Leveraging Prior Information to Detect Causal Variants via Multi-Variant Regression

Nanye Long, Samuel P Dickson, Jessica M Maia, Hee Shin Kim, Qianqian Zhu and Andrew S Allen

PLOS Computational Biology, 2013, vol. 9, issue 6, 1-11

Abstract: Although many methods are available to test sequence variants for association with complex diseases and traits, methods that specifically seek to identify causal variants are less developed. Here we develop and evaluate a Bayesian hierarchical regression method that incorporates prior information on the likelihood of variant causality through weighting of variant effects. By simulation studies using both simulated and real sequence variants, we compared a standard single variant test for analyzing variant-disease association with the proposed method using different weighting schemes. We found that by leveraging linkage disequilibrium of variants with known GWAS signals and sequence conservation (phastCons), the proposed method provides a powerful approach for detecting causal variants while controlling false positives.Author Summary: The decline in DNA sequencing cost permits the interrogation of potentially all variants across the entire allele frequency spectrum for their associations with complex human diseases and traits. However, the identification of causal variants remains challenging. Existing single variant tests do not distinguish between causal association and association induced by linkage disequilibrium and tend to be underpowered for rare or low-frequency variants, whereas variant grouping methods do not identify individual causal variants. We propose a novel Bayesian hierarchical regression approach that estimates effects of multiple variants on a disease trait simultaneously and incorporates prior information on the likelihood of causality. By simulation, we show that by combining linkage disequilibrium with known genome wide association signals and functional conservation, the proposed method, the first of its kind, is powerful to correctly detect causal variants.

Date: 2013
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Citations: View citations in EconPapers (3)

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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1003093

DOI: 10.1371/journal.pcbi.1003093

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