Assessing the quality of published genetic association. Metaanalysis of genomewide association studies in african. In a metaanalysis of prevalence studies, published between 2000 and 2015, of diabetes among older ssa persons, the overall prevalence was. Pdf how should we use information about hwe in the meta. Sep 10, 2010 meta analyses and individual patient data ipd meta analyses of genetic association studies are a powerful tool to summarize the scientific evidences, however their application present considerable potential and several pitfalls. Objective to systematically assess and quantitatively. The possibility cannot be excluded that some of the results were biased because of undetected population stratification in the original casecontrol samples 10, 77. A systematic metaanalysis of genetic association studies.
Meta analysis of the casecontrol studies 19 30, 32 and nine cohort studies 33 40, 44 that measured folate intake rather than biomarkers of folate found a summary or of 0. Persistent difficulties in obtaining robust, replicable results in genetic association studies are almost certainly because genetic effects are small, requiring studies with many thousands of subjects to be detected. Meta analysis, a rigorous, comprehensive, quantitative synthesis of all the available data, might. Genetic association metaanalyses were by far more redundant, erroneous. Background gastroschisis is strongly associated with young maternal age.
Although there is reason to hope that these discoveries will eventually lead to new preventive and therapeutic agents for obesity, this will take time because such developments require detailed mechanistic understanding of how an. Recently, consortiumbased metaanalyses of several genomewide association. Identifying these risk factors is a public health priority in order to develop prevention strategies aimed at reducing the prevalence and health consequences in offspring. This study is the first meta analysis of genomewide association studies for aaa 10 204 cases. There have been over 100 ocd genetic association studies, and so a comprehensive meta analysis of this substantial literature is warranted. Synopsis and metaanalysis of genetic association studies in. Following imputation using hapmap phase ii ceu as a reference, approximately 2. Polymorphisms were included in the meta analysis if a minimum of two studies had assessed association with dr development. Metaanalysis of genomewide association studies provides. Data were entered into a database and statistical analyses performed using revman software version 4. Craig objectivediabetic retinopathy is a sightthreatening microvascular complication of diabetes with a complex multifactorial pathogenesis. There is a variety of methods for analyzing data from gwas balding, 2006. On individual genomewide association studies and their. Results from the cochranarmitage test can be combined.
In gwass, none of the variants of the fa gene family were reported as significant, nor were the variants examined in the meta analyses captured by the genotyping platforms used in the gwass 28, 29. If we are interested in combining data from two casecontrol studies so as to make inference on a common genetic effect without adjusting for covariates, then we simply set x g, s t, where g is the genotype score and s indicates, by the values 1 versus 0, whether the subject is from the first study. Here we conduct a meta analysis of genomewide association studies gwas with 16 million genetic variants in. A meta analysis can increase power and provide standards of reporting results. Nov 18, 2019 to assess whether the horvatheaa and hannumeaa gwas meta analysis results are enriched for various genesets and provide insight into the involvement of specific biological pathways in the genetic aetiology of the phenotype, the genebased analysis results were used to perform competitive geneset and pathway analysis using default parameters. The role of gene polymorphisms in the field of pad has been mainly examined in caucasian populations. Through meta analysis, novel susceptibility loci can be discovered by effectively summing the statistical evidence of individually underpowered studies. Metaanalysis of two genomewide association studies. All models iv assumed equal genetic effects across studies or that the estimated average effect across studies is a reasonable effect. Obstacles and opportunities in metaanalysis of genetic association. The number of publications in medline and psychinfo that included the key words metaanalysis and genetic association in the past decade.
Methodological standards for metaanalyses and qualitative. This test is a scatter plot of the effect estimate from each study included in the meta analysis against the measure of its precision 1se 22. Therefore, a meta analysis was carried out to evaluate and compare the effect of ets by different family members and prenatal smoke exposure on the risk of hs in children. To assess whether the horvatheaa and hannumeaa gwas meta analysis results are enriched for various genesets and provide insight into the involvement of specific biological pathways in the genetic aetiology of the phenotype, the genebased analysis results were used to perform competitive geneset and pathway analysis using default parameters. However, the conduct of a meta analysis of gass faces a major obstacle, which is the structure and diversity of stored information in databases. Particularly, this study presents an example of a metaanalysis in.
We searched pubmed, web of science, embase, medline, chinese national knowledge infrastructure cnki, and wan fang med online up to march 2019, and all eligible casecontrol and. The number of published genetic association studies gass is increasing tremendously due to the availability of mapped singlenucleotide polymorphisms snps and advances in. Type 2 diabetes t2d is a very common disease in humans. We first highlight advances in and the limitations of using such approaches in the neurodegenerative disease literature, with a focus on alzheimers disease ad, parkinsons. Statistical test for analysis of categorical data when categories are ordered. The number of publications in medline and psychinfo that included the key words meta analysis and genetic association in the past decade. Meta analysis, a statistical tool for combining results across studies, is becoming popular as a method for resolving discrepancies in genetic association studies.
