Khoo, Saye, Lim, Wei Shen, Mentzer, Alexander J., Merson, Laura, Noursadeghi, Mahdad, Moore, Shona C., Palmarini, Massimo, Paxton, William A., Pollakis, Georgio, Price, Nichola, Rambaut, Andrew, Robertson, David L., Sancho-Shimizu, Vanessa, Scott, Janet T., de Silva, Thushan, Sigfrid, Louise, Solomon, Tom, Sriskandan, Shiranee, Stuart, David, Tedder, Richard S., Thomson, Emma C., Roger Thompson, A. A., Thwaites, Ryan S., Turtle, Lance C. W., Gupta, Rishi K., Palmieri, Carlo, Swann, Olivia V., Zambon, Maria, Dumas, Marc-Emmanuel, Griffin, Julian L., Takats, Zoltan, Chechi, Kanta, Andrikopoulos, Petro, Osagie, Anthonia, Olanipekun, Michael, Liggi, Sonia, Lewis, Matthew R., Correia, Gonçalo dos Santo, Sands, Caroline J., Takis, Panteleimon, Maslen, Lynn, Greenhalf, William, Shaw, Victoria, Mcdonald, Sarah E., Keating, Seán, Ahmed, Katie A., Armstrong, Jane A., Ashworth, Milton, Asiimwe, Innocent G., Bakshi, Siddharth, Barlow, Samantha L., Booth, Laura, Brennan, Benjamin, Bullock, Katie, Catterall, Benjamin W. A., Clark, Jordan J., Clarke, Emily A., Cooper, Louise, Cox, Helen, Davis, Christopher, Dincarslan, Oslem, Dunn, Chri, Dyer, Philip, Elliott, Angela, Evans, Anthony, Finch, Lorna, Fisher, Lewis W. 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Eunice, Flaherty, Lisa, Maziere, Nicole, Cass, Emily, Carracedo, Alejandra Doce, Carlucci, Nicola, Holmes, Anthony, Massey, Hannah, Murphy, Lee, Wrobel, Nicola, Mccafferty, Sarah, Morrice, Kirstie, Maclean, Alan, Armstrong, Ruth, Boz, Ceilia, Brown, Adam, Coutts, Audrey, Cullum, Louise, Day, Nicky, Donnelly, Lorna, Duncan, Esther, Fawkes, Angie, Finernan, Paul, Gilchrist, Tammy, Golightly, Ailsa, Hafezi, Katarzyna, Law, Dawn, Law, Rachel, Law, Sarah, Macgillivray, Louise, Mal, Hanning, Mcmaster, Ellie, Meikle, Jen, Oosthuyzen, Wilna, Paterson, Trevor, Stenhouse, Andrew, Swets, Maaike, Szoor-McElhinney, Helen, Taneski, Filip, Wackett, Tony, Ward, Mairi, Weaver, Jane, Coyle, Judy, Gallagher, Bernadette, Lidstone-Scott, Rebecca, Hamilton, Debbie, Schon, Katherine, Furlong, Anita, Biggs, Heather, Griffiths, Fiona, Andrews, Eleanor, Brickell, Kathy, Smyth, Michelle, Murphy, Lorna, Carson, Gail, Hardwick, Hayley, Donohue, Chloe, Pérez-Tur, Jordi [0000-0002-9111-1712], Martín, Javier [0000-0002-2202-0622], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], A list of authors and their affiliations appears in the Supplementary Information, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Niemi, M, Karjalainen, J, Liao, R, Neale, B, Daly, M, Ganna, A, Pathak, G, Andrews, S, Kanai, M, Veerapen, K, Fernandez-Cadenas, I, Schulte, E, Striano, P, Marttila, M, Minica, C, Marouli, E, Karim, M, Wendt, F, Savage, J, Sloofman, L, Butler-Laporte, G, Kim, H, Kanoni, S, Okada, Y, Byun, J, Han, Y, Uddin, M, Smith, G, Willer, C, Buxbaum, J, Mehtonen, J, Finucane, H, Cordioli, M, Martin, A, Zhou, W, Pasaniuc, B, Julienne, H, Aschard, H, Shi, H, Yengo, L, Polimanti, R, Ghoussaini, M, Schwartzentruber, J, Dunham, I, Chwialkowska, K, Francescatto, M, Trankiem, A, Balaconis, M, Davis, L, Lee, S, Priest, J, Renieri, A, Sankaran, V, van