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1. Health Care Students’ Knowledge of and Attitudes, Beliefs, and Practices Toward the French COVID-19 App: Cross-sectional Questionnaire Study

Author

Montagni, Ilaria, Roussel, Nicolas, Thiébaut, Rodolphe, and Tzourio, Christophe

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract

BackgroundMany countries worldwide have developed mobile phone apps capable of supporting instantaneous contact tracing to control the COVID-19 pandemic. In France, a few people have downloaded and are using the StopCovid contact tracing app. Students in the health domain are of particular concern in terms of app uptake. Exploring their use and opinions about the app can inform improvements and diffusion of StopCovid among young people. ObjectiveThe aim of this study is to investigate health care students’ knowledge of and attitudes, beliefs, and practices (KABP) toward the StopCovid app. MethodsA field survey was conducted among 318 students at the health sciences campus of the University of Bordeaux, France, between September 25 and October 16, 2020. A quota sampling method was used, and descriptive statistics and univariate analyses were performed. ResultsOf the 318 respondents, 77.3% (n=246) had heard about the app, but only 11.3% (n=36) had downloaded it, and 4.7% (n=15) were still using it at the time of the survey. Among the 210 participants who had heard about the app but did not download it, the main reasons for not using the app were a belief that it was not effective given its limited diffusion (n=37, 17.6%), a lack of interest (n=37, 17.6%), and distrust in the data security and fear of being geolocated (n=33, 15.7%). Among the 72 students who had not heard of the app and were given a brief description of its functioning and confidentiality policy, 52.7% (n=38) said they would use it. Participants reported that the main solution for increasing the use of the app would be better communication about it (227/318, 71.4%). ConclusionsEven among health students, the contact tracing app was poorly used. The findings suggest that improved communication about its advantages and simplicity of use as well as clarifying false beliefs about it could help improve uptake.

Published
2021
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2. Exploring the Health-Related Quality of Life of Patients Treated With Immune Checkpoint Inhibitors: Social Media Study

Author

Cotté, François-Emery, Voillot, Paméla, Bennett, Bryan, Falissard, Bruno, Tzourio, Christophe, Foulquié, Pierre, Gaudin, Anne-Françoise, Lemasson, Hervé, Grumberg, Valentine, McDonald, Laura, Faviez, Carole, and Schück, Stéphane

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract

BackgroundImmune checkpoint inhibitors (ICIs) are increasingly used to treat several types of tumors. Impact of this emerging therapy on patients’ health-related quality of life (HRQoL) is usually collected in clinical trials through standard questionnaires. However, this might not fully reflect HRQoL of patients under real-world conditions. In parallel, users’ narratives from social media represent a potential new source of research concerning HRQoL. ObjectiveThe aim of this study is to assess and compare coverage of ICI-treated patients’ HRQoL domains and subdomains in standard questionnaires from clinical trials and in real-world setting from social media posts. MethodsA retrospective study was carried out by collecting social media posts in French language written by internet users mentioning their experiences with ICIs between January 2011 and August 2018. Automatic and manual extractions were implemented to create a corpus where domains and subdomains of HRQoL were classified. These annotations were compared with domains covered by 2 standard HRQoL questionnaires, the EORTC QLQ-C30 and the FACT-G. ResultsWe identified 150 users who described their own experience with ICI (89/150, 59.3%) or that of their relative (61/150, 40.7%), with 137 users (91.3%) reporting at least one HRQoL domain in their social media posts. A total of 8 domains and 42 subdomains of HRQoL were identified: Global health (1 subdomain; 115 patients), Symptoms (13; 76), Emotional state (10; 49), Role (7; 22), Physical activity (4; 13), Professional situation (3; 9), Cognitive state (2; 2), and Social state (2; 2). The QLQ-C30 showed a wider global coverage of social media HRQoL subdomains than the FACT-G, 45% (19/42) and 29% (12/42), respectively. For both QLQ-C30 and FACT-G questionnaires, coverage rates were particularly suboptimal for Symptoms (68/123, 55.3% and 72/123, 58.5%, respectively), Emotional state (7/49, 14% and 24/49, 49%, respectively), and Role (17/22, 77% and 15/22, 68%, respectively). ConclusionsMany patients with cancer are using social media to share their experiences with immunotherapy. Collecting and analyzing their spontaneous narratives are helpful to capture and understand their HRQoL in real-world setting. New measures of HRQoL are needed to provide more in-depth evaluation of Symptoms, Emotional state, and Role among patients with cancer treated with immunotherapy.

Published
2020
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3. Digital Gamification to Enhance Vaccine Knowledge and Uptake: Scoping Review

Author

Montagni, Ilaria, Mabchour, Inass, and Tzourio, Christophe

Subjects
Information technology, T58.5-58.64, Public aspects of medicine, RA1-1270
Abstract

BackgroundVaccine hesitancy is a growing threat to population health, and effective interventions are needed to reduce its frequency. Digital gamification is a promising new approach to tackle this public health issue. ObjectiveThe purpose of this scoping review was to assess the amount and quality of outcomes in studies evaluating gamified digital tools created to increase vaccine knowledge and uptake. MethodsWe searched for peer-reviewed articles published between July 2009 and August 2019 in PubMed, Google Scholar, Journal of Medical Internet Research, PsycINFO, PsycARTICLES, Psychology and Behavioral Sciences Collection, and SocINDEX. Studies were coded by author, year of publication, country, journal, research design, sample size and characteristics, type of vaccine, theory used, game content, game modality, gamification element(s), data analysis, type of outcomes, and mean quality score. Outcomes were synthesized through the textual narrative synthesis method. ResultsA total of 7 articles met the inclusion criteria and were critically reviewed. Game modalities and gamification elements were diverse, but role play and a reward system were present in all studies. These articles included a mixture of randomized controlled trials, quasi-experimental studies, and studies comprising quantitative and qualitative measures. The majority of the studies were theory-driven. All the identified gamified digital tools were highly appreciated for their usability and were effective in increasing awareness of vaccine benefits and motivation for vaccine uptake. ConclusionsDespite the relative paucity of studies on this topic, this scoping review suggests that digital gamification has strong potential for increasing vaccination knowledge and, eventually, vaccination coverage.

Published
2020
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4. Exploring Digital Health Use and Opinions of University Students: Field Survey Study

Author

Montagni, Ilaria, Cariou, Tanguy, Feuillet, Tiphaine, Langlois, Emmanuel, and Tzourio, Christophe

Subjects
Information technology, T58.5-58.64, Public aspects of medicine, RA1-1270
Abstract

BackgroundDuring university, students face some potentially serious health risks, and their lifestyle can have a direct effect on health and health behaviors later in life. Concurrently, university students are digital natives having easy access to the internet and new technologies. Digital health interventions offer promising new opportunities for health promotion, disease prevention, and care in this specific population. The description of the current use of and opinions on digital health among university students can inform future digital health strategies and interventions within university settings. ObjectiveThe aim of this exploratory study was to report on university students’ use and opinions regarding information and communication technologies for health and well-being, taking into account sociodemographic and self-rated general and mental health correlates. MethodsThis field survey was conducted from March to April 2017. An informed consent form and a paper questionnaire were given to students aged 18 to 24 years in 4 university campuses in Bordeaux, France. The survey was formulated in 3 sections: (1) sociodemographic characteristics and self-rated general and mental health, (2) information about the use of digital health, and (3) opinions about digital health. Data were analyzed using descriptive statistics and tests of independence. ResultsA total of 59.8% (303/507 females) students completed the questionnaire. Concerning digital health use, 34.9% (174/498) had at least 1 health app mostly for physical activity (49.4%, 86/174) and general health monitoring (41.4%, 72/174,), but only 3.9% (20/507) of students had a wearable device. Almost all (94.8%, 450/476) had searched for Web-based health-related information at least once in the last 12 months. The most sought health-related topics were nutrition (68.1%, 324/476); pain and illnesses (64.5%, 307/476); and stress, anxiety, or depression (51.1%, 243/476). Although Wikipedia (79.7%, 357/448) and general health websites (349/448, 77.9%) were the most consulted sources, students considered institutional or official websites as the most credible sources (309/335, 92.2%). There were significant differences in digital health use by gender, field, and year of study. No statistically significant association was found between digital health use and self-rated general and mental health status. Concerning opinions on digital health, although 94.1% (475/505) of students estimated that today’s digital health cannot replace traditional health services and medical consultations, 44.6% (207/464) of students declared that this could be possible in the future, provided that digital health interventions are promoted by institutional or official entities. ConclusionsUniversity students are largely using the internet for health information seeking, but using less mobile health apps and very few wearable devices. Our data suggest that digital health has the potential for improving health and well-being at the university, especially if digital health interventions take into account students’ profiles, interests, and needs.

