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1. Performance of an Open-Source Large Language Model in Extracting Information from Free-Text Radiology Reports.

Author

Le Guellec, Bastien, Lefèvre, Alexandre, Geay, Charlotte, Shorten, Lucas, Bruge, Cyril, Hacein-Bey, Lotfi, Amouyel, Philippe, Pruvo, Jean-Pierre, Kuchcinski, Gregory, and Hamroun, Aghiles

Subjects
Brain, Generative Pretrained Transformers (GPT), Information Extraction, Large Language Model (LLM), MRI, Open Source, Report, Humans, Female, Adult, Male, Middle Aged, Magnetic Resonance Imaging, Retrospective Studies, Headache, Natural Language Processing, Sensitivity and Specificity, Emergency Service, Hospital, Brain
Abstract

Purpose To assess the performance of a local open-source large language model (LLM) in various information extraction tasks from real-life emergency brain MRI reports. Materials and Methods All consecutive emergency brain MRI reports written in 2022 from a French quaternary center were retrospectively reviewed. Two radiologists identified MRI scans that were performed in the emergency department for headaches. Four radiologists scored the reports conclusions as either normal or abnormal. Abnormalities were labeled as either headache-causing or incidental. Vicuna (LMSYS Org), an open-source LLM, performed the same tasks. Vicunas performance metrics were evaluated using the radiologists consensus as the reference standard. Results Among the 2398 reports during the study period, radiologists identified 595 that included headaches in the indication (median age of patients, 35 years [IQR, 26-51 years]; 68% [403 of 595] women). A positive finding was reported in 227 of 595 (38%) cases, 136 of which could explain the headache. The LLM had a sensitivity of 98.0% (95% CI: 96.5, 99.0) and specificity of 99.3% (95% CI: 98.8, 99.7) for detecting the presence of headache in the clinical context, a sensitivity of 99.4% (95% CI: 98.3, 99.9) and specificity of 98.6% (95% CI: 92.2, 100.0) for the use of contrast medium injection, a sensitivity of 96.0% (95% CI: 92.5, 98.2) and specificity of 98.9% (95% CI: 97.2, 99.7) for study categorization as either normal or abnormal, and a sensitivity of 88.2% (95% CI: 81.6, 93.1) and specificity of 73% (95% CI: 62, 81) for causal inference between MRI findings and headache. Conclusion An open-source LLM was able to extract information from free-text radiology reports with excellent accuracy without requiring further training. Keywords: Large Language Model (LLM), Generative Pretrained Transformers (GPT), Open Source, Information Extraction, Report, Brain, MRI Supplemental material is available for this article. Published under a CC BY 4.0 license. See also the commentary by Akinci DAntonoli and Bluethgen in this issue.

Published
2024

2. Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries

Author

García-Marín, Luis M., Campos, Adrian I., Diaz-Torres, Santiago, Rabinowitz, Jill A., Ceja, Zuriel, Mitchell, Brittany L., Grasby, Katrina L., Thorp, Jackson G., Agartz, Ingrid, Alhusaini, Saud, Ames, David, Amouyel, Philippe, Andreassen, Ole A., Arfanakis, Konstantinos, Arias-Vasquez, Alejandro, Armstrong, Nicola J., Athanasiu, Lavinia, Bastin, Mark E., Beiser, Alexa S., Bennett, David A., Bis, Joshua C., Boks, Marco P. M., Boomsma, Dorret I., Brodaty, Henry, Brouwer, Rachel M., Buitelaar, Jan K., Burkhardt, Ralph, Cahn, Wiepke, Calhoun, Vince D., Carmichael, Owen T., Chakravarty, Mallar, Chen, Qiang, Ching, Christopher R. K., Cichon, Sven, Crespo-Facorro, Benedicto, Crivello, Fabrice, Dale, Anders M., Smith, George Davey, de Geus, Eco J. C., De Jager, Philip L., de Zubicaray, Greig I., Debette, Stéphanie, DeCarli, Charles, Depondt, Chantal, Desrivières, Sylvane, Djurovic, Srdjan, Ehrlich, Stefan, Erk, Susanne, Espeseth, Thomas, Fernández, Guillén, Filippi, Irina, Fisher, Simon E., Fleischman, Debra A., Fletcher, Evan, Fornage, Myriam, Forstner, Andreas J., Francks, Clyde, Franke, Barbara, Ge, Tian, Goldman, Aaron L., Grabe, Hans J., Green, Robert C., Grimm, Oliver, Groenewold, Nynke A., Gruber, Oliver, Gudnason, Vilmundur, Håberg, Asta K., Haukvik, Unn K., Heinz, Andreas, Hibar, Derrek P., Hilal, Saima, Himali, Jayandra J., Ho, Beng-Choon, Hoehn, David F., Hoekstra, Pieter J., Hofer, Edith, Hoffmann, Wolfgang, Holmes, Avram J., Homuth, Georg, Hosten, Norbert, Ikram, M. Kamran, Ipser, Jonathan C., Jack Jr, Clifford R., Jahanshad, Neda, Jönsson, Erik G., Kahn, Rene S., Kanai, Ryota, Klein, Marieke, Knol, Maria J., Launer, Lenore J., Lawrie, Stephen M., Hellard, Stephanie Le, Lee, Phil H., Lemaître, Hervé, Li, Shuo, Liewald, David C. M., Lin, Honghuang, Longstreth, Jr, W. T., Lopez, Oscar L., Luciano, Michelle, Maillard, Pauline, Marquand, Andre F., Martin, Nicholas G., Martinot, Jean-Luc, Mather, Karen A., Mattay, Venkata S., McMahon, Katie L., Mecocci, Patrizia, Melle, Ingrid, Meyer-Lindenberg, Andreas, Mirza-Schreiber, Nazanin, Milaneschi, Yuri, Mosley, Thomas H., Mühleisen, Thomas W., Müller-Myhsok, Bertram, Maniega, Susana Muñoz, Nauck, Matthias, Nho, Kwangsik, Niessen, Wiro J., Nöthen, Markus M., Nyquist, Paul A., Oosterlaan, Jaap, Pandolfo, Massimo, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W. J. H., Pike, G. Bruce, Psaty, Bruce M., Pütz, Benno, Reppermund, Simone, Rietschel, Marcella D., Risacher, Shannon L., Romanczuk-Seiferth, Nina, Romero-Garcia, Rafael, Roshchupkin, Gennady V., Rotter, Jerome I., Sachdev, Perminder S., Sämann, Philipp G., Saremi, Arvin, Sargurupremraj, Muralidharan, Saykin, Andrew J., Schmaal, Lianne, Schmidt, Helena, Schmidt, Reinhold, Schofield, Peter R., Scholz, Markus, Schumann, Gunter, Schwarz, Emanuel, Shen, Li, Shin, Jean, Sisodiya, Sanjay M., Smith, Albert V., Smoller, Jordan W., Soininen, Hilkka S., Steen, Vidar M., Stein, Dan J., Stein, Jason L., Thomopoulos, Sophia I., Toga, Arthur W., Tordesillas-Gutiérrez, Diana, Trollor, Julian N., Valdes-Hernandez, Maria C., van ′t Ent, Dennis, van Bokhoven, Hans, van der Meer, Dennis, van der Wee, Nic J. A., Vázquez-Bourgon, Javier, Veltman, Dick J., Vernooij, Meike W., Villringer, Arno, Vinke, Louis N., Völzke, Henry, Walter, Henrik, Wardlaw, Joanna M., Weinberger, Daniel R., Weiner, Michael W., Wen, Wei, Westlye, Lars T., Westman, Eric, White, Tonya, Witte, A. Veronica, Wolf, Christiane, Yang, Jingyun, Zwiers, Marcel P., Ikram, M. Arfan, Seshadri, Sudha, Thompson, Paul M., Satizabal, Claudia L., Medland, Sarah E., and Rentería, Miguel E.

Published
2024
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3. The Alzheimer’s disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons

Author

Saha, Orthis, Melo de Farias, Ana Raquel, Pelletier, Alexandre, Siedlecki-Wullich, Dolores, Landeira, Bruna Soares, Gadaut, Johanna, Carrier, Arnaud, Vreulx, Anaïs-Camille, Guyot, Karine, Shen, Yun, Bonnefond, Amelie, Amouyel, Philippe, TCW, Julia, Kilinc, Devrim, Queiroz, Claudio Marcos, Delahaye, Fabien, Lambert, Jean-Charles, and Costa, Marcos R.

Published
2024
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4. Genetic variants for head size share genes and pathways with cancer

Author

Knol, Maria J, Poot, Raymond A, Evans, Tavia E, Satizabal, Claudia L, Mishra, Aniket, Sargurupremraj, Muralidharan, van der Auwera, Sandra, Duperron, Marie-Gabrielle, Jian, Xueqiu, Hostettler, Isabel C, van Dam-Nolen, Dianne HK, Lamballais, Sander, Pawlak, Mikolaj A, Lewis, Cora E, Carrion-Castillo, Amaia, van Erp, Theo GM, Reinbold, Céline S, Shin, Jean, Scholz, Markus, Håberg, Asta K, Kämpe, Anders, Li, Gloria HY, Avinun, Reut, Atkins, Joshua R, Hsu, Fang-Chi, Amod, Alyssa R, Lam, Max, Tsuchida, Ami, Teunissen, Mariël WA, Aygün, Nil, Patel, Yash, Liang, Dan, Beiser, Alexa S, Beyer, Frauke, Bis, Joshua C, Bos, Daniel, Bryan, R Nick, Bülow, Robin, Caspers, Svenja, Catheline, Gwenaëlle, Cecil, Charlotte AM, Dalvie, Shareefa, Dartigues, Jean-François, DeCarli, Charles, Enlund-Cerullo, Maria, Ford, Judith M, Franke, Barbara, Freedman, Barry I, Friedrich, Nele, Green, Melissa J, Haworth, Simon, Helmer, Catherine, Hoffmann, Per, Homuth, Georg, Ikram, M Kamran, Jack, Clifford R, Jahanshad, Neda, Jockwitz, Christiane, Kamatani, Yoichiro, Knodt, Annchen R, Li, Shuo, Lim, Keane, Longstreth, WT, Macciardi, Fabio, Consortium, The Cohorts for Heart and Aging Research in Genomic Epidemiology, Amouyel, Philippe, Arfanakis, Konstantinos, Aribisala, Benjamin S, Bastin, Mark E, Chauhan, Ganesh, Chen, Christopher, Cheng, Ching-Yu, de Jager, Philip L, Deary, Ian J, Fleischman, Debra A, Gottesman, Rebecca F, Gudnason, Vilmundur, Hilal, Saima, Hofer, Edith, Janowitz, Deborah, Jukema, J Wouter, Liewald, David CM, Lopez, Lorna M, Lopez, Oscar, Luciano, Michelle, Martinez, Oliver, Niessen, Wiro J, Nyquist, Paul, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Schmidt, Helena, Tiemeier, Henning, Trompet, Stella, van der Grond, Jeroen, Völzke, Henry, Wardlaw, Joanna M, Yanek, Lisa, Yang, Jingyun, and Consortium, The Enhancing NeuroImaging Genetics through Meta-Analysis

Subjects
Biomedical and Clinical Sciences, Neurosciences, Biotechnology, Genetics, Cancer, Stem Cell Research, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Humans, Genome-Wide Association Study, Head, Neoplasms, Female, Male, Polymorphism, Single Nucleotide, Genetic Variation, Organ Size, Signal Transduction, Adult, Genetic Predisposition to Disease, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium, cancer, genetics, genome-wide association study, head circumference, head size, intracranial volume, meta-analysis, Biomedical and clinical sciences
Abstract

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Published
2024

10. Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation.