Heel, D, Deelen, P, Richards, J, Nakanishi, T, Biesecker, L, Kerchberger, V, Baillie, J, Mari, F, Bernasconi, A, Baillie, S, Canakoglu, A, Wolford, B, Faucon, A, Dutta, A, Schurmann, C, Harry, E, Birney, E, Nguyen, H, Nasir, J, Kaunisto, M, Solomonson, M, Dueker, N, Vadgama, N, Limou, S, Rahmouni, S, Mbarek, H, Darwish, D, Albertos, R, Pérez-Tur, J, Li, R, Folkersen, L, Moltke, I, Koelling, N, Teumer, A, Kousathanas, A, Utrilla, A, Verdugo, R, Zárate, R, Medina-Gómez, C, Gómez-Cabrero, D, Carnero-Montoro, E, Cadilla, C, Moreno-Estrada, A, Garmendia, A, Moya, L, Sedaghati-Khayat, B, Boua, P, Favé, M, Francioli, L, Lemaçon, A, Migeotte, I, Patel, S, Varnai, R, Szentpeteri, J, Sipeky, C, Colombo, F, von Hohenstaufen, K, Lio, P, Vallerga, C, Wang, Q, Tanigawa, Y, Im, H, Han, C, Song, H, Lim, J, Lee, Y, Kim, S, Im, S, Atanasovska, B, Ahmad, H, Boer, C, Jansen, P, Franke, L, Kaja, E, Pasko, D, Kennis-Szilagyi, I, Kornilov, S, Prijatelj, V, Prokić, I, Sivanadhan, I, Perumal, S, Esmaeeli, S, Pearson, N, Auton, A, Shelton, J, Shastri, A, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, O’Connell, J, 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Law, D., Law, R., Law, S., Macgillivray, L., Maclean, A., Mal, H., Mcmaster, E., Meikle, J., Oosthuyzen, W., Paterson, T., Stenhouse, A., Swets, M., Szoor-McElhinney, H., Taneski, F., Wackett, T., Ward, M., Weaver, J., Coyle, J., Gallagher, B., Lidstone-Scott, R., Hamilton, D., Schon, K., Furlong, A., Biggs, H., Griffiths, F., Andrews, E., Brickell, K., Smyth, M., Carson, G., Hardwick, H., Donohue, C., Neale, Benjamin M. [0000-0003-1513-6077], Apollo - University of Cambridge Repository, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, Infectious diseases, Center of Experimental and Molecular Medicine, APH - Aging & Later Life, APH - Global Health, APH - Quality of Care, Amsterdam institute for Infection and Immunity, APH - Health Behaviors & Chronic Diseases, Global Health, APH - Methodology, Graduate School, ACS - Heart failure & arrhythmias, Anesthesiology, ACS - Diabetes & metabolism, APH - Digital Health, APH - Personalized Medicine, ACS - Microcirculation, Niemi, M. E. K., Liao, R. G., Neale, B. M., Pathak, G. A., Andrews, S. J., Schulte, E. C., Karim, M. A., Wendt, F. 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A., de Almeida Martins, L. G., Mclaughlan, D., Mcmorrow, L., Mccormick, J., Mitchell, A. M., Maccallum, N., Hughes, R. A., Jones, T. O., Mcphail, M., Mckenley, I., Sutherland, S. -B., de Gordoa, L. O. -R., Gude, E. T., Macgoey, P., Mckenna, E., Patel, B. V., Zborowski, A. C., Garcia, S. M., Howe, G. S., Heron, A. E., Mills, G. H., Brown, C. W., Akhtar, M. N., Delgado, C. C., Saluzzio, R. P., Da Gloria, E. F., Hurt, W. J., Wood, H. -L., Mcalindon, M., Mccurdy, A., Ali, I. A. M., Ally, S. M., Hamilton, D. O., Lopez Martinez, M., Waite, A. A. C., Welters, I. D., Rosa, A. D., Baikady, R. R., Tatham, K. C., Beith, C. M., Mcgregor, A., Mcivor, S., Allison, K. S., Jones, G. A. L., Mchugh, T., Peters, M. J., Tomas, A. L., Mckechnie, S., Mccormack, L., Michael, H. T., Durrans, L. J., Suarez, J. C., Death, Y., Mccormick, W., Mccreath, G., Rai, S. G., Mcculloch, C., Mcfarland, D., Barclay, W. S., Cooke, G. S., Docherty, A. B., Green, C. A., Harrison, E. M., Hiscox, J. A., Lim, W. S., Mentzer, A. J., Paxton, W. A., Robertson, D. L., Scott, J. T., Tedder, R. S., Thomson, E. C., Thwaites, R. S., Gupta, R. K., Swann, O. V., Dumas, M. -E., Griffin, J. L., Lewis, M. R., dos