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Abstract Background Genome-wide association studies (GWASes) aim to identify single nucleotide polymorphisms (SNPs) associated with a given phenotype. A common approach for the analysis of GWAS is single marker analysis (SMA) based on linear mixed models (LMMs). However, LMM-based SMA usually yields a large number of false discoveries and cannot be directly applied to non-Gaussian phenotypes such as count data. Results We present a novel Bayesian method to find SNPs associated with non-Gaussian phenotypes. To that end, we use generalized linear mixed models (GLMMs) and, thus, call our method Bayesian GLMMs for GWAS (BG2). To deal with the high dimensionality of GWAS analysis, we propose novel nonlocal priors specifically tailored for GLMMs. In addition, we develop related fast approximate Bayesian computations. BG2 uses a two-step procedure: first, BG2 screens for candidate SNPs; second, BG2 performs model selection that considers all screened candidate SNPs as possible regressors. A simulation study shows favorable performance of BG2 when compared to GLMM-based SMA. We illustrate the usefulness and flexibility of BG2 with three case studies on cocaine dependence (binary data), alcohol consumption (count data), and number of root-like structures in a model plant (count data).
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BGWAS: Bayesian variable selection in linear mixed models with nonlocal priors for genome-wide association studies
Abstract Background Genome-wide association studies (GWAS) seek to identify single nucleotide polymorphisms (SNPs) that cause observed phenotypes. However, with highly correlated SNPs, correlated observations, and the number of SNPs being two orders of magnitude larger than the number of observations, GWAS procedures often suffer from high false positive rates. Results We propose BGWAS, a novel Bayesian variable selection method based on nonlocal priors for linear mixed models specifically tailored for genome-wide association studies. Our proposed method BGWAS uses a novel nonlocal prior for linear mixed models (LMMs). BGWAS has two steps: screening and model selection. The screening step scans through all the SNPs fitting one LMM for each SNP and then uses Bayesian false discovery control to select a set of candidate SNPs. After that, a model selection step searches through the space of LMMs that may have any number of SNPs from the candidate set. A simulation study shows that, when compared to popular GWAS procedures, BGWAS greatly reduces false positives while maintaining the same ability to detect true positive SNPs. We show the utility and flexibility of BGWAS with two case studies: a case study on salt stress in plants, and a case study on alcohol use disorder. Conclusions BGWAS maintains and in some cases increases the recall of true SNPs while drastically lowering the number of false positives compared to popular SMA procedures.
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- PAR ID:
- 10413766
- Date Published:
- Journal Name:
- BMC Bioinformatics
- Volume:
- 24
- Issue:
- 1
- ISSN:
- 1471-2105
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Background Single marker analysis (SMA) with linear mixed models for genome wide association studies has uncovered the contribution of genetic variants to many observed phenotypes. However, SMA has weak false discovery control. In addition, when a few variants have large effect sizes, SMA has low statistical power to detect small and medium effect sizes, leading to low recall of true causal single nucleotide polymorphisms (SNPs). Results We present the Bayesian Iterative Conditional Stochastic Search (BICOSS) method that controls false discovery rate and increases recall of variants with small and medium effect sizes. BICOSS iterates between a screening step and a Bayesian model selection step. A simulation study shows that, when compared to SMA, BICOSS dramatically reduces false discovery rate and allows for smaller effect sizes to be discovered. Finally, two real world applications show the utility and flexibility of BICOSS. Conclusions When compared to widely used SMA, BICOSS provides higher recall of true SNPs while dramatically reducing false discovery rate.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1186/s12859-023-05316-x
