title: Inclusion of biological knowledge in a Bayesian shrinkage model for joint estimation of SNP effects.
abstract: With the aim of improving detection of novel single-nucleotide polymorphisms (SNPs) in genetic association studies, we propose a method of including prior biological information in a Bayesian shrinkage model that jointly estimates SNP effects. We assume that the SNP effects follow a normal distribution centered at zero with variance controlled by a shrinkage hyperparameter. We use biological information to define the amount of shrinkage applied on the SNP effects distribution, so that the effects of SNPs with more biological support are less shrunk toward zero, thus being more likely detected. The performance of the method was tested in a simulation study (1,000 datasets, 500 subjects with ∼200 SNPs in 10 linkage disequilibrium (LD) blocks) using a continuous and a binary outcome. It was further tested in an empirical example on body mass index (continuous) and overweight (binary) in a dataset of 1,829 subjects and 2,614 SNPs from 30 blocks. Biological knowledge was retrieved using the bioinformatics tool Dintor, which queried various databases. The joint Bayesian model with inclusion of prior information outperformed the standard analysis: in the simulation study, the mean ranking of the true LD block was 2.8 for the Bayesian model versus 3.6 for the standard analysis of individual SNPs; in the empirical example, the mean ranking of the six true blocks was 8.5 versus 9.3 in the standard analysis. These results suggest that our method is more powerful than the standard analysis. We expect its performance to improve further as more biological information about SNPs becomes available.
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Miguel
authors.initials: M
authors.lastname: Pereira
authors.affiliation: Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.affiliation: Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), Bolzano, Italy, Affiliated to the University of Lübeck, Lübeck, Germany.
authors.forename: Christian X
authors.initials: CX
authors.lastname: Weichenberger
authors.affiliation: Biostatistics Division, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Thomas
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Cosetta
authors.initials: C
authors.lastname: Minelli
mesh_terms: D001499:Bayes Theorem; D015992:Body Mass Index; D003198:Computer Simulation; D056726:Genetic Association Studies; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008957:Models, Genetic; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012119:Respiration
keywords: Bayesian model; genetic association studies; prior knowledge; shrinkage