Author

Adlam, David, Berrandou, Takiy-Eddine, Georges, Adrien, Nelson, Christopher, Giannoulatou, Eleni, Henry, Joséphine, Ma, Lijiang, Blencowe, Montgomery, Turley, Tamiel, Yang, Min-Lee, Chopade, Sandesh, Finan, Chris, Braund, Peter, Sadeg-Sayoud, Ines, Iismaa, Siiri, Kosel, Matthew, Zhou, Xiang, Hamby, Stephen, Cheng, Jenny, Liu, Lu, Tarr, Ingrid, Muller, David, dEscamard, Valentina, King, Annette, Brunham, Liam, Baranowska-Clarke, Ania, Debette, Stéphanie, Amouyel, Philippe, Olin, Jeffrey, Patil, Snehal, Hesselson, Stephanie, Junday, Keerat, Kanoni, Stavroula, Aragam, Krishna, Butterworth, Adam, Tweet, Marysia, Gulati, Rajiv, Combaret, Nicolas, Kadian-Dodov, Daniella, Kalman, Jonathan, Fatkin, Diane, Hingorani, Aroon, Saw, Jacqueline, Webb, Tom, Hayes, Sharonne, Yang, Xia, Ganesh, Santhi, Olson, Timothy, Kovacic, Jason, Graham, Robert, Samani, Nilesh, and Bouatia-Naji, Nabila

Subjects
Humans, Female, Genome-Wide Association Study, Vascular Diseases, Coronary Artery Disease, Myocardial Infarction
Abstract

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Published
2023

11. Is surgery without curettage effective for periacetabular Metastasis? Insights from a survival study of 93 patients

Author

Thomas Amouyel, Marie-Hélène Vieillard, Alain Duhamel, Carlos Maynou, Martine Duterque-Coquillaud, and Cyrielle Dumont

Subjects
Acetabular, Bone metastasis, Survival, Total hip arthroplasty, Curettage, Diseases of the musculoskeletal system, RC925-935, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: The main aim of this study was to analyse the 6-month survival rates in peri-acetabular metastasis patients undergoing total hip arthroplasty (THA) with an acetabular cage and without curettage. The secondary objectives were to analyse the global survival rates, the factors influencing patient survival and to evaluate mechanical complication rates after THA. Methods: This study was carried out on a cohort of 93 consecutive patients who underwent THA with an acetabular cage without curettage for acetabular metastasis or multiple myeloma lesions between 2010 and 2020. The National Death Registry was consulted to obtain the exact date of death of the patients; the minimum follow-up time was 2 years. Results: The 6-month survival rate for all types of cancer was 78 % [68 – 85], the 1-year survival rate was 66 % [55 – 74], and the 5-year survival rate was 26 % [17 – 36]. The median overall survival for the cohort was 24.37 months [16.10 – 32.63]. The mean overall survival was 46.02 months [32.89 – 59.16]. At last contact, 86 % of the operated patients were walking again.No patient died from surgery. The ECOG performance status score, the number of bone metastatic sites, the presence of visceral metastases and the number of lines of systemic therapy undertaken prior to surgery were negative survival factors. Three patients (3.2 %) had early prosthetic dislocation, 2 patients (2.2 %) showed aseptic loosening of her partial hip implant after 10 and 11 years respectively and 4 patients (4.3 %) had an early infection treated by debridement, antibiotics and implant retention to control the infection. During the follow-up period, no new femoral metastases were detected in any patient. Conclusion: Surgery without curettage is an effective treatment for periacetabular metastasis. It gives reliable results, regardless of the type of acetabular lesion, allowing most patients to walk again and does not modify the patient’s survival.

Published
2024
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12. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Author

Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen GJ, Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J, Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W, Berr, Claudine, Bis, Joshua C, Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L, Farrer, Lindsay A, Fernández, Maria Victoria, Fox, Nick C, Galimberti, Daniela, Genin, Emmanuelle, Gille, Johan JP, Le Guen, Yann, Guerreiro, Rita, Haines, Jonathan L, Holmes, Clive, Ikram, M Arfan, Ikram, M Kamran, Jansen, Iris E, Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W, Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel MAM, Marshall, Rachel, Martin, Eden R, Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O, Morgan, Kevin, Myers, Richard M, Nacmias, Benedetta, Naj, Adam C, Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A, Raybould, Rachel, Redon, Richard, Reinders, Marcel JT, Richard, Anne-Claire, Riedel-Heller, Steffi G, Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S, Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D, Scheltens, Philip, Schott, Jonathan M, Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A, Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo’, Tijms, Betty, Uitterlinden, André G, van der Lee, Sven J, Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C, Greicius, Michael D, Yokoyama, Jennifer S, Cruchaga, Carlos, Hardy, John, and Ramirez, Alfredo

Subjects
Biological Sciences, Genetics, Dementia, Alzheimer's Disease, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Prevention, Acquired Cognitive Impairment, Neurodegenerative, Aging, Clinical Research, Biotechnology, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Adenosine Triphosphatases, Alzheimer Disease, ATP Binding Cassette Transporter 1, Genome-Wide Association Study, Risk Factors, Exosomes, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

Published
2022

13. Recherche d’association entre les polymorphismes du gène codant l’Ornithine Transcarbamylase (OTC) et l’Infarctus du Myocarde dans la population Ouest-Algérienne

Author

Djabaria Naima Meroufel, Sounia Médiène-Benchekor, Julie Dumont, Philippe Amouyel, Thierry Brousseau, and Soraya Benhammamouch

Subjects
Epidemiology-genetics, West-Algerian population, genetic polymorphisms, OTC candidate gene, Myocardial infarction., Medicine (General), R5-920
Abstract

Résumé Objectif - Il a été démontré que le polymorphisme rs5963409 du gène codant l’Or­nithine TransCarbamylase (OTC) est associé à l’hypertension et à la vasomotricité coronaire dans les populations caucasiennes. Sur la base de ces résultats, nous avons choisi d’étudier l’association de deux polymorphismes rs5963409, localisé au niveau de la région 5’ du promoteur et rs1800321, localisé au niveau de l’exon 2, du gène OTC avec le risque de survenue d’infarctus du myocarde (IDM) et les valeurs de pres­sions artérielles systolique et diastolique. Population étudiée et Méthodes - Cette étude a été réalisée dans la population de l’étude ECTOR (Etude Cas Témoins sur l’Infarctus du myocarde en ORanie). La popu­lation étudiée est composée de deux groupes : 68 cas ayant survécu à un Infarctus Du Myocarde (IDM) et 67 sujets témoins ne souffrant d’aucune maladie apparente. La caractérisation génétique des deux polymorphismes a été réalisée par la technique PCR (Polymerase Chain Reaction) suivie d’une digestion enzymatique. Résultats - Les polymorphismes rs5963409 et rs1800321 ne sont pas associés ni à l’IDM ni aux variations des valeurs de pressions artérielles systolique et diastolique. Cependant, nous avons observé une interaction significative entre le polymorphisme rs5963409 et l’Indice de Masse Corporelle (IMC) sur le risque de survenue d’IDM. Conclusion - Nos résultats indiquent queles deux polymorphismes du gène de l’OTC ne sont pas associés à l’IDM dans la population Ouest-Algérienne. Abstract Objective - The polymorphism rs5963409 of the gene coding for Ornithine Trans­Carbamylase (OTC) has been shown to be associated with hypertension and co­ronary vasomotricity in Caucasian populations. On the basis of these results, we chose to study the association of two polymorphisms rs5963409, located at the 5 ‘region of the promoter and rs1800321, located at exon 2, of the OTC gene with the risk of The occurrence of myocardial infarction (MI) and the systolic and diastolic blood pressure values. Patients and methods- the SNPs were characterised in a case control study (70 cases vs 68 controls) based on the male population originating from Oran, Alge­ria ECTOR study. Genetic characterization of both polymorphisms was carried out using the Polymerase Chain Reaction (PCR) technique followed by enzymatic digestion. Results -The rs5963409 and rs1800321 polymorphisms are not associated with MI or changes in systolic and diastolic blood pressure values. However, we observed a significant interaction between the polymorphism rs5963409 and the Body Mass Index (BMI) on the risk of the occurrence of MI. Conclusion: Our results indicate that both polymorphisms of the OTC gene are not associated with MI in the West-Algerian population.

Published
2024

14. Multiple air pollutant exposure is associated with higher risk of all-cause mortality in dialysis patients: a French registry-based nationwide study

Author

Aghiles Hamroun, Michaël Génin, François Glowacki, Bénédicte Sautenet, Karen Leffondré, Antoine De Courrèges, Luc Dauchet, Victoria Gauthier, Florian Bayer, Mathilde Lassalle, Cécile Couchoud, Philippe Amouyel, and Florent Occelli

Subjects
air pollution, environmental exposure, all-cause mortality, dialysis, particulate matter, nitrogen dioxide, Public aspects of medicine, RA1-1270
Abstract

BackgroundLittle is known about the effect of combined exposure to different air pollutants on mortality in dialysis patients. This study aimed to investigate the association of multiple exposures to air pollutants with all-cause and cause-specific death in dialysis patients.Materials and methodsThis registry-based nationwide cohort study included 90,373 adult kidney failure patients initiating maintenance dialysis between 2012 and 2020 identified from the French REIN registry. Estimated mean annual municipality levels of PM2.5, PM10, and NO2 between 2009 and 2020 were combined in different composite air pollution scores to estimate each participant’s exposure at the residential place one to 3 years before dialysis initiation. Adjusted cause-specific Cox proportional hazard models were used to estimate hazard ratios (HRs) per interquartile range (IQR) greater air pollution score. Effect measure modification was assessed for age, sex, dialysis care model, and baseline comorbidities.ResultsHigher levels of the main air pollution score were associated with a greater rate of all-cause deaths (HR, 1.082 [95% confidence interval (CI), 1.057–1.104] per IQR increase), regardless of the exposure lag. This association was also confirmed in cause-specific analyses, most markedly for infectious mortality (HR, 1.686 [95% CI, 1.470–1.933]). Sensitivity analyses with alternative composite air pollution scores showed consistent findings. Subgroup analyses revealed a significantly stronger association among women and fewer comorbid patients.DiscussionLong-term multiple air pollutant exposure is associated with all-cause and cause-specific mortality among patients receiving maintenance dialysis, suggesting that air pollution may be a significant contributor to the increasing trend of CKD-attributable mortality worldwide.

