Multilocus Bayesian Meta-Analysis of Gene-Disease Associations

Newcombe, Paul; Verzilli, Claudio; Casas, Juan P.; Hingorani, Aroon D.; Smeeth, Liam; Whittaker, John C.

doi:10.1016/j.ajhg.2009.04.001

Cited by 29 publications

(23 citation statements)

References 24 publications

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“…Bayesian analysis was performed with the Java package “BayesMeta,” described in Newcombe et al (22). Post hoc power calculations were performed with G*power software package.…”

Section: Methodsmentioning

confidence: 99%

Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden

Chan

Patel

Newcombe

et al. 2013

Journal of the American College of Cardiology

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Objectives This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. Background Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. Methods We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. Results We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. Conclusions The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

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“…Bayesian analysis was performed with the Java package “BayesMeta,” described in Newcombe et al (22). Post hoc power calculations were performed with G*power software package.…”

Section: Methodsmentioning

confidence: 99%

Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden

Chan

Patel

Newcombe

et al. 2013

Journal of the American College of Cardiology

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“…In the current scenario for the role of PDE4D gene in the development of stroke, SNP 83 seems to be more reproducible in its association with stroke especially among the Chinese and Asians. Additionally, it has been J U S T A C C E P T E D found that meta-analysis reports too can be compromised due to partial genotyping of overlapping marker sets and so to overcome this, a multi-locus Bayesian meta-analysis approach was proposed that revealed no association despite increase in statistical power [56]. This method provided the most thorough meta-analysis for PDE4D association study in stroke which was consistent with the results obtained by Bevan et al (2008) [46].…”

Section: Pharmacology Studiesmentioning

confidence: 98%

Association between PDE4D gene and ischemic stroke: recent advancements

Das

Roy

Munshi

2015

International Journal of Neuroscience

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Stroke is a severe complication and a leading cause of death worldwide and genetic studies among different ethnicities has provided the basis for involvement of phosphodiesterase 4D (PDE4D) gene in cerebrovascular diseases. Recent advancements have evaluated the role of this gene in stroke and these studies have provided a stronger support for the involvement of this gene in stroke development and few studies also suggest that it may influence outcome. Furthermore, case-control studies and meta-analysis studies have provided strong evidence for certain variants in PDE4D to predispose to stroke only among certain ethnicities. Thus, this review focuses on recent progress made in PDE4D gene research involving genetic, molecular and pharmacological aspect. A strong conclusion has emerged that clearly indicates a pivotal role played by this gene in ischemic stroke globally. Studies have also noticeably highlighted that PDE4D gene/pathway can be a suitable drug target for managing stroke; however, a more comprehensive research is still required to understand the molecular and cellular intricacies this gene plays in stroke development, progression and its outcome.

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“…The performance of the two methods is comparable and both methods correctly identify SNP 5 as the causal marker. However, it should be kept in mind that the method presented by Newcombe et al [2009] is currently only applicable under an additive genetic model assumption, and makes stronger (parametric) assumptions on the exchangeability of genotype distributions between studies. Under a multinomial‐logit transformation, haplotype frequencies are hierarchically linked via Normal distributions, all with the same variance.…”

Section: Simulationsmentioning

confidence: 99%

“…Our goal is to combine information across studies and markers to investigate the role of PDE4D in risk of stroke. Our meta‐analysis is based on an existing thorough systematic review [Newcombe et al, 2009] and incorporated nine SNPs from seven studies [Lövkvist et al, 2008; Meschia et al, 2005; Nakayama et al, 2006; Nilsson‐Ardnor et al, 2005; Saleheen et al, 2005; Staton et al, 2006; Zee et al, 2006]. As described in Bevan et al [2008] and Newcombe et al [2009], studies were identified by searching two electronic databases (PubMed Medline and EMBASE) for literature published from 1996 to August 12, 2008, by using the keywords “stroke,” “SNP polymorphism,” “PDE4D” and “phosphodiestrase 4D” in isolation and combination with one another.…”

Section: Pde4d Gene and Risk Of Strokementioning

confidence: 99%

Bayesian semiparametric meta-analysis for genetic association studies

et al. 2011

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We present a Bayesian semiparametric model for the meta-analysis of candidate gene studies with a binary outcome. Such studies often report results from association tests for different, possibly study-specific and non-overlapping genetic markers in the same genetic region. Meta-analyses of the results at each marker in isolation are seldom appropriate as they ignore the correlation that may exist between markers due to linkage disequilibrium (LD) and cannot assess the relative importance of variants at each marker. Also such marker-wise meta-analyses are restricted to only those studies that have typed the marker in question, with a potential loss of power. A better strategy is one which incorporates information about the LD between markers so that any combined estimate of the effect of each variant is corrected for the effect of other variants, as in multiple regression. Here we develop a Bayesian semiparametric model which models the observed genotype group frequencies conditional to the case/control status and uses pairwise LD measurements between markers as prior information to make posterior inference on adjusted effects. The approach allows borrowing of strength across studies and across markers. The analysis is based on a mixture of Dirichlet processes model as the underlying semiparametric model. Full posterior inference is performed through Markov chain Monte Carlo algorithms. The approach is demonstrated on simulated and real data.

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Multilocus Bayesian Meta-Analysis of Gene-Disease Associations

Cited by 29 publications

References 24 publications

Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden

Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden

Association between PDE4D gene and ischemic stroke: recent advancements

Bayesian semiparametric meta-analysis for genetic association studies

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