Santos Correia, G., Sands, C. J., Mcdonald, S. E., Ahmed, K. A., Armstrong, J. A., Asiimwe, I. G., Barlow, S. L., Catterall, B. W. A., Clark, J. J., Clarke, E. A., Fisher, L. W. S., Jensen, R. L., Jones, C. B., Jones, T. R., Kiy, R. T., Livoti, L. A., Mcdonald, S., Mcevoy, L., Mclauchlan, J., Miah, N. S., Moore, S. C., Murphy, E. G., Matthew Ridley, P., Shaw, V. E., Shears, R. K., Subramaniam, K. S., Eunice Zhang, J., Carracedo, A. D., Mccafferty, S., Turtle, L. C. W., Data Science Genetic Epidemiology Lab, Institute for Molecular Medicine Finland, HUS Helsinki and Uusimaa Hospital District, University of Helsinki, Research Programs Unit, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, and University of Zurich

Subjects
Male, 45/43, Autoimmunity, Autoimmunity/genetics, Body Mass Index, COVID-19/genetics, COVID-19/virology, Critical Illness, Female, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Geographic Mapping, Hospitalization, Host-Pathogen Interactions/genetics, Humans, Inflammation/complications, Information Dissemination, Multifactorial Inheritance, Racial Groups/genetics, SARS-CoV-2/pathogenicity, Smoking, environmental risk factors, Q1, 631/208, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Genetics, Genome-wide association studies, SARS-CoV-2, Viral infection, GWAS, Aetiology, Lung, QC, 0303 health sciences, HERITABILITY, 3. Good health, covid-19, Science & Technology - Other Topics, Identification (biology), Infection, Human, 631/208/205/2138, Settore BIO/11 - Biologia Molecolare, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Clinical Research, Biodefense, Genetics, GENOME-WIDE ASSOCIATION, Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], METAANALYSIS, 1000 Multidisciplinary, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Prevention, Racial Groups, Pneumonia, genetic architecture, Human genetics, Genetic Loci, genetic factors, 570 Life sciences, biology, 030217 neurology & neurosurgery, Medizin, Infektionsmedicin, Genome-wide association studies, Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Pandemic, 2.1 Biological and endogenous factors, pandemi, Multidisciplinary, article, Public Health, Global Health, Social Medicine and Epidemiology, Racial Group, 10124 Institute of Molecular Life Sciences, Host-Pathogen Interaction, Multidisciplinary Sciences, Infectious Diseases, Host-Pathogen Interactions, Critical Illne, COVID-19, GWAS, genetic factors, environmental risk factors, therapy, Infectious Medicine, Coronavirus disease 2019 (COVID-19), SUSCEPTIBILITY LOCI, General Science & Technology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Computational biology, Biology, Vaccine Related, 692/699/255/2514, Environmental risk, Mendelian randomization, COVID-19 Host Genetics Initiative, QH426, 631/326/596/4130, 030304 developmental biology, Inflammation, therapy, SARS-CoV-2, Human Genome, COVID-19, Genetic architecture, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Emerging Infectious Diseases, Good Health and Well Being, Viral infection, 3111 Biomedicine
Abstract

Niemi, Mari E. K. et al. 39 páginas, figuras y tablas. Contiene material suplementario., The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Published
2021

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