Genome-Wide Association Study of Retinopathy in Individuals Without Diabetes
University of Washington1, National University of Singapore2, Cedars-Sinai Medical Center3, National Institutes of Health4, Erasmus University Rotterdam5, University of Newcastle6, University of Wisconsin-Madison7, University of Iceland8, University of Texas Health Science Center at Houston9, University of Melbourne10, University of Sydney11, Boston University12, University of Auckland13, Group Health Cooperative14, University of Amsterdam15, Singapore National Eye Center16, Agency for Science, Technology and Research17, University of California, San Francisco18, University of Michigan19, Harvard University20
TL;DR: This genome-wide association study of retinopathy in individuals without diabetes showed little evidence of genetic associations and further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
Abstract: Background
Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
Citations
More filters
TL;DR: This review article contains almost a complete set of details, which may affect seed biology during dormancy and growth, including the hormonal signaling of IAA and gibberellins and the significance of plant hormones.
539 citations
University of Leicester1, British Geological Survey2, University of Western Ontario3, University of California, Berkeley4, University of the Basque Country5, Jan Kochanowski University6, Paul Sabatier University7, Free University of Berlin8, University of Washington9, Australian National University10, Scott Polar Research Institute11, University of Vienna12, University of Alberta13
TL;DR: In a recent study, this paper found that plastic particles are abundant and widespread in marine sedimentary deposits in both shallow and deep-water settings, and their distribution in both the terrestrial and marine realms suggests that they are a key geological indicator of the Anthropocene, as a distinctive stratal component.
535 citations
TL;DR: A systematic review and meta‐analysis of the literature was conducted to determine the diagnostic accuracy of the MoCA for differentiating healthy cognitive aging from possible MCI.
Abstract: Objective
The Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005) is a cognitive screening tool that aims to differentiate healthy cognitive aging from Mild Cognitive Impairment (MCI). Several validation studies have been conducted on the MoCA, in a variety of clinical populations. Some studies have indicated that the originally suggested cutoff score of 26/30 leads to an inflated rate of false positives, particularly for those of older age and/or lower education. We conducted a systematic review and meta-analysis of the literature to determine the diagnostic accuracy of the MoCA for differentiating healthy cognitive aging from possible MCI.
Methods
Of the 304 studies identified, nine met inclusion criteria for the meta-analysis. These studies were assessed across a range of cutoff scores to determine the respective sensitivities, specificities, positive and negative predictive accuracies, likelihood ratios for positive and negative results, classification accuracies, and Youden indices.
Results
Meta-analysis revealed a cutoff score of 23/30 yielded the best diagnostic accuracy across a range of parameters.
Conclusions
A MoCA cutoff score of 23, rather than the initially recommended score of 26, lowers the false positive rate and shows overall better diagnostic accuracy. We recommend the use of this cutoff score going forward. Copyright © 2017 John Wiley & Sons, Ltd.
457 citations
TL;DR: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases, as well as single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.
Abstract: IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
376 citations
TL;DR: In this article, the authors identify emerging hypotheses on how urbanization drives eco-evolutionary dynamics and study how human-driven microevolutional changes interact with ecological processes and provide new insights for maintaining biodiversity and ecosystem function over the long term.
Abstract: A great challenge for ecology in the coming decades is to understand the role humans play in eco-evolutionary dynamics. If, as emerging evidence shows, rapid evolutionary change affects ecosystem functioning and stability, current rapid environmental change and its evolutionary effects might have significant implications for ecological and human wellbeing on a relatively short time scale. Humans are major selective agents with potential for unprecedented evolutionary consequences for Earth's ecosystems, especially as cities expand rapidly. In this review, I identify emerging hypotheses on how urbanization drives eco-evolutionary dynamics. Studying how human-driven micro-evolutionary changes interact with ecological processes offers us the chance to advance our understanding of eco-evolutionary feedbacks and will provide new insights for maintaining biodiversity and ecosystem function over the long term.
332 citations
References
More filters
TL;DR: A new quantity is developed, I 2, which the authors believe gives a better measure of the consistency between trials in a meta-analysis, which is susceptible to the number of trials included in the meta- analysis.
Abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice?
Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.
Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4
Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted?
A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …
45,105 citations
"Genome-Wide Association Study of Re..." refers background in this paper
...These plots incorporated the I(2) heterogeneity statistic to measure the percentage of variation attributable to differences in effect size between cohorts [46,47]....
[...]
TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.