Published
2024
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15. The neurophysiological brain-fingerprint of Parkinson’s diseaseResearch in context

Author

Jason da Silva Castanheira, Alex I. Wiesman, Justine Y. Hansen, Bratislav Misic, Sylvain Baillet, John Breitner, Judes Poirier, Pierre Bellec, Véronique Bohbot, Mallar Chakravarty, Louis Collins, Pierre Etienne, Alan Evans, Serge Gauthier, Rick Hoge, Yasser Ituria-Medina, Gerhard Multhaup, Lisa-Marie Münter, Natasha Rajah, Pedro Rosa-Neto, Jean-Paul Soucy, Etienne Vachon-Presseau, Sylvia Villeneuve, Philippe Amouyel, Melissa Appleby, Nicholas Ashton, Daniel Auld, Gülebru Ayranci, Christophe Bedetti, Marie-Lise Beland, Kaj Blennow, Ann Brinkmalm Westman, Claudio Cuello, Mahsa Dadar, Leslie-Ann Daoust, Samir Das, Marina Dauar-Tedeschi, Louis De Beaumont, Doris Dea, Maxime Descoteaux, Marianne Dufour, Sarah Farzin, Fabiola Ferdinand, Vladimir Fonov, Julie Gonneaud, Justin Kat, Christina Kazazian, Anne Labonté, Marie-Elyse Lafaille-Magnan, Marc Lalancette, Jean-Charles Lambert, Jeannie-Marie Leoutsakos, Laura Mahar, Axel Mathieu, Melissa McSweeney, Pierre-François Meyer, Justin Miron, Jamie Near, Holly NewboldFox, Nathalie Nilsson, Pierre Orban, Cynthia Picard, Alexa Pichet Binette, Jean-Baptiste Poline, Sheida Rabipour, Alyssa Salaciak, Matthew Settimi, Sivaniya Subramaniapillai, Angela Tam, Christine Tardif, Louise Théroux, Jennifer Tremblay-Mercier, Stephanie Tullo, Irem Ulku, Isabelle Vallée, Henrik Zetterberg, Vasavan Nair, Jens Pruessner, Paul Aisen, Elena Anthal, Alan Barkun, Thomas Beaudry, Fatiha Benbouhoud, Jason Brandt, Leopoldina Carmo, Charles Edouard Carrier, Laksanun Cheewakriengkrai, Blandine Courcot, Doris Couture, Suzanne Craft, Christian Dansereau, Clément Debacker, René Desautels, Sylvie Dubuc, Guerda Duclair, Mark Eisenberg, Rana El-Khoury, Anne-Marie Faubert, David Fontaine, Josée Frappier, Joanne Frenette, Guylaine Gagné, Valérie Gervais, Renuka Giles, Renee Gordon, Clifford Jack, Benoit Jutras, Zaven Khachaturian, David Knopman, Penelope Kostopoulos, Félix Lapalme, Tanya Lee, Claude Lepage, Illana Leppert, Cécile Madjar, David Maillet, Jean-Robert Maltais, Sulantha Mathotaarachchi, Ginette Mayrand, Diane Michaud, Thomas Montine, John Morris, Véronique Pagé, Tharick Pascoal, Sandra Peillieux, Mirela Petkova, Galina Pogossova, Pierre Rioux, Mark Sager, Eunice Farah Saint-Fort, Mélissa Savard, Reisa Sperling, Shirin Tabrizi, Pierre Tariot, Eduard Teigner, Ronald Thomas, Paule-Joanne Toussaint, Miranda Tuwaig, Vinod Venugopalan, Sander Verfaillie, Jacob Vogel, Karen Wan, Seqian Wang, Elsa Yu, Isabelle Beaulieu-Boire, Pierre Blanchet, Sarah Bogard, Manon Bouchard, Sylvain Chouinard, Francesca Cicchetti, Martin Cloutier, Alain Dagher, Clotilde Degroot, Alex Desautels, Marie Hélène Dion, Janelle Drouin-Ouellet, Anne-Marie Dufresne, Nicolas Dupré, Antoine Duquette, Thomas Durcan, Lesley K. Fellows, Edward Fon, Jean-François Gagnon, Ziv Gan-Or, Angela Genge, Nicolas Jodoin, Jason Karamchandani, Anne-Louise Lafontaine, Mélanie Langlois, Etienne Leveille, Martin Lévesque, Calvin Melmed, Oury Monchi, Jacques Montplaisir, Michel Panisset, Martin Parent, Minh-Thy Pham-An, Ronald Postuma, Emmanuelle Pourcher, Trisha Rao, Jean Rivest, Guy Rouleau, Madeleine Sharp, Valérie Soland, Michael Sidel, Sonia Lai Wing Sun, Alexander Thiel, and Paolo Vitali

Subjects
Movement disorders, Parkinson’s disease, Neural dynamics, Oscillations, Arrhythmic brain activity, Magnetoencephalography, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Research in healthy young adults shows that characteristic patterns of brain activity define individual “brain-fingerprints” that are unique to each person. However, variability in these brain-fingerprints increases in individuals with neurological conditions, challenging the clinical relevance and potential impact of the approach. Our study shows that brain-fingerprints derived from neurophysiological brain activity are associated with pathophysiological and clinical traits of individual patients with Parkinson’s disease (PD). Methods: We created brain-fingerprints from task-free brain activity recorded through magnetoencephalography in 79 PD patients and compared them with those from two independent samples of age-matched healthy controls (N = 424 total). We decomposed brain activity into arrhythmic and rhythmic components, defining distinct brain-fingerprints for each type from recording durations of up to 4 min and as short as 30 s. Findings: The arrhythmic spectral components of cortical activity in patients with Parkinson’s disease are more variable over short periods, challenging the definition of a reliable brain-fingerprint. However, by isolating the rhythmic components of cortical activity, we derived brain-fingerprints that distinguished between patients and healthy controls with about 90% accuracy. The most prominent cortical features of the resulting Parkinson’s brain-fingerprint are mapped to polyrhythmic activity in unimodal sensorimotor regions. Leveraging these features, we also demonstrate that Parkinson’s symptom laterality can be decoded directly from cortical neurophysiological activity. Furthermore, our study reveals that the cortical topography of the Parkinson’s brain-fingerprint aligns with that of neurotransmitter systems affected by the disease’s pathophysiology. Interpretation: The increased moment-to-moment variability of arrhythmic brain-fingerprints challenges patient differentiation and explains previously published results. We outline patient-specific rhythmic brain signaling features that provide insights into both the neurophysiological signature and symptom laterality of Parkinson’s disease. Thus, the proposed definition of a rhythmic brain-fingerprint of Parkinson’s disease may contribute to novel, refined approaches to patient stratification. Symmetrically, we discuss how rhythmic brain-fingerprints may contribute to the improved identification and testing of therapeutic neurostimulation targets. Funding: Data collection and sharing for this project was provided by the Quebec Parkinson Network (QPN), the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD; release 6.0) program, the Cambridge Centre for Aging Neuroscience (Cam-CAN), and the Open MEG Archives (OMEGA). The QPN is funded by a grant from Fonds de Recherche du Québec - Santé (FRQS). PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the FRQS, an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. The Brainstorm project is supported by funding to SB from the NIH (R01-EB026299-05). Further funding to SB for this study included a Discovery grant from the Natural Sciences and Engineering Research Council of Canada of Canada (436355-13), and the CIHR Canada research Chair in Neural Dynamics of Brain Systems (CRC-2017-00311).

Published
2024
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16. LIPCAR levels in plasma-derived extracellular vesicles is associated with left ventricle remodeling post-myocardial infarction

Author

Annie Turkieh, Olivia Beseme, Ouriel Saura, Henri Charrier, Jean-Baptiste Michel, Philippe Amouyel, Thomas Thum, Christophe Bauters, and Florence Pinet

Subjects
Myocardial infarction, Cardiac remodeling, Extracellular vesicles, LIPCAR, Long noncoding RNA, Biomarker, Medicine
Abstract

Abstract Background Long Intergenic noncoding RNA predicting CARdiac remodeling (LIPCAR) is a long noncoding RNA identified in plasma of patients after myocardial infarction (MI) to be associated with left ventricle remodeling (LVR). LIPCAR was also shown to be a predictor of early death in heart failure (HF) patients. However, no information regarding the expression of LIPCAR and its function in heart as well as the mechanisms involved in its transport to the circulation is known. The aims of this study are (1) to characterize the transporter of LIPCAR from heart to circulation; (2) to determine whether LIPCAR levels in plasma isolated-extracellular vesicles (EVs) reflect the alteration of its expression in total plasma and could be used as biomarkers of LVR post-MI. Methods Since expression of LIPCAR is restricted to human species and the limitation of availability of cardiac biopsy samples, serum-free conditioned culture media from HeLa cells were first used to characterize the extracellular transporter of LIPCAR before validation in EVs isolated from human cardiac biopsies (non-failing and ischemic HF patients) and plasma samples (patients who develop or not LVR post-MI). Differential centrifugation at 20,000g and 100,000g were performed to isolate the large (lEVs) and small EVs (sEVs), respectively. Western blot and nanoparticle tracking (NTA) analysis were used to characterize the isolated EVs. qRT-PCR analysis was used to quantify LIPCAR in all samples. Results We showed that LIPCAR is present in both lEVs and sEVs isolated from all samples. The levels of LIPCAR are higher in lEVs compared to sEVs isolated from HeLa conditioned culture media and cardiac biopsies. No difference of LIPCAR expression was observed in tissue or EVs isolated from cardiac biopsies obtained from ischemic HF patients compared to non-failing patients. Interestingly, LIPCAR levels were increased in lEVs and sEVs isolated from MI patients who develop LVR compared to patients who did not develop LVR. Conclusion Our data showed that large EVs are the main extracellular vesicle transporter of LIPCAR from heart into the circulation independently of the status, non-failing or HF, in patients. The levels of LIPCAR in EVs isolated from plasma could be used as biomarkers of LVR in post-MI patients.

Published
2024
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17. Occupational exposure to crystalline silica in a sample of the French general population

Author

Pierre-Marie Wardyn, Jean-Louis Edme, Virginie de Broucker, Nathalie Cherot-Kornobis, David Ringeval, Philippe Amouyel, Annie Sobaszek, Luc Dauchet, and Sébastien Hulo

Subjects
Silicon dioxide, Dust, Occupational exposure, Construction industry, Metallurgy, Industrial medicine. Industrial hygiene, RC963-969
Abstract

Abstract Objective To describe the proportions of subjects exposed to crystalline silica and the sectors of activity concerned between 1965 and 2010 in a sample of the general French population. Methods We included 2942 participants aged 40 to 65 years, recruited at random from electoral rolls, from the French general population in the cross-sectional ELISABET study between 2011 and 2013. The proportions of subjects exposed to crystalline silica and their sectors of activity were determined on the basis of their career history and the use of the Matgéné job-exposure matrix. Results In the total sample, occupational exposure to crystalline silica was found for 291 subjects (9.9%) between 1965 and 2010, with a predominance of men (20.2% of exposed subjects among men (282 out of 1394) versus 0.6% among women (9 out of 1548)). The highest proportion of participants exposed to crystalline silica was reached in 1980 with 6.1% and then decreases to 4.4% in 2010. Among men, the most frequently exposed sectors of activity were manufacture of basic metals (41.5% of exposed men (117 out of 282)), specialised construction activities (23.1% of exposed men (65 out of 282)) and construction of buildings (14.2% of exposed men (40 out of 282)). Conclusions Although the proportion of workers exposed to crystalline silica has been decreasing since the 1980s, it is still significant at least until 2010, particularly in the construction sector, and further research is needed to improve the monitoring of workers who are or have been exposed to crystalline silica.