Published
2018
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5. A location-scale joint model for studying the link between the time-dependent subject-specific variability of blood pressure and competing events

Author

Courcoul, Léonie, Tzourio, Christophe, Woodward, Mark, Barbieri, Antoine, and Jacqmin-Gadda, Hélène

Subjects
Statistics - Methodology
Abstract

Given the high incidence of cardio and cerebrovascular diseases (CVD), and its association with morbidity and mortality, its prevention is a major public health issue. A high level of blood pressure is a well-known risk factor for these events and an increasing number of studies suggest that blood pressure variability may also be an independent risk factor. However, these studies suffer from significant methodological weaknesses. In this work we propose a new location-scale joint model for the repeated measures of a marker and competing events. This joint model combines a mixed model including a subject-specific and time-dependent residual variance modeled through random effects, and cause-specific proportional intensity models for the competing events. The risk of events may depend simultaneously on the current value of the variance, as well as, the current value and the current slope of the marker trajectory. The model is estimated by maximizing the likelihood function using the Marquardt-Levenberg algorithm. The estimation procedure is implemented in a R-package and is validated through a simulation study. This model is applied to study the association between blood pressure variability and the risk of CVD and death from other causes. Using data from a large clinical trial on the secondary prevention of stroke, we find that the current individual variability of blood pressure is associated with the risk of CVD and death. Moreover, the comparison with a model without heterogeneous variance shows the importance of taking into account this variability in the goodness-of-fit and for dynamic predictions.

Published
2023

9. Identification of circulating proteins associated with general cognitive function among middle-aged and older adults

Author

Tin, Adrienne, Fohner, Alison E, Yang, Qiong, Brody, Jennifer A, Davies, Gail, Yao, Jie, Liu, Dan, Caro, Ilana, Lindbohm, Joni V, Duggan, Michael R, Meirelles, Osorio, Harris, Sarah E, Gudmundsdottir, Valborg, Taylor, Adele M, Henry, Albert, Beiser, Alexa S, Shojaie, Ali, Coors, Annabell, Fitzpatrick, Annette L, Langenberg, Claudia, Satizabal, Claudia L, Sitlani, Colleen M, Wheeler, Eleanor, Tucker-Drob, Elliot M, Bressler, Jan, Coresh, Josef, Bis, Joshua C, Candia, Julián, Jennings, Lori L, Pietzner, Maik, Lathrop, Mark, Lopez, Oscar L, Redmond, Paul, Gerszten, Robert E, Rich, Stephen S, Heckbert, Susan R, Austin, Thomas R, Hughes, Timothy M, Tanaka, Toshiko, Emilsson, Valur, Vasan, Ramachandran S, Guo, Xiuqing, Zhu, Yineng, Tzourio, Christophe, Rotter, Jerome I, Walker, Keenan A, Ferrucci, Luigi, Kivimäki, Mika, Breteler, Monique MB, Cox, Simon R, Debette, Stephanie, Mosley, Thomas H, Gudnason, Vilmundur G, Launer, Lenore J, Psaty, Bruce M, Seshadri, Sudha, and Fornage, Myriam

Subjects
Biochemistry and Cell Biology, Biological Sciences, Brain Disorders, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Aging, Alzheimer's Disease, Clinical Research, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Middle Aged, Humans, Aged, Alzheimer Disease, Cognition, Cognitive Dysfunction, Neurons, Biomarkers, Biological sciences, Biomedical and clinical sciences
Abstract

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p

Published
2023

10. 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

11. Genomic Studies Across the Lifespan Point to Early Mechanisms Determining Subcortical Volumes

Author

Le Grand, Quentin, Satizabal, Claudia L, Sargurupremraj, Muralidharan, Mishra, Aniket, Soumaré, Aicha, Laurent, Alexandre, Crivello, Fabrice, Tsuchida, Ami, Shin, Jean, Macalli, Mélissa, Singh, Baljeet, Beiser, Alexa S, DeCarli, Charles, Fletcher, Evan, Paus, Tomas, Lathrop, Mark, Adams, Hieab HH, Bis, Joshua C, Seshadri, Sudha, Tzourio, Christophe, Mazoyer, Bernard, and Debette, Stéphanie

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Prevention, Aging, Human Genome, Genetics, Neurosciences, Neurodegenerative, Underpinning research, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, Adult, Aged, Aged, 80 and over, Brain, Genomics, Humans, Longevity, Magnetic Resonance Imaging, Organ Size, Dementia, Epidemiology, Life course approach, Subcortical volumes, Biological psychology, Clinical and health psychology
Abstract

BackgroundSubcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration.MethodsUsing large population-based brain imaging datasets across the lifespan (N ≤ 40,628), we aimed to 1) estimate the heritability of subcortical volumes in young (18-35 years), middle (35-65 years), and older (65+ years) age, and their genetic correlation across age groups; 2) identify whether genetic loci associated with subcortical volumes in older persons also show associations in early adulthood, and explore underlying genes using transcriptome-wide association studies; and 3) explore their association with neurological phenotypes.ResultsHeritability of subcortical volumes consistently decreased with increasing age. Genetic risk scores for smaller caudate nucleus, putamen, and hippocampus volume in older adults were associated with smaller volumes in young adults. Individually, 10 loci associated with subcortical volumes in older adults also showed associations in young adults. Within these loci, transcriptome-wide association studies showed that expression of several genes in brain tissues (especially MYLK2 and TUFM) was associated with subcortical volumes in both age groups. One risk variant for smaller caudate nucleus volume (TUFM locus) was associated with lower cognitive performance. Genetically predicted Alzheimer's disease was associated with smaller subcortical volumes in middle and older age.ConclusionsOur findings provide novel insights into the genetic determinants of subcortical volumes across the lifespan. More studies are needed to decipher the underlying biology and clinical impact.