9,244 citations
Baylor College of Medicine1, Chinese Academy of Sciences2, Chinese National Human Genome Center3, University of Hong Kong4, The Chinese University of Hong Kong5, Hong Kong University of Science and Technology6, Illumina7, McGill University8, Washington University in St. Louis9, University of California, San Francisco10, Wellcome Trust Sanger Institute11, Beijing Normal University12, Health Sciences University of Hokkaido13, Shinshu University14, University of Tsukuba15, Howard University16, University of Ibadan17, Case Western Reserve University18, University of Utah19, Cold Spring Harbor Laboratory20, Johns Hopkins University21, University of Oxford22, North Carolina State University23, National Institutes of Health24, Massachusetts Institute of Technology25, Chinese Academy of Social Sciences26, Kyoto University27, Nagasaki University28, Wellcome Trust29, Genome Canada30, Foundation for the National Institutes of Health31, University of Maryland, Baltimore32, Vanderbilt University33, Stanford University34, University of California, Berkeley35, New York University36, University of Oklahoma37, University of New Mexico38, Université de Montréal39, University of California, Los Angeles40, University of Michigan41, University of Wisconsin-Madison42, London School of Economics and Political Science43, Genetic Alliance44, GlaxoSmithKline45, University of Washington46, Harvard University47, University of Chicago48, Fred Hutchinson Cancer Research Center49, University of Tokyo50
TL;DR: The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance the ability to choose targets for therapeutic intervention.
Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.
5,926 citations
TL;DR: These examinations in CHS permit evaluation of CVD risk factors in older adults, particularly in groups previously under-represented in epidemiologic studies, such as women and the very old.
3,631 citations
"Genome-Wide Association Study of Re..." refers background or methods in this paper
...The AGES and CHS used the Illumina HumanCNV370Duo....
[...]
...Participants of European ancestry came from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium [24] {the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study [25], the Atherosclerosis Risk in Communities (ARIC) Study [26], the Cardiovascular Health Study (CHS) [27], and the Rotterdam Study (RS) [28]}, the Blue Mountain Eye Study [29] (BMES) and the Multi-Ethnic Study of Atherosclerosis (MESA) [30]....
[...]
...Some sites took photographs through undilated pupils (ARIC, CHS, MESA), some sites were limited to photographs using 1 field of view (ARIC, CHS, RS) and one site (CHS) did not take photographs of both eyes....
[...]
...ARIC and CHS also adjusted for clinic site, BMES adjusted for four multi-dimensional scaling dimensions and MESA adjusted for population structure using 10 principal components....
[...]
...Participants of European ancestry came from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium [24] {the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study [25], the Atherosclerosis Risk in Communities (ARIC) Study [26], the Cardiovascular Health Study (CHS) [27], and the Rotterdam Study (RS) [28]}, the Blue Mountain Eye Study [29] (BMES) and the Multi-Ethnic Study of Atherosclerosis (MESA) [30]....
[...]
TL;DR: The Multi-Ethnic Study of Atherosclerosis was initiated in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD) in a population-based sample of 6,500 men and women aged 45-84 years for identification and characterization of CVD events.
Abstract: The Multi-Ethnic Study of Atherosclerosis was initiated in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD) in a population-based sample of 6,500 men and women aged 45-84 years. The cohort will be selected from six US field centers. Approximately 38% of the cohort will be White, 28% African-American, 23% Hispanic, and 11% Asian (of Chinese descent). Baseline measurements will include measurement of coronary calcium using computed tomography; measurement of ventricular mass and function using cardiac magnetic resonance imaging; measurement of flow-mediated brachial artery endothelial vasodilation, carotid intimal-medial wall thickness, and distensibility of the carotid arteries using ultrasonography; measurement of peripheral vascular disease using ankle and brachial blood pressures; electrocardiography; and assessments of microalbuminuria, standard CVD risk factors, sociodemographic factors, life habits, and psychosocial factors. Blood samples will be assayed for putative biochemical risk factors and stored for use in nested case-control studies. DNA will be extracted and lymphocytes will be immortalized for genetic studies. Measurement of selected subclinical disease indicators and risk factors will be repeated for the study of progression over 7 years. Participants will be followed through 2008 for identification and characterization of CVD events, including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, and congestive heart failure; therapeutic interventions for CVD; and mortality.
3,367 citations
"Genome-Wide Association Study of Re..." refers background or methods in this paper
...Participants of European ancestry came from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium [24] {the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study [25], the Atherosclerosis Risk in Communities (ARIC) Study [26], the Cardiovascular Health Study (CHS) [27], and the Rotterdam Study (RS) [28]}, the Blue Mountain Eye Study [29] (BMES) and the Multi-Ethnic Study of Atherosclerosis (MESA) [30]....
[...]
...MESA is a prospective study of 6,814 adults aged 45–84 years with no history of clinical cardiovascular disease at the baseline exam (July 2000–July 2002) [30]....
[...]