Published
2024
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18. Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate

Author

Mishra, Aniket, Duplaà, Cécile, Vojinovic, Dina, Suzuki, Hideaki, Sargurupremraj, Muralidharan, Zilhão, Nuno R, Li, Shuo, Bartz, Traci M, Jian, Xueqiu, Zhao, Wei, Hofer, Edith, Wittfeld, Katharina, Harris, Sarah E, van der Auwera-Palitschka, Sandra, Luciano, Michelle, Bis, Joshua C, Adams, Hieab HH, Satizabal, Claudia L, Gottesman, Rebecca F, Gampawar, Piyush G, Bülow, Robin, Weiss, Stefan, Yu, Miao, Bastin, Mark E, Lopez, Oscar L, Vernooij, Meike W, Beiser, Alexa S, Völker, Uwe, Kacprowski, Tim, Soumare, Aicha, Smith, Jennifer A, Knopman, David S, Morris, Zoe, Zhu, Yicheng, Rotter, Jerome I, Dufouil, Carole, Hernández, Maria Valdés, Maniega, Susana Muñoz, Lathrop, Mark, Boerwinkle, Erik, Schmidt, Reinhold, Ihara, Masafumi, Mazoyer, Bernard, Yang, Qiong, Joutel, Anne, Tournier-Lasserve, Elizabeth, Launer, Lenore J, Deary, Ian J, Mosley, Thomas H, Amouyel, Philippe, DeCarli, Charles S, Psaty, Bruce M, Tzourio, Christophe, Kardia, Sharon LR, Grabe, Hans J, Teumer, Alexander, van Duijn, Cornelia M, Schmidt, Helena, Wardlaw, Joanna M, Ikram, M Arfan, Fornage, Myriam, Gudnason, Vilmundur, Seshadri, Sudha, Matthews, Paul M, Longstreth, William T, Couffinhal, Thierry, and Debette, Stephanie

Subjects
Epidemiology, Health Sciences, Acquired Cognitive Impairment, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Stroke, Neurosciences, Human Genome, Biotechnology, Clinical Research, Dementia, Aging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Cardiovascular, Animals, Brain Ischemia, Cerebral Small Vessel Diseases, Endothelial Cells, Genome-Wide Association Study, Mice, cerebral small vessel disease, endothelial cells, GWAS, TRIM47, whole-exome association study, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

Published
2022

19. Author Correction: 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 A. L., Meggy, Alun, Pastor, Ana Belén, Espinosa, Ana, Corma-Gómez, Anaïs, Martín Montes, Angel, Sanabria, Ángela, DeStefano, Anita L., Schneider, Anja, Haapasalo, Annakaisa, Kinhult Ståhlbom, Anne, Tybjærg-Hansen, Anne, Hartmann, Annette M., Spottke, Annika, Corbatón-Anchuelo, Arturo, Rongve, Arvid, Borroni, Barbara, Arosio, Beatrice, Nacmias, Benedetta, Nordestgaard, Børge G., Kunkle, Brian W., Charbonnier, Camille, Abdelnour, Carla, Masullo, Carlo, Martínez Rodríguez, Carmen, Muñoz-Fernandez, Carmen, Dufouil, Carole, Graff, Caroline, Ferreira, Catarina B., Chillotti, Caterina, Reynolds, Chandra A., Fenoglio, Chiara, Van Broeckhoven, Christine, Clark, Christopher, Pisanu, Claudia, Satizabal, Claudia L., Holmes, Clive, Buiza-Rueda, Dolores, Aarsland, Dag, Rujescu, Dan, Alcolea, Daniel, Galimberti, Daniela, Wallon, David, Seripa, Davide, Grünblatt, Edna, Dardiotis, Efthimios, Düzel, Emrah, Scarpini, Elio, Conti, Elisa, Rubino, Elisa, Gelpi, Ellen, Rodriguez-Rodriguez, Eloy, Duron, Emmanuelle, Boerwinkle, Eric, Ferri, Evelyn, Tagliavini, Fabrizio, Küçükali, Fahri, Pasquier, Florence, Sanchez-Garcia, Florentino, Mangialasche, Francesca, Jessen, Frank, Nicolas, Gaël, Selbæk, Geir, Ortega, Gemma, Chêne, Geneviève, Hadjigeorgiou, Georgios, Rossi, Giacomina, Spalletta, Gianfranco, Giaccone, Giorgio, Grande, Giulia, Binetti, Giuliano, Papenberg, Goran, Hampel, Harald, Bailly, Henri, Zetterberg, Henrik, Soininen, Hilkka, Karlsson, Ida K., Alvarez, Ignacio, Appollonio, Ildebrando, Giegling, Ina, Skoog, Ingmar, Saltvedt, Ingvild, Rainero, Innocenzo, Rosas Allende, Irene, Hort, Jakub, Diehl-Schmid, Janine, Van Dongen, Jasper, Vidal, Jean-Sebastien, Lehtisalo, Jenni, Wiltfang, Jens, Thomassen, Jesper Qvist, Kornhuber, Johannes, Haines, Jonathan L., Vogelgsang, Jonathan, Pineda, Juan A., Fortea, Juan, Popp, Julius, Deckert, Jürgen, Buerger, Katharina, Morgan, Kevin, Fließbach, Klaus, Sleegers, Kristel, Molina-Porcel, Laura, Kilander, Lena, Weinhold, Leonie, Farrer, Lindsay A., Wang, Li-San, Kleineidam, Luca, Farotti, Lucia, Parnetti, Lucilla, Tremolizzo, Lucio, Hausner, Lucrezia, Benussi, Luisa, Froelich, Lutz, Ikram, M. Arfan, Deniz-Naranjo, M. Candida, Tsolaki, Magda, Rosende-Roca, Maitée, Löwenmark, Malin, Hulsman, Marc, Spallazzi, Marco, Pericak-Vance, Margaret A., Esiri, Margaret, Bernal Sánchez-Arjona, María, Dalmasso, Maria Carolina, Martínez-Larrad, María Teresa, Arcaro, Marina, Nöthen, Markus M., Fernández-Fuertes, Marta, Dichgans, Martin, Ingelsson, Martin, Herrmann, Martin J., Scherer, Martin, Vyhnalek, Martin, Kosmidis, Mary H., Yannakoulia, Mary, Schmid, Matthias, Ewers, Michael, Heneka, Michael T., Wagner, Michael, Scamosci, Michela, Kivipelto, Miia, Hiltunen, Mikko, Zulaica, Miren, Alegret, Montserrat, Fornage, Myriam, Roberto, Natalia, van Schoor, Natasja M., Seidu, Nazib M., Banaj, Nerisa, Armstrong, Nicola J., Scarmeas, Nikolaos, Scherbaum, Norbert, Goldhardt, Oliver, Hanon, Oliver, Peters, Oliver, Skrobot, Olivia Anna, Quenez, Olivier, Lerch, Ondrej, Bossù, Paola, Caffarra, Paolo, Dionigi Rossi, Paolo, Sakka, Paraskevi, 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 A. L., 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

Published
2023
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21. Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome‐wide association study in over 12,000 non‐demented participants

Author

Damotte, Vincent, van der Lee, Sven J, Chouraki, Vincent, Grenier‐Boley, Benjamin, Simino, Jeannette, Adams, Hieab, Tosto, Giuseppe, White, Charles, Terzikhan, Natalie, Cruchaga, Carlos, Knol, Maria J, Li, Shuo, Schraen, Susanna, Grove, Megan L, Satizabal, Claudia, Amin, Najaf, Berr, Claudine, Younkin, Steven, Initiative, Alzheimer's Disease Neuroimaging, Gottesman, Rebecca F, Buée, Luc, Beiser, Alexa, Knopman, David S, Uitterlinden, Andre, DeCarli, Charles, Bressler, Jan, DeStefano, Anita, Dartigues, Jean‐François, Yang, Qiong, Boerwinkle, Eric, Tzourio, Christophe, Fornage, Myriam, Ikram, M Arfan, Amouyel, Philippe, de Jager, Phil, Reitz, Christiane, Mosley, Thomas H, Lambert, Jean‐Charles, Seshadri, Sudha, and van Duijn, Cornelia M

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Brain Disorders, Alzheimer's Disease, Dementia, Prevention, Genetics, Aging, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid, Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Apolipoproteins E, Aspartic Acid Endopeptidases, Brain, Genome-Wide Association Study, Healthy Volunteers, Humans, Positron-Emission Tomography, Presenilin-2, Alzheimer&apos, s disease, APOE, APP, BACE1, endophenotype, genetic epidemiology, genome&#8209, wide association study, plasma amyloid beta levels, plasma biomarkers, preclinical biomarkers, PSEN2, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's disease, genome-wide association study, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionThere is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.MethodsWe included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk.ResultsSingle-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.DiscussionIdentification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.

Published
2021

22. Life expectancy associated with different ages at diagnosis of type 2 diabetes in high-income countries: 23 million person-years of observation