Jan 10, 2020 the past 15 years have seen a boom in the use and integration of omic approaches limited here to genomic, transcriptomic, and epigenomic techniques to study neurodegenerative disease in an unprecedented way. Metaanalysis for genomewide association studies using. Most genetic discoveries for complex traits are now made through meta analysis collaborations, which so far have been restricted to singlelocus analyses, testing for main effects at a single. Association of the 5httlpr genotype and unipolar depression. Obstacles and opportunities in metaanalysis of genetic. Metaanalysis of genetic association studies may be subject to publication bias. The number of published genetic association studies gass is increasing tremendously due to the availability of mapped singlenucleotide polymorphisms snps and advances in genotyping technologies. Metaanalysis indicated evidence of a small but statistically significant association between the 5httlpr polymorphism and unipolar depression odds ratio or 1. Metaanalysis of genomewide association studies with. Used appropriately, metaanalysis has the potential to overcome the lack of power that is a problem in. Systematic metaanalysis of genetic variants associated. Similar problems are expected for gwass, though the data are not yet publicly available.
Armitage, 1955, a special case of the score test from a logistic regression, can be used to test for a linear relationship between an ordered dose variable for example, a dose of a treatment and the log odds of being a case vs. Meta analyses of observational and genetic association. The first n columns of your file can contain any type of data of the different studies that will be used at the subgroup analysis step. Marchini j, howie b 2008 comparing algorithms for genotype imputation. We searched online databases and websites and contacted experts in the field. Pdf trends in genetic and genome analyses in wheat. Overall, the pooled analysis showed that mir196a2 rs116149 was associated with a decreased cancer risk or 0. In this current study we performed metaanalysis of genetic association studies gas to pool osasusceptible genes in chinese population, to perform a more precise evaluation of the association. Linkage disequilibrium mapping has identified several promising and novel positional candidates, including the g72g30 and daminoacid oxidase daao genes. Genetic association studies are used to find candidate genes or genome regions that contribute to a specific disease by testing for a correlation between disease status and genetic variation.
A metaanalysis of genomewide association studies of. In order for a polymorphism to be included in a meta analysis, we required. Association between obesity and cardiovascular outcomes. A systematic meta analysis of genetic association studies for diabetic retinopathy sotoodeh abhary, 1alex w. The supreme importance of complete and consistent study reporting. Meta regression analysis showed that the effect of bivalirudin. Trends in obesity and diabetes across africa from 1980 to. Metaanalysis combines the effect sizes of the included studies by weighting the data according to the amount of information in each study. Molecular genetics of obsessivecompulsive disorder.
Basic statistical analysis in genetic casecontrol studies. Schizophrenia may result from a neurotransmission hypofunction of glutamatergic and n methyldaspartate nmda receptors. Trends in meta analysis of genetic association studies. Trends in metaanalysis of genetic association studies. A systematic meta analysis was undertaken to collectively assess genetic studies and determine which previously investigated polymorphisms are associated with diabetic retinopathy. Used appropriately, meta analysis has the potential to overcome the lack of power that is a problem in. The systematic literature search of pubmed, medline, embase, web of science and cnki identified 164 eligible studies. May 15, 2015 advances in genomics technology have led to a dramatic increase in the number of published genetic association studies. In genetic association studies, because the underlying genetic model is unknown, the additive version of this test is. To understand the genetic control of flavor, we report the meta analysis of genomewide association studies gwas using 775 tomato accessions and 2,316,117 snps from three gwas panels.
Genegene and geneenvironment interactions in metaanalysis of genetic association studies article pdf available in plos one 104. Munafo mr, flint j 2004 metaanalysis of genetic association studies. Stratification in genetic association studies might blur the genetic effect. Meta analysis of genetic association studies combines the results from independent studies, explores the sources of heterogeneity, and identifies subgroups associated with the factor of interest. All meta analysis problems can be formulated through equation 1. This occurs when multiple analyses have been performed but. Ioannidis 2,3 abstract meta analysis of genomewide association studies gwass has become a popular method for discovering genetic risk variants.
Meta analysis methods for genomewide association studies. They all have a common aimto demonstrate the utility and draw attention of the r environment for statistical genetics or genetic. Here, we overview both widely applied and newer statistical methods for gwas meta analysis, including issues of. Snps association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Research design and methods all studies investigating the association. Most researchers are frequentists, who believe that all experiments are performed in a vacuum, and the evidence for an association depends only on the data at hand. Genomewide association studies gwas for bmi, waisttohip ratio, and other adiposity traits have identified more than 300 singlenucleotide polymorphisms snps. Genetic association studies have the potential to advance our. Publication trends for metaanalysis of genetic association studies. Combined association tests were generated using a fixed effects meta analysis. Objective diabetic retinopathy is a sightthreatening microvascular complication of diabetes with a complex multifactorial pathogenesis. Metagenyo requires a specific data format to worth with. Field synopsis and metaanalysis of genetic association. The reason for the popularity of this method is that it has the potential to deal with a major shortcoming in most genetic association studies.