Published
2022

13. Prioritization of Kidney Cell Types Highlights Myofibroblast Cells in Regulating Human Blood Pressure

Author

Evangelou, Evangelos, Warren, Helen R., Gao, He, Ntritsos, Georgios, Dimou, Niki, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G., Jackson, Anne U., Li -Gao, Ruifang, Lin, Wei -Yu, Luan, Jian'an, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M., Zhao, Jing -Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S.F., Farrall, Martin, Menni, Cristina, Morris, Andrew D., Noordam, Raymond, Paré, Guillaume, Poulter, Neil R., Shields, Denis C., Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E., Ayers, Kristin L., Barbieri, Caterina M., Batini, Chiara, Bis, Joshua C., Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I., Bottinger, Erwin P., Braund, Peter S., Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C., Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Francis, Cordell, Heather J., Davies, Gail, de Borst, Martin H., de Geus, Eco J., Deary, Ian J., Deelen, Joris, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcus, Ehret, Georg B., Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A. Mesut, Ferreira, Teresa, Frånberg, Mattias, Franco, Oscar H., Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J., Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B., Harris, Sarah E., Hartman, Catharina A., Havulinna, Aki S., Hicks, Andrew A., Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E., Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo -Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D., Joshi, Peter K., Jousilahti, Pekka, Jukema, J. Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D., Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S., Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Maris, Larson, Marty, Launer, Lenore J., Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C.M., Lin, Li, Lind, Lars, Lindgren, Cecilia M., Liu, YongMei, Loos, Ruth J.F., Lopez, Lorna M., Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P., Morrison, Alanna C., Munson, Peter J., Nalls, Mike A., Nandakumar, Priyanka, Nelson, Christopher P., Niiranen, Teemu, Nolte, Ilja M., Nutile, Teresa, Oldehinkel, Albertine J., Oostra, Ben A., O'Reilly, Paul F., Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W.J.H., Perola, Markus, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P., Nguyen, Quang Tri, Raitakari, Olli T., Rettig, Rainer, Rice, Kenneth, Ridker, Paul M., Ried, Janina S., Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M., Rotter, Jerome I., Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F., Salomaa, Veikko, Samani, Nilesh J., Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V., Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M., Stott, David J., Strachan, David P., Strawbridge, Rona J., Sundström, Johan, Swertz, Morris A., Taylor, Kent D., Teumer, Alexander, Tobin, Martin D., Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G., Vaez, Ahmad, van der Most, Peter J., van Duijn, Cornelia M., Verwoert, Germaine C., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H., Willemsen, Gonneke, Wilson, James F., Wright, Alan F., Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R., Butterworth, Adam S., Chasman, Daniel I., Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M.M., Laakso, Markku, Lakatta, Edward G., Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O., Palmer, Colin N.A., Risch, Lorenz, Scott, Robert A., Scott, Rodney J., Sever, Peter, Spector, Tim D., van der Harst, Pim, Wareham, Nicholas J., Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B., Newton-Cheh, Christopher, Brown, Morris J., Metspalu, Andres, Psaty, Bruce M., Wain, Louise V., Elliott, Paul, Caulfield, Mark J., Ganji-Arjenaki, Mahboube, Kamali, Zoha, Sardari, Soroush, and de Borst, Martin

Published
2024
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14. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Author

Duperron, Marie-Gabrielle, Knol, Maria J., Le Grand, Quentin, Evans, Tavia E., Mishra, Aniket, Tsuchida, Ami, Roshchupkin, Gennady, Konuma, Takahiro, Trégouët, David-Alexandre, Romero, Jose Rafael, Frenzel, Stefan, Luciano, Michelle, Hofer, Edith, Bourgey, Mathieu, Dueker, Nicole D., Delgado, Pilar, Hilal, Saima, Tankard, Rick M., Dubost, Florian, Shin, Jean, Saba, Yasaman, Armstrong, Nicola J., Bordes, Constance, Bastin, Mark E., Beiser, Alexa, Brodaty, Henry, Bülow, Robin, Carrera, Caty, Chen, Christopher, Cheng, Ching-Yu, Deary, Ian J., Gampawar, Piyush G., Himali, Jayandra J., Jiang, Jiyang, Kawaguchi, Takahisa, Li, Shuo, Macalli, Melissa, Marquis, Pascale, Morris, Zoe, Muñoz Maniega, Susana, Miyamoto, Susumu, Okawa, Masakazu, Paradise, Matthew, Parva, Pedram, Rundek, Tatjana, Sargurupremraj, Muralidharan, Schilling, Sabrina, Setoh, Kazuya, Soukarieh, Omar, Tabara, Yasuharu, Teumer, Alexander, Thalamuthu, Anbupalam, Trollor, Julian N., Valdés Hernández, Maria C., Vernooij, Meike W., Völker, Uwe, Wittfeld, Katharina, Wong, Tien Yin, Wright, Margaret J., Zhang, Junyi, Zhao, Wanting, Zhu, Yi-Cheng, Schmidt, Helena, Sachdev, Perminder S., Wen, Wei, Yoshida, Kazumichi, Joutel, Anne, Satizabal, Claudia L., Sacco, Ralph L., Bourque, Guillaume, Lathrop, Mark, Paus, Tomas, Fernandez-Cadenas, Israel, Yang, Qiong, Mazoyer, Bernard, Boutinaud, Philippe, Okada, Yukinori, Grabe, Hans J., Mather, Karen A., Schmidt, Reinhold, Joliot, Marc, Ikram, M. Arfan, Matsuda, Fumihiko, Tzourio, Christophe, Wardlaw, Joanna M., Seshadri, Sudha, Adams, Hieab H. H., and Debette, Stéphanie

Published
2023
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16. Socioeconomic inequalities in dementia risk among a French population-based cohort: quantifying the role of cardiovascular health and vascular events

Author

Letellier, Noémie, Ilango, Sindana D, Mortamais, Marion, Tzourio, Christophe, Gabelle, Audrey, Empana, Jean-Philippe, Samieri, Cécilia, Berr, Claudine, and Benmarhnia, Tarik

Subjects
Epidemiology, Public Health, Health Sciences, Cardiovascular, Prevention, Brain Disorders, Behavioral and Social Science, Dementia, Acquired Cognitive Impairment, Aetiology, 2.3 Psychological, social and economic factors, Reduced Inequalities, Quality Education, Aged, Cardiovascular Diseases, Female, Health Behavior, Health Status Disparities, Health Status Indicators, Humans, Male, Mediation Analysis, Residence Characteristics, Social Class, Social Determinants of Health, Cardiovascular health, Mediation analysis, Socioeconomic status, Social determinants, Public Health and Health Services
Abstract

This study aimed to investigate the role of cardiovascular health (CVH) and vascular events as potential contributors to socioeconomic inequalities in dementia using causal mediation analyses. We used data from the Three-City Cohort, a French population-based study with 12 years of follow-up, with active search of dementia cases and validated diagnosis. Individual socioeconomic status was assessed using education, occupation and income. A CVH score as defined by the American Heart Association and incident vascular events were considered separately as mediators. We performed multi-level Cox proportional and Aalen additive hazard regression models to estimate the total effects of socioeconomic status on dementia risk. To estimate natural direct and indirect effects through CVH and vascular events, we applied two distinct weighting methods to quantify the role of CVH and vascular events: Inverse Odds Ratio Weighting (IORW) and Marginal Structural Models (MSM) respectively. Among 5581 participants, the risk of dementia was higher among participants with primary education (HR 1.60, 95%CI 1.44-1.78), blue-collar workers (HR 1.62, 95%CI 1.43-1.84) and with lower income (HR 1.23, 95%CI 1.09-1.29). Using additive models, 571 (95% CI 288-782) and 634 (95% CI 246-1020) additional cases of dementia per 100 000 person and year were estimated for primary education and blue-collar occupation, respectively. Using IORW, the CVH score mediate the relationship between education or income, and dementia (proportion mediated 17% and 26%, respectively). Yet, considering vascular events as mediator, MSM generated indirect effects that were smaller and more imprecise. Socioeconomic inequalities in dementia risk were observed but marginally explained by CVH or vascular events mediators.