Author

Kaptoge, S, Seshasai, SRK, Sun, L, Walker, M, Bolton, T, Spackman, S, Ataklte, F, Willeit, P, Bell, S, Burgess, S, Pennells, L, Altay, S, Assmann, G, Ben-Shlomo, Y, Best, LG, Björkelund, C, Blazer, DG, Brenner, H, Brunner, EJ, Dagenais, GR, Cooper, JA, Cooper, C, Crespo, CJ, Cushman, M, D'Agostino, RB, Sr, Daimon, M, Daniels, LB, Danker, R, Davidson, KW, de Jongh, RT, Donfrancesco, C, Ducimetiere, P, Elders, PJM, Engström, G, Ford, I, Gallacher, I, Bakker, SJL, Goldbourt, U, de La Cámara, G, Grimsgaard, S, Gudnason, V, Hansson, PO, Imano, H, Jukema, JW, Kabrhel, C, Kauhanen, J, Kavousi, M, Kiechl, S, Knuiman, MW, Kromhout, D, Krumholz, HM, Kuller, LH, Laatikainen, T, Lowler, DA, Meyer, HE, Mukamal, K, Nietert, PJ, Ninomiya, T, Nitsch, D, Nordestgaard, BG, Palmieri, L, Price, JF, Ridker, PM, Sun, Q, Rosengren, A, Roussel, R, Sakurai, M, Salomaa, V, Schöttker, B, Shaw, JE, Strandberg, TE, Sundström, J, Tolonen, H, Tverdal, A, Verschuren, WMM, Völzke, H, Wagenknecht, L, Wallace, RB, Wannamethee, SG, Wareham, NJ, Wassertheil-Smoller, S, Yamagishi, K, Yeap, BB, Harrison, S, Inouye, M, Griffin, S, Butterworth, AS, Wood, AM, Thompson, SG, Sattar, N, Danesh, J, Di Angelantonio, E, Tipping, RW, Russell, S, Johansen, M, Bancks, MP, Mongraw-Chaffin, M, Magliano, D, Barr, ELM, Zimmet, PZ, Whincup, PH, Willeit, J, Leitner, C, Lawlor, DA, Elwood, P, Sutherland, SE, Hunt, KJ, Selmer, RM, Haheim, LL, Ariansen, I, Tybjaer-Hansen, A, Frikkle-Schmidt, R, Langsted, A, Lo Noce, C, Balkau, B, Bonnet, F, Fumeron, F, Pablos, DL, Ferro, CR, Morales, TG, Mclachlan, S, Guralnik, J, Khaw, KT, Holleczek, B, Stocker, H, Nissinen, A, Vartiainen, E, Jousilahti, P, Harald, K, Massaro, JM, Pencina, M, Lyass, A, Susa, S, Oizumi, T, Kayama, T, Chetrit, A, Roth, J, Orenstein, L, Welin, L, Svärdsudd, K, Lissner, L, Hange, D, Mehlig, K, Tilvis, RS, Dennison, E, Westbury, L, Norman, PE, Almeida, OP, Hankey, GJ, Hata, J, Shibata, M, Furuta, Y, Bom, MT, Rutters, F, Muilwijk, M, Kraft, P, Lindstrom, S, Turman, C, Kiyama, M, Kitamura, A, Gerber, Y, Salonen, JT, van Schoor, LN, van Zutphen, EM, Melander, O, Psaty, BM, Blaha, M, de Boer, IH, Kronmal, RA, Grandits, G, Shin, H-C, Albertorio, JR, Gillum, RF, Hu, FB, Humphries, S, Hill- Briggs, F, Vrany, E, Butler, M, Schwartz, JE, Iso, H, Amouyel, P, Arveiler, D, Ferrieres, J, Gansevoort, RT, de Boer, R, Kieneker, L, Trompet, S, Kearney, P, Cantin, B, Després, JP, Lamarche, B, Laughlin, G, McEvoy, L, Aspelund, T, Thorsson, B, Sigurdsson, G, Tilly, M, Ikram, MA, Dorr, M, Schipf, S, Fretts, AM, Umans, JG, Ali, T, Shara, N, Davey-Smith, G, Can, G, Yüksel, H, Özkan, U, Nakagawa, H, Morikawa, Y, Ishizaki, M, Njølstad, I, Wilsgaard, T, Mathiesen, E, Buring, J, Cook, N, Arndt, V, Rothenbacher, D, Manson, J, Tinker, L, Shipley, M, Tabak, AG, Kivimaki, M, Packard, C, Robertson, M, Feskens, E, and Geleijnse, M

Published
2023
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23. Cerebral small vessel disease genomics and its implications across the lifespan.

Author

Sargurupremraj, Muralidharan, Suzuki, Hideaki, Jian, Xueqiu, Sarnowski, Chloé, Evans, Tavia E, Bis, Joshua C, Eiriksdottir, Gudny, Sakaue, Saori, Terzikhan, Natalie, Habes, Mohamad, Zhao, Wei, Armstrong, Nicola J, Hofer, Edith, Yanek, Lisa R, Hagenaars, Saskia P, Kumar, Rajan B, van den Akker, Erik B, McWhirter, Rebekah E, Trompet, Stella, Mishra, Aniket, Saba, Yasaman, Satizabal, Claudia L, Beaudet, Gregory, Petit, Laurent, Tsuchida, Ami, Zago, Laure, Schilling, Sabrina, Sigurdsson, Sigurdur, Gottesman, Rebecca F, Lewis, Cora E, Aggarwal, Neelum T, Lopez, Oscar L, Smith, Jennifer A, Valdés Hernández, Maria C, van der Grond, Jeroen, Wright, Margaret J, Knol, Maria J, Dörr, Marcus, Thomson, Russell J, Bordes, Constance, Le Grand, Quentin, Duperron, Marie-Gabrielle, Smith, Albert V, Knopman, David S, Schreiner, Pamela J, Evans, Denis A, Rotter, Jerome I, Beiser, Alexa S, Maniega, Susana Muñoz, Beekman, Marian, Trollor, Julian, Stott, David J, Vernooij, Meike W, Wittfeld, Katharina, Niessen, Wiro J, Soumaré, Aicha, Boerwinkle, Eric, Sidney, Stephen, Turner, Stephen T, Davies, Gail, Thalamuthu, Anbupalam, Völker, Uwe, van Buchem, Mark A, Bryan, R Nick, Dupuis, Josée, Bastin, Mark E, Ames, David, Teumer, Alexander, Amouyel, Philippe, Kwok, John B, Bülow, Robin, Deary, Ian J, Schofield, Peter R, Brodaty, Henry, Jiang, Jiyang, Tabara, Yasuharu, Setoh, Kazuya, Miyamoto, Susumu, Yoshida, Kazumichi, Nagata, Manabu, Kamatani, Yoichiro, Matsuda, Fumihiko, Psaty, Bruce M, Bennett, David A, De Jager, Philip L, Mosley, Thomas H, Sachdev, Perminder S, Schmidt, Reinhold, Warren, Helen R, Evangelou, Evangelos, Trégouët, David-Alexandre, International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium (IHGC), Ikram, Mohammad A, Wen, Wei, DeCarli, Charles, Srikanth, Velandai K, Jukema, J Wouter, Slagboom, Eline P, and Kardia, Sharon LR

Subjects
International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium, Humans, Alzheimer Disease, Hypertension, Medical History Taking, Risk Assessment, Risk Factors, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Stroke, Genome-Wide Association Study, Young Adult, Diffusion Tensor Imaging, Genetic Loci, Mendelian Randomization Analysis, Cerebral Small Vessel Diseases, White Matter, and over
Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Published
2020

24. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Author

Bakker, Mark K, van der Spek, Rick AA, van Rheenen, Wouter, Morel, Sandrine, Bourcier, Romain, Hostettler, Isabel C, Alg, Varinder S, van Eijk, Kristel R, Koido, Masaru, Akiyama, Masato, Terao, Chikashi, Matsuda, Koichi, Walters, Robin G, Lin, Kuang, Li, Liming, Millwood, Iona Y, Chen, Zhengming, Rouleau, Guy A, Zhou, Sirui, Rannikmäe, Kristiina, Sudlow, Cathie LM, Houlden, Henry, van den Berg, Leonard H, Dina, Christian, Naggara, Olivier, Gentric, Jean-Christophe, Shotar, Eimad, Eugène, François, Desal, Hubert, Winsvold, Bendik S, Børte, Sigrid, Johnsen, Marianne Bakke, Brumpton, Ben M, Sandvei, Marie Søfteland, Willer, Cristen J, Hveem, Kristian, Zwart, John-Anker, Verschuren, WM Monique, Friedrich, Christoph M, Hirsch, Sven, Schilling, Sabine, Dauvillier, Jérôme, Martin, Olivier, Jones, Gregory T, Bown, Matthew J, Ko, Nerissa U, Kim, Helen, Coleman, Jonathan RI, Breen, Gerome, Zaroff, Jonathan G, Klijn, Catharina JM, Malik, Rainer, Dichgans, Martin, Sargurupremraj, Muralidharan, Tatlisumak, Turgut, Amouyel, Philippe, Debette, Stéphanie, Rinkel, Gabriel JE, Worrall, Bradford B, Pera, Joanna, Slowik, Agnieszka, Gaál-Paavola, Emília I, Niemelä, Mika, Jääskeläinen, Juha E, von Und Zu Fraunberg, Mikael, Lindgren, Antti, Broderick, Joseph P, Werring, David J, Woo, Daniel, Redon, Richard, Bijlenga, Philippe, Kamatani, Yoichiro, Veldink, Jan H, and Ruigrok, Ynte M

Subjects
Genetics, Brain Disorders, Human Genome, Clinical Research, Prevention, Stroke, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Asian People, Blood Pressure, Case-Control Studies, Endothelial Cells, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Intracranial Aneurysm, Polymorphism, Single Nucleotide, Risk Factors, Smoking, Subarachnoid Hemorrhage, White People, HUNT All-In Stroke, China Kadoorie Biobank Collaborative Group, BioBank Japan Project Consortium, ICAN Study Group, CADISP Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators, International Stroke Genetics Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

Published
2020

25. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

Author

Letronne, Florent, Laumet, Geoffroy, Ayral, Anne-Marie, Chapuis, Julien, Demiautte, Florie, Laga, Mathias, Vandenberghe, Michel, Malmanche, Nicolas, Leroux, Florence, Eysert, Fanny, Sottejeau, Yoann, Chami, Linda, Flaig, Amandine, Bauer, Charlotte, Dourlen, Pierre, Lesaffre, Marie, Delay, Charlotte, Huot, Ludovic, Dumont, Julie, Werkmeister, Elisabeth, Lafont, Franck, Mendes, Tiago, Hansmannel, Franck, Dermaut, Bart, Deprez, Benoit, Herard, Anne-Sophie, Dhenain, Marc, Souedet, Nicolas, Pasquier, Florence, Tulasne, David, Berr, Claudine, Hauw, Jean-Jacques, Lemoine, Yves, Amouyel, Philippe, Mann, David, Déprez, Rebecca, Checler, Frédéric, Hot, David, Delzescaux, Thierry, Gevaert, Kris, and Lambert, Jean-Charles

Subjects
Quantitative Biology - Neurons and Cognition, Quantitative Biology - Tissues and Organs
Abstract

Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amy-loid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down-or up-regulation of ADAM30 expression triggered an increase/decrease in A$\beta$ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30 mut) did not affect A$\beta$ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered A$\beta$42 secretion in neuron primary cultures, soluble A$\beta$42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation.

Published
2019
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26. Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Author

Hofer, Edith, Roshchupkin, Gennady V, Adams, Hieab HH, Knol, Maria J, Lin, Honghuang, Li, Shuo, Zare, Habil, Ahmad, Shahzad, Armstrong, Nicola J, Satizabal, Claudia L, Bernard, Manon, Bis, Joshua C, Gillespie, Nathan A, Luciano, Michelle, Mishra, Aniket, Scholz, Markus, Teumer, Alexander, Xia, Rui, Jian, Xueqiu, Mosley, Thomas H, Saba, Yasaman, Pirpamer, Lukas, Seiler, Stephan, Becker, James T, Carmichael, Owen, Rotter, Jerome I, Psaty, Bruce M, Lopez, Oscar L, Amin, Najaf, van der Lee, Sven J, Yang, Qiong, Himali, Jayandra J, Maillard, Pauline, Beiser, Alexa S, DeCarli, Charles, Karama, Sherif, Lewis, Lindsay, Harris, Mat, Bastin, Mark E, Deary, Ian J, Veronica Witte, A, Beyer, Frauke, Loeffler, Markus, Mather, Karen A, Schofield, Peter R, Thalamuthu, Anbupalam, Kwok, John B, Wright, Margaret J, Ames, David, Trollor, Julian, Jiang, Jiyang, Brodaty, Henry, Wen, Wei, Vernooij, Meike W, Hofman, Albert, Uitterlinden, André G, Niessen, Wiro J, Wittfeld, Katharina, Bülow, Robin, Völker, Uwe, Pausova, Zdenka, Bruce Pike, G, Maingault, Sophie, Crivello, Fabrice, Tzourio, Christophe, Amouyel, Philippe, Mazoyer, Bernard, Neale, Michael C, Franz, Carol E, Lyons, Michael J, Panizzon, Matthew S, Andreassen, Ole A, Dale, Anders M, Logue, Mark, Grasby, Katrina L, Jahanshad, Neda, Painter, Jodie N, Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P, Lind, Penelope A, Pizzagalli, Fabrizio, Stein, Jason L, Thompson, Paul M, Medland, Sarah E, ENIGMA consortium, Sachdev, Perminder S, Kremen, William S, Wardlaw, Joanna M, Villringer, Arno, van Duijn, Cornelia M, Grabe, Hans J, Longstreth, William T, Fornage, Myriam, Paus, Tomas, Debette, Stephanie, Ikram, M Arfan, Schmidt, Helena, Schmidt, Reinhold, and Seshadri, Sudha

