Journal
MOLECULAR BIOLOGY AND EVOLUTION
Volume 39, Issue 8, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/molbev/msac163
Keywords
genome-wide association study; infectious disease; phylogenetic mixed model; heritability
Funding
- ETH Zurich
- Swiss National Science Foundation [201369]
- SHCS project [858]
- SHCS research foundation
- Yvonne Jacob Foundation
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Infectious diseases pose challenges for GWAS due to the influence of genetic effects from both pathogen and host. This research proposes a new method that estimates and removes heritable pathogen effects on a trait based on the pathogen phylogeny, restoring sample independence in GWAS. The method was tested in simulations and applied to data from two host-pathogen systems, showing its potential to increase GWAS power and provide insight into the evolutionary dynamics of traits in pathogen populations.
Infectious diseases are particularly challenging for genome-wide association studies (GWAS) because genetic effects from two organisms (pathogen and host) can influence a trait. Traditional GWAS assume individual samples are independent observations. However, pathogen effects on a trait can be heritable from donor to recipient in transmission chains. Thus, residuals in GWAS association tests for host genetic effects may not be independent due to shared pathogen ancestry. We propose a new method to estimate and remove heritable pathogen effects on a trait based on the pathogen phylogeny prior to host GWAS, thus restoring independence of samples. In simulations, we show this additional step can increase GWAS power to detect truly associated host variants when pathogen effects are highly heritable, with strong phylogenetic correlations. We applied our framework to data from two different host-pathogen systems, HIV in humans and X. arboricola in A. thaliana. In both systems, the heritability and thus phylogenetic correlations turn out to be low enough such that qualitative results of GWAS do not change when accounting for the pathogen shared ancestry through a correction step. This means that previous GWAS results applied to these two systems should not be biased due to shared pathogen ancestry. In summary, our framework provides additional information on the evolutionary dynamics of traits in pathogen populations and may improve GWAS if pathogen effects are highly phylogenetically correlated amongst individuals in a cohort.
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