Published
2021

17. 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

18. 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

19. 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, Dementia, Acquired Cognitive Impairment, Aging, Neurosciences, Genetics, Stroke, Brain Disorders, Biotechnology, Clinical Research, Human Genome, Prevention, Aetiology, 2.1 Biological and endogenous factors, Neurological, 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

20. Investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis.

Author

Peters, Ruth, Yasar, Sevil, Anderson, Craig S, Andrews, Shea, Antikainen, Riitta, Arima, Hisatomi, Beckett, Nigel, Beer, Joanne C, Bertens, Anne Suzanne, Booth, Andrew, van Boxtel, Martin, Brayne, Carol, Brodaty, Henry, Carlson, Michelle C, Chalmers, John, Corrada, Maria, DeKosky, Steven, Derby, Carol, Dixon, Roger A, Forette, Françoise, Ganguli, Mary, van Gool, Willem A, Guaita, Antonio, Hever, Ann M, Hogan, David B, Jagger, Carol, Katz, Mindy, Kawas, Claudia, Kehoe, Patrick G, Keinanen-Kiukaanniemi, Sirkka, Kenny, Rose Ann, Köhler, Sebastian, Kunutsor, Setor K, Laukkanen, Jari, Maxwell, Colleen, McFall, G Peggy, van Middelaar, Tessa, Moll van Charante, Eric P, Ng, Tze-Pin, Peters, Jean, Rawtaer, Iris, Richard, Edo, Rockwood, Kenneth, Rydén, Lina, Sachdev, Perminder S, Skoog, Ingmar, Skoog, Johan, Staessen, Jan A, Stephan, Blossom CM, Sebert, Sylvain, Thijs, Lutgarde, Trompet, Stella, Tully, Phillip J, Tzourio, Christophe, Vaccaro, Roberta, Vaaramo, Eeva, Walsh, Erin, Warwick, Jane, and Anstey, Kaarin J

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Trials and Supportive Activities, Aging, Brain Disorders, Clinical Research, Cardiovascular, Dementia, Alzheimer's Disease, Prevention, Neurological, Aged, Aged, 80 and over, Antihypertensive Agents, Cognitive Dysfunction, Female, Humans, Hypertension, Male, Middle Aged, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveHigh blood pressure is one of the main modifiable risk factors for dementia. However, there is conflicting evidence regarding the best antihypertensive class for optimizing cognition. Our objective was to determine whether any particular antihypertensive class was associated with a reduced risk of cognitive decline or dementia using comprehensive meta-analysis including reanalysis of original participant data.MethodsTo identify suitable studies, MEDLINE, Embase, and PsycINFO and preexisting study consortia were searched from inception to December 2017. Authors of prospective longitudinal human studies or trials of antihypertensives were contacted for data sharing and collaboration. Outcome measures were incident dementia or incident cognitive decline (classified using the reliable change index method). Data were separated into mid and late-life (>65 years) and each antihypertensive class was compared to no treatment and to treatment with other antihypertensives. Meta-analysis was used to synthesize data.ResultsOver 50,000 participants from 27 studies were included. Among those aged >65 years, with the exception of diuretics, we found no relationship by class with incident cognitive decline or dementia. Diuretic use was suggestive of benefit in some analyses but results were not consistent across follow-up time, comparator group, and outcome. Limited data precluded meaningful analyses in those ≤65 years of age.ConclusionOur findings, drawn from the current evidence base, support clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals.Clinical trials registrationThe review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454.

Published
2020

21. Association of LIfestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline

Author

Neuffer, Jeanne, primary, Wagner, Maude, additional, Moreno, Elisa, additional, Grand, Quentin Le, additional, Mishra, Aniket, additional, Trégouët, David‐Alexandre, additional, Leffondre, Karen, additional, Proust‐Lima, Cécile, additional, Foubert‐Samier, Alexandra, additional, Berr, Claudine, additional, Tzourio, Christophe, additional, Helmer, Catherine, additional, Debette, Stéphanie, additional, and Samieri, Cécilia, additional

Published
2024
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22. Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia

Author

Sargurupremraj, Muralidharan, primary, Soumaré, Aicha, additional, Bis, Joshua C., additional, Surakka, Ida, additional, Jürgenson, Tuuli, additional, Joly, Pierre, additional, Knol, Maria J., additional, Wang, Ruiqi, additional, Yang, Qiong, additional, Satizabal, Claudia L., additional, Gudjonsson, Alexander, additional, Mishra, Aniket, additional, Bouteloup, Vincent, additional, Phuah, Chia-Ling, additional, van Duijn, Cornelia M., additional, Cruchaga, Carlos, additional, Dufouil, Carole, additional, Chêne, Geneviève, additional, Lopez, Oscar L., additional, Psaty, Bruce M., additional, Tzourio, Christophe, additional, Amouyel, Philippe, additional, Adams, Hieab H., additional, Jacqmin-Gadda, Hélène, additional, Ikram, Mohammad Arfan, additional, Gudnason, Vilmundur, additional, Milani, Lili, additional, Winsvold, Bendik S., additional, Hveem, Kristian, additional, Matthews, Paul M., additional, Longstreth, W. T., additional, Seshadri, Sudha, additional, Launer, Lenore J., additional, and Debette, Stéphanie, additional

Published
2024
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23. 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

24. 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

25. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Turman, Constance, Germain, Marine, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, Kraft, Peter, Hansen, John‐Bjarne, Heit, John A, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Pulit, Sara L, Rannikmäe, Kristiina, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Rost, Natalia S, Rothwell, Peter M, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Published
2022
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27. Brain artery diameters and risk of dementia and stroke

Author

Melgarejo, Jesus D., Gurel, Kursat, Compton, Cassidy Rose, Liu, Minghua, Guzman, Vanessa, Assuras, Stephanie, Levin, Bonnie E., Elkind, Mitchell S.V., Ikram, M. Kamran, Kavousi, Maryam, Ikram, M. Arfan, Wright, Clinton, Crivello, Fabrice, Laurent, Alexandre, Tzourio, Christophe, Vernooij, Meike W., Rundek, Tatjana, Zhang, Zhen Yu, Bos, Daniel, Gutierrez, Jose, Melgarejo, Jesus D., Gurel, Kursat, Compton, Cassidy Rose, Liu, Minghua, Guzman, Vanessa, Assuras, Stephanie, Levin, Bonnie E., Elkind, Mitchell S.V., Ikram, M. Kamran, Kavousi, Maryam, Ikram, M. Arfan, Wright, Clinton, Crivello, Fabrice, Laurent, Alexandre, Tzourio, Christophe, Vernooij, Meike W., Rundek, Tatjana, Zhang, Zhen Yu, Bos, Daniel, and Gutierrez, Jose

Abstract

INTRODUCTION: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images.METHODS: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke. RESULT: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13–2.68) and 1.48 (95% CI, 1.12–1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04–2.42) for overall arteries and 2.11 (95% CI, 1.45–3.08) for basilar artery diameters > 95th percentile. DISCUSSION: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke.

