A Phylogeny-aware GWAS Framework to Correct for Heritable Pathogen Effects on Infectious Disease Traits-Reference-Cited by-同舟云学术

A Phylogeny-aware GWAS Framework to Correct for Heritable Pathogen Effects on Infectious Disease Traits

Published:2022-08-01 Issue:8 Volume:39 Page:
ISSN:0737-4038
Container-title:Molecular Biology and Evolution
language:en
Short-container-title:

Author:

Nadeau Sarah¹²^ORCID,Thorball Christian W³,Kouyos Roger⁴⁵,Günthard Huldrych F⁴⁵,Böni Jürg⁴,Yerly Sabine⁶,Perreau Matthieu⁷,Klimkait Thomas⁸,Rauch Andri⁹,Hirsch Hans H⁸¹⁰¹¹^ORCID,Cavassini Matthias¹²^ORCID,Vernazza Pietro¹³,Bernasconi Enos¹⁴,Fellay Jacques²³¹⁵,Mitov Venelin¹²^ORCID,Stadler Tanja¹²^ORCID,Abela I,Aebi-Popp K,Anagnostopoulos A,Battegay M,Bernasconi E,Braun DL,Bucher HC,Calmy A,Cavassini M,Ciuffi A,Dollenmaier G,Egger M,Elzi L,Fehr J,Fellay J,Furrer H,Fux CA,Günthard HF,Hachfeld A,Haerry D,Hasse B,Hirsch HH,Hoffmann M,Hösli I,Huber M,Kahlert CR,Kaiser L,Keiser O,Klimkait T,Kouyos RD,Kovari H,Kusejko K,Martinetti G,Martinez de Tejada B,Marzolini C,Metzner KJ,Müller N,Nemeth J,Nicca D,Paioni P,Pantaleo G,Perreau M,Rauch A,Schmid P,Speck R,Stöckle M,Tarr P,Trkola A,Wandeler G,Yerly S,

Affiliation:

1. Department of Biosystems Science and Engineering, ETH Zürich , Basel , Switzerland

2. Swiss Institute of Bioinformatics , Lausanne , Switzerland

3. Precision Medicine Unit, Lausanne University Hospital and University of Lausanne , Lausanne , Switzerland

4. Institute of Medical Virology, University of Zurich , Zurich , Switzerland

5. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich , Zurich , Switzerland

6. Division of Infectious Diseases, Laboratory of Virology, Geneva University Hospital , Geneva , Switzerland

7. Division of Immunology and Allergy, University Hospital Lausanne , Lausanne , Switzerland

8. Department of Biomedicine, University of Basel , Basel , Switzerland

9. Department of Infectious Diseases, Bern University Hospital and University of Bern , Bern , Switzerland

10. Transplantation and Clinical Virology, Department of Biomedicine, University of Basel , Basel , Switzerland

11. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel , Basel , Switzerland

12. Division of Infectious Diseases, University Hospital Lausanne , Lausanne , Switzerland

13. Division of Infectious Diseases, Cantonal Hospital St. Gallen , St. Gallen , Switzerland

14. Division of Infectious Diseases, Regional Hospital Lugano , Lugano , Switzerland

15. Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne , Lausanne , Switzerland

Abstract

Abstract 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.

Publisher

Oxford University Press (OUP)

Subject

Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics

Link

https://academic.oup.com/mbe/advance-article-pdf/doi/10.1093/molbev/msac163/45228998/msac163.pdf

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