Subjects
ENIGMA consortium, Brain, Chromosome Structures, Humans, Neurodegenerative Diseases, Cognition, Mental Disorders, Genomics, Aging, Phenotype, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Genetics, Neurosciences, Human Genome, Brain Disorders, Biotechnology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Neurological
Abstract

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Published
2020

27. Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities

Author

Armstrong, Nicola J, Mather, Karen A, Sargurupremraj, Muralidharan, Knol, Maria J, Malik, Rainer, Satizabal, Claudia L, Yanek, Lisa R, Wen, Wei, Gudnason, Vilmundur G, Dueker, Nicole D, Elliott, Lloyd T, Hofer, Edith, Bis, Joshua, Jahanshad, Neda, Li, Shuo, Logue, Mark A, Luciano, Michelle, Scholz, Markus, Smith, Albert V, Trompet, Stella, Vojinovic, Dina, Xia, Rui, Alfaro-Almagro, Fidel, Ames, David, Amin, Najaf, Amouyel, Philippe, Beiser, Alexa S, Brodaty, Henry, Deary, Ian J, Fennema-Notestine, Christine, Gampawar, Piyush G, Gottesman, Rebecca, Griffanti, Ludovica, Jack, Clifford R, Jenkinson, Mark, Jiang, Jiyang, Kral, Brian G, Kwok, John B, Lampe, Leonie, C.M. Liewald, David, Maillard, Pauline, Marchini, Jonathan, Bastin, Mark E, Mazoyer, Bernard, Pirpamer, Lukas, Rafael Romero, José, Roshchupkin, Gennady V, Schofield, Peter R, Schroeter, Matthias L, Stott, David J, Thalamuthu, Anbupalam, Trollor, Julian, Tzourio, Christophe, van der Grond, Jeroen, Vernooij, Meike W, Witte, Veronica A, Wright, Margaret J, Yang, Qiong, Morris, Zoe, Siggurdsson, Siggi, Psaty, Bruce, Villringer, Arno, Schmidt, Helena, Haberg, Asta K, van Duijn, Cornelia M, Jukema, J Wouter, Dichgans, Martin, Sacco, Ralph L, Wright, Clinton B, Kremen, William S, Becker, Lewis C, Thompson, Paul M, Mosley, Thomas H, Wardlaw, Joanna M, Ikram, M Arfan, Adams, Hieab HH, Seshadri, Sudha, Sachdev, Perminder S, Smith, Stephen M, Launer, Lenore, Longstreth, William, DeCarli, Charles, Schmidt, Reinhold, Fornage, Myriam, Debette, Stephanie, and Nyquist, Paul A

Subjects
Epidemiology, Health Sciences, Brain Disorders, Biotechnology, Neurosciences, Cerebrovascular, Stroke, Neurodegenerative, Dementia, Vascular Cognitive Impairment/Dementia, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Aging, Genetics, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aged, Brain, Cerebral Small Vessel Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, White Matter, brain, genome-wide association study, neuroimaging, risk factors, white matter, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Neurology & Neurosurgery, Clinical sciences, Allied health and rehabilitation science
Abstract

Background and purposePeriventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.MethodsParticipants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.ResultsIn the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.ConclusionsOur study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Published
2020

28. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Published
2022
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29. Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Author

Jansen, Iris E., van der Lee, Sven J., Gomez-Fonseca, Duber, de Rojas, Itziar, Dalmasso, Maria Carolina, Grenier-Boley, Benjamin, Zettergren, Anna, Mishra, Aniket, Ali, Muhammad, Andrade, Victor, Bellenguez, Céline, Kleineidam, Luca, Küçükali, Fahri, Sung, Yun Ju, Tesí, Niccolo, Vromen, Ellen M., Wightman, Douglas P., Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Amouyel, Philippe, Athanasiu, Lavinia, Bahrami, Shahram, Bailly, Henri, Belbin, Olivia, Bergh, Sverre, Bertram, Lars, Biessels, Geert Jan, Blennow, Kaj, Blesa, Rafael, Boada, Mercè, Boland, Anne, Buerger, Katharina, Carracedo, Ángel, Cervera-Carles, Laura, Chene, Geneviève, Claassen, Jurgen A. H. R., Debette, Stephanie, Deleuze, Jean-Francois, de Deyn, Peter Paul, Diehl-Schmid, Janine, Djurovic, Srdjan, Dols-Icardo, Oriol, Dufouil, Carole, Duron, Emmanuelle, Düzel, Emrah, Fladby, Tormod, Fortea, Juan, Frölich, Lutz, García-González, Pablo, Garcia-Martinez, Maria, Giegling, Ina, Goldhardt, Oliver, Gobom, Johan, Grimmer, Timo, Haapasalo, Annakaisa, Hampel, Harald, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernández, Isabel, Herukka, Sanna-Kaisa, Holstege, Henne, Jarholm, Jonas, Kern, Silke, Knapskog, Anne-Brita, Koivisto, Anne M., Kornhuber, Johannes, Kuulasmaa, Teemu, Lage, Carmen, Laske, Christoph, Leinonen, Ville, Lewczuk, Piotr, Lleó, Alberto, de Munain, Adolfo López, Lopez-Garcia, Sara, Maier, Wolfgang, Marquié, Marta, Mol, Merel O., Montrreal, Laura, Moreno, Fermin, Moreno-Grau, Sonia, Nicolas, Gael, Nöthen, Markus M., Orellana, Adelina, Pålhaugen, Lene, Papma, Janne M., Pasquier, Florence, Perneczky, Robert, Peters, Oliver, Pijnenburg, Yolande A. L., Popp, Julius, Posthuma, Danielle, Pozueta, Ana, Priller, Josef, Puerta, Raquel, Quintela, Inés, Ramakers, Inez, Rodriguez-Rodriguez, Eloy, Rujescu, Dan, Saltvedt, Ingvild, Sanchez-Juan, Pascual, Scheltens, Philip, Scherbaum, Norbert, Schmid, Matthias, Schneider, Anja, Selbæk, Geir, Selnes, Per, Shadrin, Alexey, Skoog, Ingmar, Soininen, Hilkka, Tárraga, Lluís, Teipel, Stefan, Tijms, Betty, Tsolaki, Magda, Van Broeckhoven, Christine, 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., Zetterberg, Henrik, Zulaica, Miren, van Duijn, Cornelia M., Bjerke, Maria, Engelborghs, Sebastiaan, Jessen, Frank, Teunissen, Charlotte E., Pastor, Pau, Hiltunen, Mikko, Ingelsson, Martin, Andreassen, Ole A., Clarimón, Jordi, Sleegers, Kristel, Ruiz, Agustín, Ramirez, Alfredo, Cruchaga, Carlos, Lambert, Jean-Charles, and van der Flier, Wiesje

Published
2022
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30. Identification of several eating habits that mediate the association between eating behaviors and the risk of obesity

Author

Estelle Aymes, Gabrielle Lisembard, Jean Dallongeville, Julien Rousseaux, Marie‐Pierre Dumont, Philippe Amouyel, Monique Romon, and Aline Meirhaeghe

Subjects
activity level, eating behavior, eating habits, mediation, obesity, Internal medicine, RC31-1245
Abstract

Abstract Objective Eating behaviors play important roles in the development of obesity. A better knowledge of the psychological aspects of eating behaviors in individuals with and without obesity and their consequences on daily eating and lifestyle habits would be informative. The Three‐Factor Eating Questionnaire (TFEQ)‐R21 assesses the psychometrics of eating behavior. The objectives of the study were to establish which eating habits were or were not associated with TFEQ eating behaviors, and to quantify the extent to which those eating habits mediated the association between TFEQ eating behaviors and obesity risk. Methods Data were obtained from the Gene and Environment Case‐Control Obesity Study from northern France. It included 2237 individuals with obesity and 403 individuals without obesity. Eating behaviors were assessed according to the TFEQ‐R21. Two activity levels (physical activity and television watching) and six eating habits (e.g., plate size, having one serving or at least two servings of the main meal, …) were evaluated. Regression and mediation analyses were performed. Results Higher cognitive restraint, higher uncontrolled eating (UE) and higher emotional eating (EE) were associated with a higher risk of obesity, independently of each other and of age, sex, socio‐economic status and physical activity. Cognitive restraint was negatively associated with having at least two servings, while UE and EE were associated with several obesogenic habits such as eating in front of the television or eating at night. Each of these obesogenic habits mediated between 3% and 20% of the association between UE or EE and obesity. Conclusions Psychological eating behaviors were associated with several lifestyle and eating habits in both individuals with and without obesity. Moreover, some eating habits partially mediated (between 3% and 20%) the association between TFEQ eating behaviors and obesity risk. For clinicians, this study shows that simple, easy‐to‐ask questions on specific daily eating habits can provide essential information to better understand and manage patients with obesity.

Published
2022
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31. A genome-wide association study identifies genetic loci associated with specific lobar brain volumes

Author

van der Lee, Sven J, Knol, Maria J, Chauhan, Ganesh, Satizabal, Claudia L, Smith, Albert Vernon, Hofer, Edith, Bis, Joshua C, Hibar, Derrek P, Hilal, Saima, van den Akker, Erik B, Arfanakis, Konstantinos, Bernard, Manon, Yanek, Lisa R, Amin, Najaf, Crivello, Fabrice, Cheung, Josh W, Harris, Tamara B, Saba, Yasaman, Lopez, Oscar L, Li, Shuo, van der Grond, Jeroen, Yu, Lei, Paus, Tomas, Roshchupkin, Gennady V, Amouyel, Philippe, Jahanshad, Neda, Taylor, Kent D, Yang, Qiong, Mathias, Rasika A, Boehringer, Stefan, Mazoyer, Bernard, Rice, Ken, Cheng, Ching Yu, Maillard, Pauline, van Heemst, Diana, Wong, Tien Yin, Niessen, Wiro J, Beiser, Alexa S, Beekman, Marian, Zhao, Wanting, Nyquist, Paul A, Chen, Christopher, Launer, Lenore J, Psaty, Bruce M, Ikram, M Kamran, Vernooij, Meike W, Schmidt, Helena, Pausova, Zdenka, Becker, Diane M, De Jager, Philip L, Thompson, Paul M, van Duijn, Cornelia M, Bennett, David A, Slagboom, P Eline, Schmidt, Reinhold, Longstreth, WT, Ikram, M Arfan, Seshadri, Sudha, Debette, Stéphanie, Gudnason, Vilmundur, Adams, Hieab HH, and DeCarli, Charles

Subjects
Biological Sciences, Genetics, Neurosciences, Mental Health, Brain Disorders, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Frontal Lobe, Gene Expression Regulation, Developmental, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Genotype, Heredity, Humans, Magnetic Resonance Imaging, Occipital Lobe, Organ Size, Parietal Lobe, Phenotype, Temporal Lobe, United Kingdom, Biomarkers, Genome-wide association studies, Neurology, Biological sciences, Biomedical and clinical sciences
Abstract

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.