Published
2024

28. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author

Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J.E., Veldink, Jan H., Ruigrok, Ynte M., Hege Aamodt, Anne, Heidi Skogholt, Anne, Brumpton, Ben M, Willer, Cristen J, Sandset, Else C, Kristoffersen, Espen S, Ellekjær, Hanne, Heuch, Ingrid, Nielsen, Jonas B, Hagen, Knut, Hveem, Kristian, Fritsche, Lars G, Thomas, Laurent F, Pedersen, Linda M, Gabrielsen, Maiken E, Holmen, Oddgeir L, Børte, Sigrid, Zhou, Wei, Abboud, Shérine, Pandolfo, Massimo, Thijs, Vincent, Leys, Didier, Bodenant, Marie, Louillet, Fabien, Touzé, Emmanuel, Mas, Jean-Louis, Samson, Yves, Leder, Sara, Léger, Anne, Deltour, Sandrine, Crozier, Sophie, Méresse, Isabelle, Canaple, Sandrine, Godefroy, Olivier, Giroud, Maurice, Béjot, Yannick, Decavel, Pierre, Medeiros, Elizabeth, Montiel, Paola, Moulin, Thierry, Vuillier, Fabrice, Dallongeville, Jean, Metso, Antti J, Metso, Tiina, Tatlisumak, Turgut, Grond-Ginsbach, Caspar, Lichy, Christoph, Kloss, Manja, Werner, Inge, Arnold, Marie-Luise, Dos Santos, Michael, Grau, Armin, Dichgans, Martin, Thomas-Feles, Constanze, Weber, Ralf, Brandt, Tobias, Pezzini, Alessandro, De Giuli, Valeria, Caria, Filomena, Poli, Loris, Padovani, Alessandro, Bersano, Anna, Lanfranconi, Silvia, Beretta, Simone, Ferrarese, Carlo, Giacolone, Giacomo, Paolucci, Stefano, Lyrer, Philippe, Engelter, Stefan, Fluri, Felix, Hatz, Florian, Gisler, Dominique, Bonati, Leo, Gensicke, Henrik, Amort, Margareth, Markus, Hugh, Majersik, Jennifer, Worrall, Bradford, Southerland, Andrew, Cole, John, Kittner, Steven, Evangelou, Evangelos, Warren, Helen R, Gao, He, Ntritsos, Georgios, Dimou, Niki, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian’an, Mangino, Massimo, Oldmeadow, Christopher, Peter Prins, Bram, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Connell, John, de Mutsert, Renée, Doney, Alex SF, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Francis, Cordell, Heather J, Davies, Gail, de Borst, Martin H, de Geus, Eco J, Deary, Ian J, Deelen, Joris, Del Greco M, Fabiola, Yusuf Demirkale, Cumhur, Dörr, Marcus, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Mesut Erzurumluoglu, A, Ferreira, Teresa, Frånberg, Mattias, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Wouter Jukema, J, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Maris, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David CM, Lin, Li, Lind, Lars, Lindgren, Cecilia M, Liu, YongMei, Loos, Ruth JF, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O’Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, WJH Penninx, Brenda, Perola, Markus, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Tri Nguyen, Quang, Raitakari, Olli T, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna MM, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin NA, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andres, Psaty, Bruce M., Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Gormley, Padhraig, Anttila, Verneri, Palta, Priit, Esko, Tonu, Pers, Tune H, Farh, Kai-How, Cuenca-Leon, Ester, Muona, Mikko, Furlotte, Nicholas A, Kurth, Tobias, Ingason, Andres, McMahon, George, Ligthart, Lannie, Terwindt, Gisela M, Kallela, Mikko, Freilinger, Tobias M, Ran, Caroline, Gordon, Scott G, Stam, Anine H, Steinberg, Stacy, Borck, Guntram, Koiranen, Markku, Quaye, Lydia, Adams, Hieab H H, Lehtimäki, Terho, Sarin, Antti-Pekka, Wedenoja, Juho, Hinds, David A, Buring, Julie E, Schürks, Markus, Ridker, Paul M, Gudlaug Hrafnsdottir, Maria, Stefansson, Hreinn, Ring, Susan M, Hottenga, Jouke-Jan, Penninx, Brenda W J H, Färkkilä, Markus, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Malik, Rainer, Heath, Andrew C, Madden, Pamela A F, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Kals, Mart, Mägi, Reedik, Pärn, Kalle, Hämäläinen, Eija, Huang, Hailiang, Byrnes, Andrea E, Franke, Lude, Huang, Jie, Stergiakouli, Evie, Lee, Phil H, Sandor, Cynthia, Webber, Caleb, Cader, Zameel, Muller-Myhsok, Bertram, Schreiber, Stefan, Meitinger, Thomas, Eriksson, Johan G, Salomaa, Veikko, Heikkilä, Kauko, Loehrer, Elizabeth, Uitterlinden, Andre G, Hofman, Albert, van Duijn, Cornelia M, Cherkas, Lynn, Pedersen, Linda M, Stubhaug, Audun, Nielsen, Christopher S, Männikkö, Minna, Mihailov, Evelin, Milani, Lili, Göbel, Hartmut, Esserlind, Ann-Louise, Francke Christensen, Anne, Folkmann Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Aromaa, Arpo J, Raitakari, Olli, Arfan Ikram, M, Spector, Tim, Järvelin, Marjo-Riitta, Metspalu, Andres, Kubisch, Christian, Strachan, David P, Ferrari, Michel D, Belin, Andrea C, Dichgans, Martin, Wessman, Maija, van den Maagdenberg, Arn M J M, Boomsma, Dorret I, Davey Smith, George, Stefansson, Kari, Eriksson, Nicholas, Daly, Mark J, Neale, Benjamin M, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Palotie, Aarno, Akiyama, Masato, Alg, Varinder S., Børte, Sigrid, Broderick, Joseph P., Brumpton, Ben M., Dauvillier, Jérôme, Desal, Hubert, Dina, Christian, Friedrich, Christoph M., Gaál-Paavola, Emília I., Gentric, Jean-Christophe, Hirsch, Sven, Hostettler, Isabel C., Houlden, Henry, Hveem, Kristian, Jääskeläinen, Juha E., Johnsen, Marianne Bakke, Li, Liming, Lin, Kuang, Lindgren, Antti, Martin, Olivier, Matsuda, Koichi, Millwood, Iona Y., Naggara, Olivier, Niemelä, Mika, Pera, Joanna, Redon, Richard, Rouleau, Guy A., Sandvei, Marie Søfteland, Schilling, Sabine, Shotar, Eimad, Slowik, Agnieszka, Terao, Chikashi, Verschuren, W. M. Monique, Walters, Robin G., Werring, David J., Willer, Cristen J., Woo, Daniel, Worrall, Bradford B., and Zhou, Sirui

Published
2023
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29. Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases.

Author

Chen, Jason A, Chen, Zhongbo, Won, Hyejung, Huang, Alden Y, Lowe, Jennifer K, Wojta, Kevin, Yokoyama, Jennifer S, Bensimon, Gilbert, Leigh, P Nigel, Payan, Christine, Shatunov, Aleksey, Jones, Ashley R, Lewis, Cathryn M, Deloukas, Panagiotis, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-Francois, Ludolph, Albert, Boxer, Adam L, Bronstein, Jeff M, Al-Chalabi, Ammar, Geschwind, Daniel H, and Coppola, Giovanni

Subjects
Humans, Supranuclear Palsy, Progressive, Neurodegenerative Diseases, Genetic Predisposition to Disease, Genotype, Polymorphism, Single Nucleotide, Female, Male, Genome-Wide Association Study, Genome-wide association study, Neurodegeneration, Progressive supranuclear palsy, Supranuclear Palsy, Progressive, Polymorphism, Single Nucleotide, Prevention, Clinical Trials and Supportive Activities, Neurodegenerative, Rare Diseases, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Neurological, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.MethodsWe conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry.ResultsWe identified 5 associated loci at a genome-wide significance threshold P

