Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death
University of Amsterdam1, University of Nantes2, French Institute of Health and Medical Research3, Centre national de la recherche scientifique4, University of Pavia5, Pierre-and-Marie-Curie University6, Paris Diderot University7, Heidelberg University8, St George's, University of London9, Copenhagen University Hospital10, National Research Foundation of South Africa11, Ludwig Maximilian University of Munich12, Vanderbilt University13, Niigata University14, Shiga University of Medical Science15, Nagasaki University16, Nippon Medical School17, Imperial College London18, Pasteur Institute19, university of lille20, University of Paris-Sud21, IRSA22, University of Würzburg23
TL;DR: The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia and indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
Abstract: Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
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TL;DR: It is concluded that multiple Imputation for Nonresponse in Surveys should be considered as a legitimate method for answering the question of why people do not respond to survey questions.
Abstract: 25. Multiple Imputation for Nonresponse in Surveys. By D. B. Rubin. ISBN 0 471 08705 X. Wiley, Chichester, 1987. 258 pp. £30.25.
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TL;DR: 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 cardiovascul...
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 cardiovascul...
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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.
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TL;DR: Improved analytical approaches that evaluate which genes and variant classes are interpretable are outlined and it is proposed that these will increase the clinical utility of testing across a range of Mendelian diseases.
532 citations
Cites background from "Common variants at SCN5A-SCN10A and..."
...We have not tested more common variants (MAF>1x10), which could be mechanistically informative but are likely to have smaller effects (45) and have not evaluated individual level data to assess the impact of co-inheritance of variants, which are limitations of the analyses....
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TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Abstract: Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
26,280 citations
TL;DR: It is concluded that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity, and one or both should be presented in publishedMeta-an analyses in preference to the test for heterogeneity.
Abstract: The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity.
25,460 citations
Book•
01 Jan 1987
TL;DR: This work states that maximum Likelihood for General Patterns of Missing Data: Introduction and Theory with Ignorable Nonresponse and large-Sample Inference Based on Maximum Likelihood Estimates is likely to be high.
Abstract: Preface.PART I: OVERVIEW AND BASIC APPROACHES.Introduction.Missing Data in Experiments.Complete-Case and Available-Case Analysis, Including Weighting Methods.Single Imputation Methods.Estimation of Imputation Uncertainty.PART II: LIKELIHOOD-BASED APPROACHES TO THE ANALYSIS OF MISSING DATA.Theory of Inference Based on the Likelihood Function.Methods Based on Factoring the Likelihood, Ignoring the Missing-Data Mechanism.Maximum Likelihood for General Patterns of Missing Data: Introduction and Theory with Ignorable Nonresponse.Large-Sample Inference Based on Maximum Likelihood Estimates.Bayes and Multiple Imputation.PART III: LIKELIHOOD-BASED APPROACHES TO THE ANALYSIS OF MISSING DATA: APPLICATIONS TO SOME COMMON MODELS.Multivariate Normal Examples, Ignoring the Missing-Data Mechanism.Models for Robust Estimation.Models for Partially Classified Contingency Tables, Ignoring the Missing-Data Mechanism.Mixed Normal and Nonnormal Data with Missing Values, Ignoring the Missing-Data Mechanism.Nonignorable Missing-Data Models.References.Author Index.Subject Index.
18,201 citations
Book•
01 Jan 1987
TL;DR: In this article, a survey of drinking behavior among men of retirement age was conducted and the results showed that the majority of the participants reported that they did not receive any benefits from the Social Security Administration.
Abstract: Tables and Figures. Glossary. 1. Introduction. 1.1 Overview. 1.2 Examples of Surveys with Nonresponse. 1.3 Properly Handling Nonresponse. 1.4 Single Imputation. 1.5 Multiple Imputation. 1.6 Numerical Example Using Multiple Imputation. 1.7 Guidance for the Reader. 2. Statistical Background. 2.1 Introduction. 2.2 Variables in the Finite Population. 2.3 Probability Distributions and Related Calculations. 2.4 Probability Specifications for Indicator Variables. 2.5 Probability Specifications for (X,Y). 2.6 Bayesian Inference for a Population Quality. 2.7 Interval Estimation. 2.8 Bayesian Procedures for Constructing Interval Estimates, Including Significance Levels and Point Estimates. 2.9 Evaluating the Performance of Procedures. 2.10 Similarity of Bayesian and Randomization--Based Inferences in Many Practical Cases. 3. Underlying Bayesian Theory. 3.1 Introduction and Summary of Repeated--Imputation Inferences. 3.2 Key Results for Analysis When the Multiple Imputations are Repeated Draws from the Posterior Distribution of the Missing Values. 3.3 Inference for Scalar Estimands from a Modest Number of Repeated Completed--Data Means and Variances. 3.4 Significance Levels for Multicomponent Estimands from a Modest Number of Repeated Completed--Data Means and Variance--Covariance Matrices. 3.5 Significance Levels from Repeated Completed--Data Significance Levels. 3.6 Relating the Completed--Data and Completed--Data Posterior Distributions When the Sampling Mechanism is Ignorable. 4. Randomization--Based Evaluations. 4.1 Introduction. 4.2 General Conditions for the Randomization--Validity of Infinite--m Repeated--Imputation Inferences. 4.3Examples of Proper and Improper Imputation Methods in a Simple Case with Ignorable Nonresponse. 4.4 Further Discussion of Proper Imputation Methods. 4.5 The Asymptotic Distibution of (Qm,Um,Bm) for Proper Imputation Methods. 4.6 Evaluations of Finite--m Inferences with Scalar Estimands. 4.7 Evaluation of Significance Levels from the Moment--Based Statistics Dm and Dm with Multicomponent Estimands. 4.8 Evaluation of Significance Levels Based on Repeated Significance Levels. 5. Procedures with Ignorable Nonresponse. 5.1 Introduction. 5.2 Creating Imputed Values under an Explicit Model. 5.3 Some Explicit Imputation Models with Univariate YI and Covariates. 5.4 Monotone Patterns of Missingness in Multivariate YI. 5.5 Missing Social Security Benefits in the Current Population Survey. 5.6 Beyond Monotone Missingness. 6. Procedures with Nonignorable Nonresponse. 6.1 Introduction. 6.2 Nonignorable Nonresponse with Univariate YI and No XI. 6.3 Formal Tasks with Nonignorable Nonresponse. 6.4 Illustrating Mixture Modeling Using Educational Testing Service Data. 6.5 Illustrating Selection Modeling Using CPS Data. 6.6 Extensions to Surveys with Follow--Ups. 6.7 Follow--Up Response in a Survey of Drinking Behavior Among Men of Retirement Age. References. Author Index. Subject Index. Appendix I. Report Written for the Social Security Administration in 1977. Appendix II. Report Written for the Census Bureau in 1983.
14,574 citations
National Institutes of Health1, University of Chicago2, Duke University3, Harvard University4, University of Oxford5, GlaxoSmithKline6, Johns Hopkins University7, Yale University8, deCODE genetics9, Howard Hughes Medical Institute10, Princeton University11, Washington University in St. Louis12, University of California, Berkeley13, Stanford University14, University of Michigan15, Cornell University16, University of Washington17, University of Queensland18, Vanderbilt University19, North Carolina State University20, QIMR Berghofer Medical Research Institute21
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
7,797 citations