Published
2019

32. Genome‐wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy

Author

Chen, Zhongbo, Chen, Jason A, Shatunov, Aleksey, Jones, Ashley R, Kravitz, Stephanie N, Huang, Alden Y, Lawrence, Lauren, Lowe, Jennifer K, Lewis, Cathryn M, Payan, Christine AM, Lieb, Wolfgang, Franke, Andre, Deloukas, Panagiotis, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean‐François, Groups, NNIPPS and BBBIPPS Study, Ludolph, Albert, Bensimon, Gilbert, Leigh, P Nigel, Bronstein, Jeff M, Coppola, Giovanni, Geschwind, Daniel H, and Al‐Chalabi, Ammar

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Prevention, Clinical Research, Neurodegenerative, Genetics, Brain Disorders, Rare Diseases, Genetic Testing, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Age of Onset, Aged, Aged, 80 and over, DNA Copy Number Variations, Female, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Supranuclear Palsy, Progressive, tau Proteins, copy number variation, genome-wide association study, progressive supranuclear palsy, NNIPPS and BBBIPPS Study Groups, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundProgressive supranuclear palsy is a neurodegenerative tauopathy manifesting clinically as a progressive akinetic-rigid syndrome. In this study, we sought to identify genetic variants influencing PSP susceptibility through a genome-wide association analysis of a cohort of well-characterized patients who had participated in the Neuroprotection and Natural History in Parkinson Plus Syndromes and Blood Brain Barrier in Parkinson Plus Syndromes studies.MethodsWe genotyped single-nucleotide polymorphisms in 283 PSP cases from the United Kingdom, Germany, and France and compared these with genotypes from 4472 controls. Copy number variants were identified from genotyping data.ResultsWe observed associations on chromosome 17 within or close to the MAPT gene and explored the genetic architecture at this locus. We confirmed the previously reported association of rs1768208 in the MOBP gene (P = 3.29 × 10-13 ) and rs1411478 in STX6 (P = 3.45 × 10-10 ). The population-attributable risk from the MAPT, MOBP, and STX6 single-nucleotide polymorphisms was found to be 0.37, 0.26, and 0.08, respectively. In addition, we found 2 instances of copy number variants spanning the MAPT gene in patients with PSP. These copy number variants include tau but few other genes within the chromosome 17 haplotype region, providing additional support for the direct pathogenicity of MAPT in PSP.ConclusionsClinicians should also be aware of MAPT duplication as a possible genetic cause of PSP, especially in patients presenting with young age at onset. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

33. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Author

Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, and Kleineidam, Luca

Abstract

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Published
2019

34. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Author

Justice, Anne E, Karaderi, Tugce, Highland, Heather M, Young, Kristin L, Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L, Fine, Rebecca S, Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W, Locke, Adam E, Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Dörr, Marcus, Drenos, Fotios, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Fornage, Myriam, Fox, Caroline S, Franks, Paul W, Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, and Hattersley, Andrew T

Subjects
Clinical Research, Obesity, Genetics, Nutrition, Prevention, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Cardiovascular, Animals, Body Fat Distribution, Body Mass Index, Case-Control Studies, Drosophila, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeostasis, Humans, Lipids, Male, Proteins, Risk Factors, Waist-Hip Ratio, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF

Published
2019

35. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe GN, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, Ross, Robert V MacKenzie, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Noordegraaf, Anton Vonk, Waisfisz, Quinten, and Walsworth, Anna K

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Genetics, Human Genome, Lung, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, HLA-DP alpha-Chains, HLA-DP beta-Chains, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Arterial Hypertension, Risk Assessment, SOXF Transcription Factors, Signal Transduction, Survival Analysis, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, Public Health and Health Services, Other Medical and Health Sciences, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Published
2019

36. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, Ganesh, Adams, Hieab HH, Satizabal, Claudia L, Bis, Joshua C, Teumer, Alexander, Sargurupremraj, Muralidharan, Hofer, Edith, Trompet, Stella, Hilal, Saima, Smith, Albert Vernon, Jian, Xueqiu, Malik, Rainer, Traylor, Matthew, Pulit, Sara L, Amouyel, Philippe, Mazoyer, Bernard, Zhu, Yi-Cheng, Kaffashian, Sara, Schilling, Sabrina, Beecham, Gary W, Montine, Thomas J, Schellenberg, Gerard D, Kjartansson, Olafur, Guðnason, Vilmundur, Knopman, David S, Griswold, Michael E, Windham, B Gwen, Gottesman, Rebecca F, Mosley, Thomas H, Schmidt, Reinhold, Saba, Yasaman, Schmidt, Helena, Takeuchi, Fumihiko, Yamaguchi, Shuhei, Nabika, Toru, Kato, Norihiro, Rajan, Kumar B, Aggarwal, Neelum T, De Jager, Philip L, Evans, Denis A, Psaty, Bruce M, Rotter, Jerome I, Rice, Kenneth, Lopez, Oscar L, Liao, Jiemin, Chen, Christopher, Cheng, Ching-Yu, Wong, Tien Y, Ikram, Mohammad K, van der Lee, Sven J, Amin, Najaf, Chouraki, Vincent, DeStefano, Anita L, Aparicio, Hugo J, Romero, Jose R, Maillard, Pauline, DeCarli, Charles, Wardlaw, Joanna M, del C. Valdés Hernández, Maria, Luciano, Michelle, Liewald, David, Deary, Ian J, Starr, John M, Bastin, Mark E, Maniega, Susana Muñoz, Slagboom, P Eline, Beekman, Marian, Deelen, Joris, Uh, Hae-Won, Lemmens, Robin, Brodaty, Henry, Wright, Margaret J, Ames, David, Boncoraglio, Giorgio B, Hopewell, Jemma C, Beecham, Ashley H, Blanton, Susan H, Wright, Clinton B, Sacco, Ralph L, Wen, Wei, Thalamuthu, Anbupalam, Armstrong, Nicola J, Chong, Elizabeth, Schofield, Peter R, Kwok, John B, van der Grond, Jeroen, Stott, David J, Ford, Ian, Jukema, J Wouter, Vernooij, Meike W, Hofman, Albert, Uitterlinden, André G, van der Lugt, Aad, Wittfeld, Katharina, Grabe, Hans J, Hosten, Norbert, von Sarnowski, Bettina, Völker, Uwe, Levi, Christopher, and Jimenez-Conde, Jordi

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Genetics, Cardiovascular, Prevention, Aging, Cerebrovascular, Stroke, Human Genome, 2.1 Biological and endogenous factors, Good Health and Well Being, Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.ConclusionIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

Published
2019

37. Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities

Author

Catherine M. Francis, Matthias E. Futschik, Jian Huang, Wenjia Bai, Muralidharan Sargurupremraj, Alexander Teumer, Monique M. B. Breteler, Enrico Petretto, Amanda S. R. Ho, Philippe Amouyel, Stefan T. Engelter, Robin Bülow, Uwe Völker, Henry Völzke, Marcus Dörr, Mohammed-Aslam Imtiaz, N. Ahmad Aziz, Valerie Lohner, James S. Ware, Stephanie Debette, Paul Elliott, Abbas Dehghan, and Paul M. Matthews

Subjects
Science
Abstract

Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.

Published
2022
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38. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Author

Franceschini, Nora, Giambartolomei, Claudia, de Vries, Paul S, Finan, Chris, Bis, Joshua C, Huntley, Rachael P, Lovering, Ruth C, Tajuddin, Salman M, Winkler, Thomas W, Graff, Misa, Kavousi, Maryam, Dale, Caroline, Smith, Albert V, Hofer, Edith, van Leeuwen, Elisabeth M, Nolte, Ilja M, Lu, Lingyi, Scholz, Markus, Sargurupremraj, Muralidharan, Pitkänen, Niina, Franzén, Oscar, Joshi, Peter K, Noordam, Raymond, Marioni, Riccardo E, Hwang, Shih-Jen, Musani, Solomon K, Schminke, Ulf, Palmas, Walter, Isaacs, Aaron, Correa, Adolfo, Zonderman, Alan B, Hofman, Albert, Teumer, Alexander, Cox, Amanda J, Uitterlinden, André G, Wong, Andrew, Smit, Andries J, Newman, Anne B, Britton, Annie, Ruusalepp, Arno, Sennblad, Bengt, Hedblad, Bo, Pasaniuc, Bogdan, Penninx, Brenda W, Langefeld, Carl D, Wassel, Christina L, Tzourio, Christophe, Fava, Cristiano, Baldassarre, Damiano, O'Leary, Daniel H, Teupser, Daniel, Kuh, Diana, Tremoli, Elena, Mannarino, Elmo, Grossi, Enzo, Boerwinkle, Eric, Schadt, Eric E, Ingelsson, Erik, Veglia, Fabrizio, Rivadeneira, Fernando, Beutner, Frank, Chauhan, Ganesh, Heiss, Gerardo, Snieder, Harold, Campbell, Harry, Völzke, Henry, Markus, Hugh S, Deary, Ian J, Jukema, J Wouter, de Graaf, Jacqueline, Price, Jacqueline, Pott, Janne, Hopewell, Jemma C, Liang, Jingjing, Thiery, Joachim, Engmann, Jorgen, Gertow, Karl, Rice, Kenneth, Taylor, Kent D, Dhana, Klodian, Kiemeney, Lambertus ALM, Lind, Lars, Raffield, Laura M, Launer, Lenore J, Holdt, Lesca M, Dörr, Marcus, Dichgans, Martin, Traylor, Matthew, Sitzer, Matthias, Kumari, Meena, Kivimaki, Mika, Nalls, Mike A, Melander, Olle, Raitakari, Olli, Franco, Oscar H, Rueda-Ochoa, Oscar L, Roussos, Panos, Whincup, Peter H, Amouyel, Philippe, and Giral, Philippe

Subjects
MEGASTROKE Consortium, Humans, Coronary Disease, Genetic Predisposition to Disease, Amino Acid Oxidoreductases, Protein-Lysine 6-Oxidase, Risk Factors, Lod Score, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Plaque, Atherosclerotic, Carotid Intima-Media Thickness, ADAMTS9 Protein, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide
Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Published
2018

39. The relationship between residential exposure to atmospheric pollution and circulating miRNA in adults living in an urban area in northern France

Author

Audrey Hubert, Djamal Achour, Céline Grare, Gianni Zarcone, Manon Muntaner, Aghiles Hamroun, Victoria Gauthier, Philippe Amouyel, Régis Matran, Farid Zerimech, Jean-Marc Lo-Guidice, and Luc Dauchet