Published
2018

30. Prioritization of Kidney Cell Types Highlights Myofibroblast Cells in Regulating Human Blood Pressure

Author

Ganji-Arjenaki, Mahboube, primary, Kamali, Zoha, additional, Evangelou, Evangelos, additional, Warren, Helen R., additional, Gao, He, additional, Ntritsos, Georgios, additional, Dimou, Niki, additional, Esko, Tonu, additional, Mägi, Reedik, additional, Milani, Lili, additional, Almgren, Peter, additional, Boutin, Thibaud, additional, Debette, Stéphanie, additional, Ding, Jun, additional, Giulianini, Franco, additional, Holliday, Elizabeth G., additional, Jackson, Anne U., additional, Li -Gao, Ruifang, additional, Lin, Wei -Yu, additional, Luan, Jian'an, additional, Mangino, Massimo, additional, Oldmeadow, Christopher, additional, Prins, Bram Peter, additional, Qian, Yong, additional, Sargurupremraj, Muralidharan, additional, Shah, Nabi, additional, Surendran, Praveen, additional, Thériault, Sébastien, additional, Verweij, Niek, additional, Willems, Sara M., additional, Zhao, Jing -Hua, additional, Amouyel, Philippe, additional, Connell, John, additional, de Mutsert, Renée, additional, Doney, Alex S.F., additional, Farrall, Martin, additional, Menni, Cristina, additional, Morris, Andrew D., additional, Noordam, Raymond, additional, Paré, Guillaume, additional, Poulter, Neil R., additional, Shields, Denis C., additional, Stanton, Alice, additional, Thom, Simon, additional, Abecasis, Gonçalo, additional, Amin, Najaf, additional, Arking, Dan E., additional, Ayers, Kristin L., additional, Barbieri, Caterina M., additional, Batini, Chiara, additional, Bis, Joshua C., additional, Blake, Tineka, additional, Bochud, Murielle, additional, Boehnke, Michael, additional, Boerwinkle, Eric, additional, Boomsma, Dorret I., additional, Bottinger, Erwin P., additional, Braund, Peter S., additional, Brumat, Marco, additional, Campbell, Archie, additional, Campbell, Harry, additional, Chakravarti, Aravinda, additional, Chambers, John C., additional, Chauhan, Ganesh, additional, Ciullo, Marina, additional, Cocca, Massimiliano, additional, Collins, Francis, additional, Cordell, Heather J., additional, Davies, Gail, additional, de Borst, Martin H., additional, de Geus, Eco J., additional, Deary, Ian J., additional, Deelen, Joris, additional, Del Greco M, Fabiola, additional, Demirkale, Cumhur Yusuf, additional, Dörr, Marcus, additional, Ehret, Georg B., additional, Elosua, Roberto, additional, Enroth, Stefan, additional, Erzurumluoglu, A. Mesut, additional, Ferreira, Teresa, additional, Frånberg, Mattias, additional, Franco, Oscar H., additional, Gandin, Ilaria, additional, Gasparini, Paolo, additional, Giedraitis, Vilmantas, additional, Gieger, Christian, additional, Girotto, Giorgia, additional, Goel, Anuj, additional, Gow, Alan J., additional, Gudnason, Vilmundur, additional, Guo, Xiuqing, additional, Gyllensten, Ulf, additional, Hamsten, Anders, additional, Harris, Tamara B., additional, Harris, Sarah E., additional, Hartman, Catharina A., additional, Havulinna, Aki S., additional, Hicks, Andrew A., additional, Hofer, Edith, additional, Hofman, Albert, additional, Hottenga, Jouke-Jan, additional, Huffman, Jennifer E., additional, Hwang, Shih-Jen, additional, Ingelsson, Erik, additional, James, Alan, additional, Jansen, Rick, additional, Jarvelin, Marjo -Riitta, additional, Joehanes, Roby, additional, Johansson, Åsa, additional, Johnson, Andrew D., additional, Joshi, Peter K., additional, Jousilahti, Pekka, additional, Jukema, J. Wouter, additional, Jula, Antti, additional, Kähönen, Mika, additional, Kathiresan, Sekar, additional, Keavney, Bernard D., additional, Khaw, Kay-Tee, additional, Knekt, Paul, additional, Knight, Joanne, additional, Kolcic, Ivana, additional, Kooner, Jaspal S., additional, Koskinen, Seppo, additional, Kristiansson, Kati, additional, Kutalik, Zoltan, additional, Laan, Maris, additional, Larson, Marty, additional, Launer, Lenore J., additional, Lehne, Benjamin, additional, Lehtimäki, Terho, additional, Liewald, David C.M., additional, Lin, Li, additional, Lind, Lars, additional, Lindgren, Cecilia M., additional, Liu, YongMei, additional, Loos, Ruth J.F., additional, Lopez, Lorna M., additional, Lu, Yingchang, additional, Lyytikäinen, Leo-Pekka, additional, Mahajan, Anubha, additional, Mamasoula, Chrysovalanto, additional, Marrugat, Jaume, additional, Marten, Jonathan, additional, Milaneschi, Yuri, additional, Morgan, Anna, additional, Morris, Andrew P., additional, Morrison, Alanna C., additional, Munson, Peter J., additional, Nalls, Mike A., additional, Nandakumar, Priyanka, additional, Nelson, Christopher P., additional, Niiranen, Teemu, additional, Nolte, Ilja M., additional, Nutile, Teresa, additional, Oldehinkel, Albertine J., additional, Oostra, Ben A., additional, O'Reilly, Paul F., additional, Org, Elin, additional, Padmanabhan, Sandosh, additional, Palmas, Walter, additional, Palotie, Aarno, additional, Pattie, Alison, additional, Penninx, Brenda W.J.H., additional, Perola, Markus, additional, Peters, Annette, additional, Polasek, Ozren, additional, Pramstaller, Peter P., additional, Nguyen, Quang Tri, additional, Raitakari, Olli T., additional, Rettig, Rainer, additional, Rice, Kenneth, additional, Ridker, Paul M., additional, Ried, Janina S., additional, Riese, Harriëtte, additional, Ripatti, Samuli, additional, Robino, Antonietta, additional, Rose, Lynda M., additional, Rotter, Jerome I., additional, Rudan, Igor, additional, Ruggiero, Daniela, additional, Saba, Yasaman, additional, Sala, Cinzia F., additional, Salomaa, Veikko, additional, Samani, Nilesh J., additional, Sarin, Antti-Pekka, additional, Schmidt, Reinhold, additional, Schmidt, Helena, additional, Shrine, Nick, additional, Siscovick, David, additional, Smith, Albert V., additional, Snieder, Harold, additional, Sõber, Siim, additional, Sorice, Rossella, additional, Starr, John M., additional, Stott, David J., additional, Strachan, David P., additional, Strawbridge, Rona J., additional, Sundström, Johan, additional, Swertz, Morris A., additional, Taylor, Kent D., additional, Teumer, Alexander, additional, Tobin, Martin D., additional, Tomaszewski, Maciej, additional, Toniolo, Daniela, additional, Traglia, Michela, additional, Trompet, Stella, additional, Tuomilehto, Jaakko, additional, Tzourio, Christophe, additional, Uitterlinden, André G., additional, Vaez, Ahmad, additional, van der Most, Peter J., additional, van Duijn, Cornelia M., additional, Verwoert, Germaine C., additional, Vitart, Veronique, additional, Völker, Uwe, additional, Vollenweider, Peter, additional, Vuckovic, Dragana, additional, Watkins, Hugh, additional, Wild, Sarah H., additional, Willemsen, Gonneke, additional, Wilson, James F., additional, Wright, Alan F., additional, Yao, Jie, additional, Zemunik, Tatijana, additional, Zhang, Weihua, additional, Attia, John R., additional, Butterworth, Adam S., additional, Chasman, Daniel I., additional, Conen, David, additional, Cucca, Francesco, additional, Danesh, John, additional, Hayward, Caroline, additional, Howson, Joanna M.M., additional, Laakso, Markku, additional, Lakatta, Edward G., additional, Langenberg, Claudia, additional, Melander, Olle, additional, Mook-Kanamori, Dennis O., additional, Palmer, Colin N.A., additional, Risch, Lorenz, additional, Scott, Robert A., additional, Scott, Rodney J., additional, Sever, Peter, additional, Spector, Tim D., additional, van der Harst, Pim, additional, Wareham, Nicholas J., additional, Zeggini, Eleftheria, additional, Levy, Daniel, additional, Munroe, Patricia B., additional, Newton-Cheh, Christopher, additional, Brown, Morris J., additional, Metspalu, Andres, additional, Psaty, Bruce M., additional, Wain, Louise V., additional, Elliott, Paul, additional, Caulfield, Mark J., additional, Sardari, Soroush, additional, and de Borst, Martin, additional

Published
2024
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32. Brain artery diameters and risk of dementia and stroke

