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

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

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.

Suggested Citation

  • Nanye Long & Samuel P Dickson & Jessica M Maia & Hee Shin Kim & Qianqian Zhu & Andrew S Allen, 2013. "Leveraging Prior Information to Detect Causal Variants via Multi-Variant Regression," PLOS Computational Biology, Public Library of Science, vol. 9(6), pages 1-11, June.
  • Handle: RePEc:plo:pcbi00:1003093
    DOI: 10.1371/journal.pcbi.1003093
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    Cited by:

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    2. Xinge Jessie Jeng & Zhongyin John Daye & Wenbin Lu & Jung-Ying Tzeng, 2016. "Rare Variants Association Analysis in Large-Scale Sequencing Studies at the Single Locus Level," PLOS Computational Biology, Public Library of Science, vol. 12(6), pages 1-23, June.
    3. Sunyoung Shin & Sündüz Keleş, 2017. "Annotation Regression for Genome-Wide Association Studies with an Application to Psychiatric Genomic Consortium Data," Statistics in Biosciences, Springer;International Chinese Statistical Association, vol. 9(1), pages 50-72, June.

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