Author
Wouter van Rheenen
Bio: Wouter van Rheenen is an academic researcher from Utrecht University. The author has contributed to research in topics: Genome-wide association study & Project MinE. The author has an hindex of 8, co-authored 12 publications receiving 162 citations.
Papers
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Utrecht University1, Geneva College2, University of Geneva3, University of Nantes4, Technische Universität München5, University College London6, University of Tokyo7, Kyushu University8, Clinical Trial Service Unit9, University of Oxford10, Peking University11, Montreal Neurological Institute and Hospital12, McGill University13, University of Edinburgh14, Paris Descartes University15, Norwegian University of Science and Technology16, Oslo University Hospital17, University of Oslo18, University of Michigan19, Zürcher Fachhochschule20, Swiss Institute of Bioinformatics21, University of Otago22, University of Leicester23, National Institute for Health Research24, University of California, San Francisco25, South London and Maudsley NHS Foundation Trust26, King's College London27, Kaiser Permanente28, Radboud University Nijmegen29, Ludwig Maximilian University of Munich30, University of Bordeaux31, University of Gothenburg32, Lille University of Science and Technology33, University of Virginia34, Jagiellonian University Medical College35, University of Helsinki36, University of Eastern Finland37, University of Cincinnati Academic Health Center38
TL;DR: A cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry discovered 17 risk loci, 11 of which are new, which reveal a polygenic architecture and explain over half of the disease heritability.
Abstract: Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
127 citations
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Wouter van Rheenen1, Rick A.A. van der Spek1, Mark K Bakker1, Joke J.F.A. van Vugt1 +209 more•Institutions (82)
TL;DR: All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
110 citations
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TL;DR: The Project MinE data browser (databrowser.com) is presented, a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4366 ALS cases and 1832 matched controls.
Abstract: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting one in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through ...
56 citations
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TL;DR: An R tool is provided to calculate genetic parameters from epidemiological parameters and vice versa to discuss how the single nucleotide polymorphism-based estimates of heritability and genetic correlation relate to those estimated from family records.
49 citations
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TL;DR: It is shown that whole blood transcriptome profiles are able to reveal biological processes involved in ALS and that using these profiles to differentiate between ALS and mimic syndromes will be challenging, even when taking batch effects in transcriptome data into account.
Abstract: The biological pathways involved in amyotrophic lateral sclerosis (ALS) remain elusive and diagnostic decision-making can be challenging. Gene expression studies are valuable in overcoming such challenges since they can shed light on differentially regulated pathways and may ultimately identify valuable biomarkers. This two-stage transcriptome-wide study, including 397 ALS patients and 645 control subjects, identified 2,943 differentially expressed transcripts predominantly involved in RNA binding and intracellular transport. When batch effects between the two stages were overcome, three different models (support vector machines, nearest shrunken centroids, and LASSO) discriminated ALS patients from control subjects in the validation stage with high accuracy. The models' accuracy reduced considerably when discriminating ALS from diseases that mimic ALS clinically (N = 75), nor could it predict survival. We here show that whole blood transcriptome profiles are able to reveal biological processes involved in ALS. Also, this study shows that using these profiles to differentiate between ALS and mimic syndromes will be challenging, even when taking batch effects in transcriptome data into account.
31 citations
Cited by
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TL;DR: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update as discussed by the authors .
Abstract: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2022 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population and an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, and the global burden of cardiovascular disease and healthy life expectancy.Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
1,483 citations
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TL;DR: For instance, the authors found that monozygotic twins had higher concordance rates than dizygotic twins for autism spectrum disorders, attention defcit hyperactivity disorder (ADHD), developmental coordination disorder, and tic disorder.
Abstract: Objective: Autism spectrum disorders are considered to be among the most heritable mental disorders, a notion based on surprisingly sparse data from small clinical studies. Population-based studies of the heritability of other neuro-psychiatric disorders and comorbidities among them have also been sparse. The authors sought to address both of these issues. Method: Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2000 (N=10,895) were interviewed regarding autism spectrum disorders and associated conditions (response rate, 80%). Concordance rates and structural equation modeling were used for evaluating causes for familial aggregation and overlap between conditions. Results: Monozygotic twins had higher concordance rates than dizygotic twins for autism spectrum disorders, attention defcit hyperactivity disorder (ADHD), developmental coordination disorder, and tic disorder. Genetic effects accounted for 80% (95% CI=29-91) of the variation in liability for autism spectrum disorders, 79% (95% CI=61-88) for ADHD, 70% (95% CI=35-83) for developmental coordination disorder, and 56% (95% CI=37-68) for tic disorder. Among monozygotic co-twins of children with autism spectrum disorders, the probability of having a diagnosis of ADHD was 44%, compared with 15% for dizygotic co-twins. Differences in cross-disorder effects between monozygotic and dizygotic twins were observed for most other comorbidities, and substantial proportions of the genetic variance for autism spectrum disorders was shared with each of the other disorders. Conclusions: Different neuropsychiatric disorders seem to have a common genetic etiology, suggesting caution in the use of diagnostic entities and proband status in efforts to uncover genes predisposing to autism spectrum disorders.
574 citations
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TL;DR: Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria.
540 citations
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TL;DR: The 2023 Statistical Update as mentioned in this paper provides the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health.
Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). Methods: The American Heart Association, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year’s worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year’s edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. Results: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. Conclusions: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
300 citations
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TL;DR: The underlying basic science ofPRS is reviewed, providing a foundation for understanding the potential clinical utility and limitations of PRS, and suggests that in principle, PRS could contribute to treatment choices, but more data are needed to allow development in this context.
Abstract: Importance Polygenic risk scores (PRS) are predictors of the genetic susceptibilities of individuals to diseases. All individuals have DNA risk variants for all common diseases, but genetic susceptibility differences between people reflect the cumulative burden of these. Polygenic risk scores for an individual are calculated as weighted counts of thousands of risk variants that they carry, where the risk variants and their weights have been identified in genome-wide association studies. Here, we review the underlying basic science of PRS, providing a foundation for understanding the potential clinical utility and limitations of PRS. Observations Polygenic risk scores can be calculated for a wide range of diseases from a saliva or blood sample using genotyping technologies that are inexpensive. While genotyping only needs to be done once for each individual in their lifetime, the PRS can be recalculated as identification of risk variants improves. On their own, PRS will never be able to establish or definitively predict future diagnoses of common complex conditions because genetic factors only contribute part of the risk, and PRS will only ever capture part of the genetic contributions. Nonetheless, just as clinical medicine uses a multitude of other predictive measures, PRS either on their own or as part of multivariable predictive algorithms could play a role. Conclusions and Relevance Utility of PRS in clinical medicine and ethical issues related to their use should be evaluated in the context of realistic expectations of what PRS can and cannot deliver. For different diseases, PRS could have utility in community settings (stratification to better triage people into established screening programs) or could contribute to clinical decision-making for those presenting with symptoms but where formal diagnosis is unclear. In principle, PRS could contribute to treatment choices, but more data are needed to allow development of PRS in this context.
168 citations