Author

Melgarejo, Jesus D., primary, Gurel, Kursat, additional, Compton, Cassidy Rose, additional, Liu, Minghua, additional, Guzman, Vanessa, additional, Assuras, Stephanie, additional, Levin, Bonnie E., additional, Elkind, Mitchell S. V., additional, Ikram, M. Kamran, additional, Kavousi, Maryam, additional, Ikram, M. Arfan, additional, Wright, Clinton, additional, Crivello, Fabrice, additional, Laurent, Alexandre, additional, Tzourio, Christophe, additional, Vernooij, Meike W., additional, Rundek, Tatjana, additional, Zhang, Zhen‐Yu, additional, Bos, Daniel, additional, and Gutierrez, Jose, additional

Published
2024
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33. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Author

van Rheenen, Wouter, Shatunov, Aleksey, Dekker, Annelot M, McLaughlin, Russell L, Diekstra, Frank P, Pulit, Sara L, van der Spek, Rick AA, Võsa, Urmo, de Jong, Simone, Robinson, Matthew R, Yang, Jian, Fogh, Isabella, van Doormaal, Perry Tc, Tazelaar, Gijs HP, Koppers, Max, Blokhuis, Anna M, Sproviero, William, Jones, Ashley R, Kenna, Kevin P, van Eijk, Kristel R, Harschnitz, Oliver, Schellevis, Raymond D, Brands, William J, Medic, Jelena, Menelaou, Androniki, Vajda, Alice, Ticozzi, Nicola, Lin, Kuang, Rogelj, Boris, Vrabec, Katarina, Ravnik-Glavač, Metka, Koritnik, Blaž, Zidar, Janez, Leonardis, Lea, Grošelj, Leja Dolenc, Millecamps, Stéphanie, Salachas, François, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S, Rojas-García, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E, Shaw, Pamela J, Hardy, John, Orrell, Richard W, Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Topp, Simon, Petri, Susanne, Abdulla, Susanne, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Ophoff, Roel A, Staats, Kim A, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M, Trojanowski, John Q, Elman, Lauren, McCluskey, Leo, Basak, A Nazli, Tunca, Ceren, Hamzeiy, Hamid, Parman, Yesim, Meitinger, Thomas, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Andres, Christian R, Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine AM, Saker-Delye, Safaa, Dürr, Alexandra, Wood, Nicholas W, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-François, Uitterlinden, Andre G, Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, and Blauw, Hylke M

Subjects
PARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group, Humans, Amyotrophic Lateral Sclerosis, Genetic Predisposition to Disease, Proteins, Cytoskeletal Proteins, Myelin Proteins, Case-Control Studies, Cohort Studies, Mutation, Netherlands, Munc18 Proteins, Genome-Wide Association Study, Neurosciences, Rare Diseases, Brain Disorders, Biotechnology, Prevention, Human Genome, Neurodegenerative, Genetics, ALS, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Published
2016

35. White Matter Lesion Progression

Author

Hofer, Edith, Cavalieri, Margherita, Bis, Joshua C, DeCarli, Charles, Fornage, Myriam, Sigurdsson, Sigurdur, Srikanth, Velandai, Trompet, Stella, Verhaaren, Benjamin FJ, Wolf, Christiane, Yang, Qiong, Adams, Hieab HH, Amouyel, Philippe, Beiser, Alexa, Buckley, Brendan M, Callisaya, Michele, Chauhan, Ganesh, de Craen, Anton JM, Dufouil, Carole, van Duijn, Cornelia M, Ford, Ian, Freudenberger, Paul, Gottesman, Rebecca F, Gudnason, Vilmundur, Heiss, Gerardo, Hofman, Albert, Lumley, Thomas, Martinez, Oliver, Mazoyer, Bernard, Moran, Chris, Niessen, Wiro J, Phan, Thanh, Psaty, Bruce M, Satizabal, Claudia L, Sattar, Naveed, Schilling, Sabrina, Shibata, Dean K, Slagboom, P Eline, Smith, Albert, Stott, David J, Taylor, Kent D, Thomson, Russell, Töglhofer, Anna M, Tzourio, Christophe, van Buchem, Mark, Wang, Jing, Westendorp, Rudi GJ, Windham, B Gwen, Vernooij, Meike W, Zijdenbos, Alex, Beare, Richard, Debette, Stéphanie, Ikram, M Arfan, Jukema, J Wouter, Launer, Lenore J, Longstreth, WT, Mosley, Thomas H, Seshadri, Sudha, Schmidt, Helena, and Schmidt, Reinhold

Subjects
Aging, Clinical Research, Genetics, Human Genome, Prevention, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Cohort Studies, Disease Progression, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Leukoencephalopathies, Male, Middle Aged, Prospective Studies, White Matter, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, aging, biological factors, cerebral small vessel diseases, magnetic resonance imaging, white matter lesions, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

Background and purposeWhite matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.MethodsHeritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.ResultsA total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P

Published
2015

39. The genetic history of France

Author

Saint Pierre, Aude, Giemza, Joanna, Alves, Isabel, Karakachoff, Matilde, Gaudin, Marinna, Amouyel, Philippe, Dartigues, Jean-François, Tzourio, Christophe, Monteil, Martial, Galan, Pilar, Hercberg, Serge, Mathieson, Iain, Redon, Richard, Génin, Emmanuelle, and Dina, Christian

Published
2020
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40. Association of Alzheimer's disease GWAS loci with MRI markers of brain aging

Author

Chauhan, Ganesh, Adams, Hieab HH, Bis, Joshua C, Weinstein, Galit, Yu, Lei, Töglhofer, Anna Maria, Smith, Albert Vernon, van der Lee, Sven J, Gottesman, Rebecca F, Thomson, Russell, Wang, Jing, Yang, Qiong, Niessen, Wiro J, Lopez, Oscar L, Becker, James T, Phan, Thanh G, Beare, Richard J, Arfanakis, Konstantinos, Fleischman, Debra, Vernooij, Meike W, Mazoyer, Bernard, Schmidt, Helena, Srikanth, Velandai, Knopman, David S, Jack, Clifford R, Amouyel, Philippe, Hofman, Albert, DeCarli, Charles, Tzourio, Christophe, van Duijn, Cornelia M, Bennett, David A, Schmidt, Reinhold, Longstreth, William T, Mosley, Thomas H, Fornage, Myriam, Launer, Lenore J, Seshadri, Sudha, Ikram, M Arfan, and Debette, Stephanie

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Clinical Research, Prevention, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Aging, Acquired Cognitive Impairment, Genetics, Human Genome, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, Neurological, Alleles, Alzheimer Disease, Apolipoproteins E, Brain, Female, Genome-Wide Association Study, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Organ Size, Polymorphism, Single Nucleotide, Risk, Sialic Acid Binding Ig-like Lectin 3, Alzheimer, MRI-Markers, Genetic risk score, GWAS, Hippocampal volume, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