First, we meta analyzed data from 242 studies published between 1990 and 2007, representing the testing of 1,286,350 people. Metaanalysis methods for genomewide association studies and. As any research design, meta analysis has strengths and weaknesses. This article provides a broad outline of the design and analysis of such studies, focusing on casecontrol studies in candidate genes or regions. Among the metaanalyses that did not accompany a primary study, human. Lifestyle and sociodemographic risk factors for gastroschisis. This remained significant when data from samples of european and east asian ancestry were analyzed separately. This test is commonly used in genetic association studies to model additive genetic effects by defining dose as a genotype score defined as the number of copies of a reference allele 0, 1, or 2. Transethnic meta analysis of genomewide association studies. Genetic association studies for multigenetic diseases are like fishing for the truth in a sea of trillions of candidate analyses. The funnel plot is a commonly used graphic test to assess publication bias in meta analyses 21. However, a sizeable proportion of identified genetic associations are probably true.
An investigation of the evolution of results over time, for example using metaregression. Although linkage and candidate gene association studies have repeatedly implicated some chromosome regions and certain genes, they have not produced the level of unambiguous support required to confirm the involvement. Meta analysis of genomewide association studies for cognitive ability identifies 190 new loci and implicates 939 new genes related to neurogenesis, neuron differentiation and synaptic structure. Four novel loci were identified and 5 of the 6 previous aaa genetic associations were confirmed. Sample size refers to subjects or alleles, in the case and control groups, involved in the targeted genetic. Meta analysis improves statistical power by synthesizing association data from multiple studies regarding individual genetic loci or variants. Systematic metaanalyses and field synopsis of genetic. This association suggests the need for further investigations on non genetic risk factors. Original article a systematic metaanalysis of genetic. Oct 21, 2015 meta analysis of genetic association studies. Methods for metaanalysis in genetic association studies. These issues should be ideally anticipated upfront when the explicit meta analysis protocol is.
Publication trends for meta analysis of genetic association studies. Methods relevant studies published in english were identified by a search of. Family and twin studies attest to the importance of genetic factors influencing susceptibility to bipolar disorder and to its genetic and phenotypic complexity. However, this trend was similar in the overall metaanalyses investigating. Metaanalysis of genetic association studies europe pmc. Background the association between environmental tobacco smoke ets exposure and habitual snoring hs risk in children remains controversial. This test is commonly used in genetic association studies to model additive.
Barria perez et al 62 in a meta analysis comparing the effects of bivalirudin and heparin on outcomes after percutaneous coronary intervention used meta regression analyses to explore heterogeneity caused by patient demographics and the dose of heparin used in the included studies. A search in hugenet illustrates the rapid accumulation of evidence for. The qualitative synthesis revealed that 62 genes may be correlated with the susceptibility to kd, and. Trends in metaanalysis of genetic association studies core. Genome wide meta analysis identifies common genetic. To investigate this further, we performed a meta analysis of two genomewide association studies gwass to identify additional genetic loci influencing serum tsh levels in two populationbased samples kora and ship and replicated the results in three further independent cohort studies hunt, carla and ship trend. Genetic association studyspecific methodological issues.
The characteristics of each study and the association results of variants are shown in additional file 2. Environmental tobacco smoke exposure and risk of habitual. A more important problem in metaanalysis of genetic association studies is bias due to withinstudy selective reporting. The association of age at menopause with endometrial cancer remains controversial. The new loci showed no significant associations with other arterial disease phenotypes, potentially suggesting associations more specific to aaa than. In this article, we use meta analysis to analyze gender differences in recent studies of mathematics performance. Revision has been made in the context of genomewide association studies gwass. For the genetic score, there was a nonsignificant trend towards better. Table 4 top ranked genes for the combined analysis of echocardiographic traits and ad after genome wide association meta analysis and gene. Pdf genegene and geneenvironment interactions in meta. Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that there was a strong association between mir146a rs2910164 and overall. For studies with binary outcomes, we tested allelic association logadditive genetic model, and in studies with continuous outcomes, we tested all three genetic models dominant, recessive and additive when sufficient data were available supplementary methods. Of the 72 papers, 26 did not report information on hwe, with a trend toward.
Metagenyo is a simple, readytouse software which has been designed to perform meta analysis of genetic association studies. Metaanalysis for genomewide association studies using case. Persistent difficulties in obtaining robust, replicable results in genetic association studies are almost certainly because genetic effects are small, requiring studies with many. Red herrings are unavoidably common, and bias might cause serious misconceptions. Used appropriately, meta analysis has the potential to overcome the lack of. Used appropriately, meta analysis has the potential to overcome the lack of power that is a problem in so many genetic. This can be performed using the traditional pearsons chi. Quality of metaanalyses of genetic association studies. Since the first positive association report, many subsequent studies have attempted to replicate the association.
Metaanalysis of genomewide association studies for. Meta analysis, compared with the individual studies included in a meta analysis, can be a more powerful method of evaluating effect sizes. Therefore, we quantitatively summarized the evidence from observational studies with a meta analysis. Age at menopause and risk of developing endometrial cancer. However, summary estimates are subject to bias due to the varying methodological quality of individual. Sample size in 579 genetic association studies addressing 55 different genetic associations that have been evaluated in meta analyses with binary outcomes for a list of these associations see ref.