Subjects
Environmental sciences, GE1-350
Abstract

Introduction: MicroRNAs are epigenetic regulatory factors capable of silencing the expression of target genes and might mediate the effects of air pollution on health. The objective of the present population-based study was to investigate the association between microRNA expression and long-term, residential exposure to atmospheric PM10 and NO2. Method: We included 998 non-smoking adult participants from the cross-sectional ELISABET survey (2010–2014) in the Lille urban area of France. The mean residential annual pollution levels were estimated with an atmospheric dispersion modelling system. Ten microRNAs were selected on the basis of the literature data, together with two housekeeping microRNAs (miR-93-5p and miR-191-5p) and were quantified with RT-qPCRs. Multivariate linear regression models were used to study the association between microRNAs and air pollution. The threshold for statistical significance (after correction for the FDR) was set to p

Published
2023
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40. Identification of patient subtypes based on protein expression for prediction of heart failure after myocardial infarction

Author

Wilfried Heyse, Vincent Vandewalle, Guillemette Marot, Philippe Amouyel, Christophe Bauters, and Florence Pinet

Subjects
Cardiovascular medicine, Proteomics, Science
Abstract

Summary: This study investigates the ability of high-throughput aptamer-based platform to identify circulating biomarkers able to predict occurrence of heart failure (HF), in blood samples collected during hospitalization of patients suffering from a first myocardial infarction (MI). REVE-1 (derivation) and REVE-2 (validation) cohorts included respectively 254 and 238 patients, followed up respectively 9 · 2 ± 4 · 8 and 7 · 6 ± 3 · 0 years. A blood sample collected during hospitalization was used for quantifying 4,668 proteins. Fifty proteins were significantly associated with long-term occurrence of HF with all-cause death as the competing event. k-means, an unsupervised clustering method, identified two groups of patients based on expression levels of the 50 proteins. Group 2 was significantly associated with a higher risk of HF in both cohorts. These results showed that a subset of 50 selected proteins quantified during hospitalization of MI patients is able to stratify and predict the long-term occurrence of HF.

Published
2023
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41. New insights into the genetic etiology of Alzheimer’s disease and related dementias

Author

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

Published
2022
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42. Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities

Author

Francis, Catherine M., Futschik, Matthias E., Huang, Jian, Bai, Wenjia, Sargurupremraj, Muralidharan, Teumer, Alexander, Breteler, Monique M. B., Petretto, Enrico, Ho, Amanda S. R., Amouyel, Philippe, Engelter, Stefan T., Bülow, Robin, Völker, Uwe, Völzke, Henry, Dörr, Marcus, Imtiaz, Mohammed-Aslam, Aziz, N. Ahmad, Lohner, Valerie, Ware, James S., Debette, Stephanie, Elliott, Paul, Dehghan, Abbas, and Matthews, Paul M.

Published
2022
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43. Author Correction: Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

Author

Georges, Adrien, Yang, Min-Lee, Berrandou, Takiy-Eddine, Bakker, Mark K., Dikilitas, Ozan, Kiando, Soto Romuald, Ma, Lijiang, Satterfield, Benjamin A., Sengupta, Sebanti, Yu, Mengyao, Deleuze, Jean-François, Dupré, Delia, Hunker, Kristina L., Kyryachenko, Sergiy, Liu, Lu, Sayoud-Sadeg, Ines, Amar, Laurence, Brummett, Chad M., Coleman, Dawn M., d’Escamard, Valentina, de Leeuw, Peter, Fendrikova-Mahlay, Natalia, Kadian-Dodov, Daniella, Li, Jun Z., Lorthioir, Aurélien, Pappaccogli, Marco, Prejbisz, Aleksander, Smigielski, Witold, Stanley, James C., Zawistowski, Matthew, Zhou, Xiang, Zöllner, Sebastian, Amouyel, Philippe, De Buyzere, Marc L., Debette, Stéphanie, Dobrowolski, Piotr, Drygas, Wojciech, Gornik, Heather L., Olin, Jeffrey W., Piwonski, Jerzy, Rietzschel, Ernst R., Ruigrok, Ynte M., Vikkula, Miikka, Warchol Celinska, Ewa, Januszewicz, Andrzej, Kullo, Iftikhar J., Azizi, Michel, Jeunemaitre, Xavier, Persu, Alexandre, Kovacic, Jason C., Ganesh, Santhi K., and Bouatia-Naji, Nabila

Published
2022
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44. Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping

Author

Belloy, Michael E., Eger, Sarah J., Le Guen, Yann, Damotte, Vincent, Ahmad, Shahzad, Ikram, M. Arfan, Ramirez, Alfredo, Tsolaki, Anthoula C., Rossi, Giacomina, Jansen, Iris E., de Rojas, Itziar, Parveen, Kayenat, Sleegers, Kristel, Ingelsson, Martin, Hiltunen, Mikko, Amin, Najaf, Andreassen, Ole, Sánchez-Juan, Pascual, Kehoe, Patrick, Amouyel, Philippe, Sims, Rebecca, Frikke-Schmidt, Ruth, van der Flier, Wiesje M., Lambert, Jean-Charles, He, Zihuai, Han, Summer S., Napolioni, Valerio, and Greicius, Michael D.

Published
2022
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45. The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

Author

Lambert, Erwan, Saha, Orthis, Soares Landeira, Bruna, Melo de Farias, Ana Raquel, Hermant, Xavier, Carrier, Arnaud, Pelletier, Alexandre, Gadaut, Johanna, Davoine, Lindsay, Dupont, Cloé, Amouyel, Philippe, Bonnefond, Amélie, Lafont, Frank, Abdelfettah, Farida, Verstreken, Patrik, Chapuis, Julien, Barois, Nicolas, Delahaye, Fabien, Dermaut, Bart, Lambert, Jean-Charles, Costa, Marcos R., and Dourlen, Pierre

Published
2022
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46. Stretching and Eccentric Exercises Normalize Gait Parameters in Gastrocnemius Tightness Subjects

Author

Amine Hamza, Lucas Martinez, Riccardo Sacco, Thomas Amouyel, Eric Held, Julien Beldame, Fabien Billuart, and Matthieu Lalevée

Subjects
gastrocnemius tightness, Stanish protocol, gait analysis, stretching, eccentric exercise, foot pathologies, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

Background: Isolated gastrocnemius tightness (IGT) is a prevalent condition linked to various foot pathologies. In a previous quantitative gait analysis study, we identified an increase in knee flexion during the midstance phase in IGT patients compared with controls. Although stretching and eccentric exercises (the Stanish protocol) are commonly used for IGT management, their impact on gait parameters remains poorly understood. This study aimed to assess the influence of a Stanish protocol on gait parameters in bilateral IGT subjects. Methods: We enrolled 10 asymptomatic bilateral IGT subjects and 10 controls. Quantitative gait analysis and dynamic baropodometry were carried out on each subject. A Stanish protocol was applied for 4 weeks (five sessions/week) by the IGT group, followed by a similar gait analysis. The ankle and knee range of motion and foot pressure distribution were assessed during the midstance phase of the gait. Results: An increase in knee flexion was initially present in the IGT group compared with controls (8.9 +/− 4.6 vs. 3.4 +/− 2.3 degrees, p < 0.001). There was no difference in the ankle range of motion and foot pressures between the groups at that time. Significant reductions in knee flexion during gait were observed in the IGT subjects after the Stanish protocol (8.9 +/− 4.6 to 3.7 +/− 2.3 degrees, p < 0.001) with a normalization of this parameter (3.4 +/− 2.3 in controls vs. 3.7 +/− 2.3 degrees in IGT, p = 0.72). There was no change in ankle range of motion and foot pressure after the Stanish protocol. Conclusions: Our findings support the effectiveness of the Stanish protocol in reducing knee flexion and normalizing gait in IGT subjects. This protocol not only offers a noninvasive approach for IGT-related issues management but could also enable prophylactic care in asymptomatic cases.

Published
2023
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47. Amyloid-Beta Peptides Trigger Premature Functional and Gene Expression Alterations in Human-Induced Neurons

Author

Ana Raquel Melo de Farias, Alexandre Pelletier, Lukas Cruz Carvalho Iohan, Orthis Saha, Amélie Bonnefond, Philippe Amouyel, Fabien Delahaye, Jean-Charles Lambert, and Marcos R. Costa

Subjects
amyloid-beta peptides, human-induced neurons, single-nucleus RNA sequencing, calcium imaging, inter-cellular communication, Biology (General), QH301-705.5
Abstract

Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid-beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade hypothesis postulates that deposition of Aβ peptides is the causative agent of AD pathology, but we still lack comprehensive understanding of the molecular mechanisms connecting Aβ peptides to neuronal dysfunctions in AD. In this work, we investigate the early effects of Aβ peptide accumulation on the functional properties and gene expression profiles of human-induced neurons (hiNs). We show that hiNs acutely exposed to low concentrations of both cell-secreted Aβ peptides or synthetic Aβ1–42 exhibit alterations in the frequency of calcium transients suggestive of increased neuronal excitability. Using single-cell RNA sequencing, we also show that cell-secreted Aβ up-regulates the expression of several synapse-related genes and down-regulates the expression of genes associated with metabolic stress mainly in glutamatergic neurons and, to a lesser degree, in GABAergic neurons and astrocytes. These neuronal alterations correlate with activation of the SEMA5, EPHA and NECTIN signaling pathways, which are important regulators of synaptic plasticity. Altogether, our findings indicate that slight elevations in Aβ concentrations are sufficient to elicit transcriptional changes in human neurons, which can contribute to early alterations in neural network activity.

Published
2023
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48. Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping

Author

Michael E. Belloy, Sarah J. Eger, Yann Le Guen, Vincent Damotte, Shahzad Ahmad, M. Arfan Ikram, Alfredo Ramirez, Anthoula C. Tsolaki, Giacomina Rossi, Iris E. Jansen, Itziar de Rojas, Kayenat Parveen, Kristel Sleegers, Martin Ingelsson, Mikko Hiltunen, Najaf Amin, Ole Andreassen, Pascual Sánchez-Juan, Patrick Kehoe, Philippe Amouyel, Rebecca Sims, Ruth Frikke-Schmidt, Wiesje M. van der Flier, Jean-Charles Lambert, for the European Alzheimer & Dementia BioBank (EADB), Zihuai He, Summer S. Han, Valerio Napolioni, and Michael D. Greicius

Subjects
Alzheimer’s disease (AD), Genetics, Haplotypes, Apolipoprotein E (APOE), rs439401, Novel approaches, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Genetic variants within the APOE locus may modulate Alzheimer’s disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE. Methods We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches. Results Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. Conclusions We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.

Published
2022
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49. The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

Author

Erwan Lambert, Orthis Saha, Bruna Soares Landeira, Ana Raquel Melo de Farias, Xavier Hermant, Arnaud Carrier, Alexandre Pelletier, Johanna Gadaut, Lindsay Davoine, Cloé Dupont, Philippe Amouyel, Amélie Bonnefond, Frank Lafont, Farida Abdelfettah, Patrik Verstreken, Julien Chapuis, Nicolas Barois, Fabien Delahaye, Bart Dermaut, Jean-Charles Lambert, Marcos R. Costa, and Pierre Dourlen

Subjects
BIN1 isoforms, Neurodegeneration, Early endosome, Alzheimer’s disease, Drosophila, Human induced neurons, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer’s disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (BIN1iso9), induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.

Published
2022
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50. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Author

van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Jr., Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.

Published
2021
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