Published
2015

41. Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

Author

Verhaaren, Benjamin FJ, Debette, Stéphanie, Bis, Joshua C, Smith, Jennifer A, Ikram, M Kamran, Adams, Hieab H, Beecham, Ashley H, Rajan, Kumar B, Lopez, Lorna M, Barral, Sandra, van Buchem, Mark A, van der Grond, Jeroen, Smith, Albert V, Hegenscheid, Katrin, Aggarwal, Neelum T, de Andrade, Mariza, Atkinson, Elizabeth J, Beekman, Marian, Beiser, Alexa S, Blanton, Susan H, Boerwinkle, Eric, Brickman, Adam M, Bryan, R Nick, Chauhan, Ganesh, Chen, Christopher PLH, Chouraki, Vincent, de Craen, Anton JM, Crivello, Fabrice, Deary, Ian J, Deelen, Joris, De Jager, Philip L, Dufouil, Carole, Elkind, Mitchell SV, Evans, Denis A, Freudenberger, Paul, Gottesman, Rebecca F, Guðnason, Vilmundur, Habes, Mohamad, Heckbert, Susan R, Heiss, Gerardo, Hilal, Saima, Hofer, Edith, Hofman, Albert, Ibrahim-Verbaas, Carla A, Knopman, David S, Lewis, Cora E, Liao, Jiemin, Liewald, David CM, Luciano, Michelle, van der Lugt, Aad, Martinez, Oliver O, Mayeux, Richard, Mazoyer, Bernard, Nalls, Mike, Nauck, Matthias, Niessen, Wiro J, Oostra, Ben A, Psaty, Bruce M, Rice, Kenneth M, Rotter, Jerome I, von Sarnowski, Bettina, Schmidt, Helena, Schreiner, Pamela J, Schuur, Maaike, Sidney, Stephen S, Sigurdsson, Sigurdur, Slagboom, P Eline, Stott, David JM, van Swieten, John C, Teumer, Alexander, Töglhofer, Anna Maria, Traylor, Matthew, Trompet, Stella, Turner, Stephen T, Tzourio, Christophe, Uh, Hae-Won, Uitterlinden, André G, Vernooij, Meike W, Wang, Jing J, Wong, Tien Y, Wardlaw, Joanna M, Windham, B Gwen, Wittfeld, Katharina, Wolf, Christiane, Wright, Clinton B, Yang, Qiong, Zhao, Wei, Zijdenbos, Alex, Jukema, J Wouter, Sacco, Ralph L, Kardia, Sharon LR, Amouyel, Philippe, Mosley, Thomas H, Longstreth, WT, DeCarli, Charles C, van Duijn, Cornelia M, Schmidt, Reinhold, Launer, Lenore J, Grabe, Hans J, and Seshadri, Sudha S

Subjects
Aging, Brain Disorders, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biotechnology, Human Genome, Genetics, Acquired Cognitive Impairment, Clinical Research, Dementia, Alzheimer's Disease, Prevention, Stroke, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Chromosomes, Human, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Models, Genetic, Racial Groups, White Matter, cerebral small vessel diseases, cerebrovascular disorders, genome-wide association study, hypertension, leukoencephalopathies, polymorphisms, single nucleotide, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology
Abstract

BackgroundThe burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.Methods and resultsWe included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).ConclusionsWe identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

Published
2015

43. Association Between Blood Pressure Variability With Dementia and Cognitive Impairment: A Systematic Review and Meta-Analysis

Author

de Heus, Rianne A.A., Tzourio, Christophe, Lee, Emily Jo Lynn, Opozda, Melissa, Vincent, Andrew D., Anstey, Kaarin J., Hofman, Albert, Kario, Kazuomi, Lattanzi, Simona, Launer, Lenore J., Ma, Yuan, Mahajan, Rajiv, Mooijaart, Simon P., Nagai, Michiaki, Peters, Ruth, Turnbull, Deborah, Yano, Yuichiro, Claassen, Jurgen A.H.R., and Tully, Phillip J.

Published
2021
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44. Early detection of white matter hyperintensities using SHIVA‐WMH detector.

Author

Tsuchida, Ami, Boutinaud, Philippe, Verrecchia, Violaine, Tzourio, Christophe, Debette, Stéphanie, and Joliot, Marc

Subjects
CEREBRAL small vessel diseases, WHITE matter (Nerve tissue), LACUNAR stroke, MIDDLE-aged persons, OLDER people, OLDER patients
Abstract

White matter hyperintensities (WMHs) are well‐established markers of cerebral small vessel disease, and are associated with an increased risk of stroke, dementia, and mortality. Although their prevalence increases with age, small and punctate WMHs have been reported with surprisingly high frequency even in young, neurologically asymptomatic adults. However, most automated methods to segment WMH published to date are not optimized for detecting small and sparse WMH. Here we present the SHIVA‐WMH tool, a deep‐learning (DL)‐based automatic WMH segmentation tool that has been trained with manual segmentations of WMH in a wide range of WMH severity. We show that it is able to detect WMH with high efficiency in subjects with only small punctate WMH as well as in subjects with large WMHs (i.e., with confluency) in evaluation datasets from three distinct databases: magnetic resonance imaging‐Share consisting of young university students, MICCAI 2017 WMH challenge dataset consisting of older patients from memory clinics, and UK Biobank with community‐dwelling middle‐aged and older adults. Across these three cohorts with a wide‐ranging WMH load, our tool achieved voxel‐level and individual lesion cluster‐level Dice scores of 0.66 and 0.71, respectively, which were higher than for three reference tools tested: the lesion prediction algorithm implemented in the lesion segmentation toolbox (LPA: Schmidt), PGS tool, a DL‐based algorithm and the current winner of the MICCAI 2017 WMH challenge (Park et al.), and HyperMapper tool (Mojiri Forooshani et al.), another DL‐based method with high reported performance in subjects with mild WMH burden. Our tool is publicly and openly available to the research community to facilitate investigations of WMH across a wide range of severity in other cohorts, and to contribute to our understanding of the emergence and progression of WMH. [ABSTRACT FROM AUTHOR]

Published
2024
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48. Brain MRI markers and dropout in a longitudinal study of cognitive aging

Author

Glymour, M Maria, Chêne, Geneviève, Tzourio, Christophe, and Dufouil, Carole

Subjects
Acquired Cognitive Impairment, Neurosciences, Basic Behavioral and Social Science, Clinical Research, Dementia, Aging, Brain Disorders, Neurodegenerative, Biomedical Imaging, Behavioral and Social Science, Neurological, Aged, Biomarkers, Brain, Cognition Disorders, Female, France, Humans, Interview, Psychological, Leukoencephalopathies, Longitudinal Studies, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Patient Dropouts, Predictive Value of Tests, Prospective Studies, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveLongitudinal studies of dementia rely on the assumption that individuals who drop out are comparable to those who remain in the study, adjusting for measured covariates. Existing methods to handle dropouts account for differences based on past health and cognitive measures. We assess whether such adjustments fully account for differences in future dementia risk.MethodsAmong Three-City Study participants in Dijon, France, with 1 (n = 1,633) or 2 (n = 1,168) brain MRI scans, we tested whether white matter lesion volume (WMLV), hippocampal volume, or brain CSF volume predicted dropout ("unable to contact" or "refused interview") in repeated-measures logistic regression with up to 4 follow-ups (average 3.5 waves). Using linear regression, we also estimated differences in MRI volumes and MRI changes by subsequent dropout status and estimated plausible ranges for selective attrition bias based on these associations. Models were adjusted for demographic, health, and cognitive score covariates.ResultsBaseline greater WMLV predicted increased odds of dropping out (adjusted odds ratio = 1.71; 95% confidence interval [CI] 1.20-2.43). Among participants with 2 MRI scans, individuals who subsequently dropped out had significantly worse declines in hippocampal volume (-0.30 SD difference; 95% CI -0.43 to -0.17) between the first and second MRI scans.ConclusionsHigher future dementia risk, indicated by worse past brain MRI findings, predicted future study dropout. Adjustment for selective attrition, based on MRI markers when available, may help reduce bias in estimates of dementia incidence and improve research on dementia risk factors. MRI findings may also help prospectively identify cohort members at elevated risk of attrition.

Published
2012

50. ASSOCIATION BETWEEN BLOOD PRESSURE VARIABILITY WITH DEMENTIA AND COGNITIVE IMPAIRMENT: A SYSTEMATIC REVIEW AND META-ANALYSIS

Author

de Heus, RianRianne, Tzourio, Christophe, Lee, Emily, Opozda, Melissa, Vincent, Andrew, Anstey, Kaarin, Hofman, Albert, Kario, Kazuomi, Lattanzi, Simona, Launer, Lenore, Ma, Yuan, Mahajan, Rajiv, Mooijaart, Simon, Nagai, Michiaki, Peters, Ruth, Turnbull, Deborah, Yano, Yuichiro, Claa, Jurgen, ssen, Claassen, Jurgen, and Tully, Philip

Published
2024
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