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Genome-wide association study of HIV whole genome sequences validated using drug resistance

Robert A. Power, Siva Davaniah, Anne Derache, Eduan Wilkinson, Frank Tanser, Ravindra K. Gupta, Deenan Pillay, Tulio de Oliveira
doi: https://doi.org/10.1101/076216
Robert A. Power
1Africa Centre for Population Health, University of KwaZulu-Natal, South Africa
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  • For correspondence: rpower@africacentre.ac.za
Siva Davaniah
1Africa Centre for Population Health, University of KwaZulu-Natal, South Africa
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Anne Derache
1Africa Centre for Population Health, University of KwaZulu-Natal, South Africa
2Sorbonne Universités, UPMC Univ Paris 06, Inserm, Institut Pierre Louis d’Epidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France
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Eduan Wilkinson
1Africa Centre for Population Health, University of KwaZulu-Natal, South Africa
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Frank Tanser
1Africa Centre for Population Health, University of KwaZulu-Natal, South Africa
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Ravindra K. Gupta
3Division of Infection and Immunity, University College London, London, UK
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Deenan Pillay
1Africa Centre for Population Health, University of KwaZulu-Natal, South Africa
3Division of Infection and Immunity, University College London, London, UK
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Tulio de Oliveira
1Africa Centre for Population Health, University of KwaZulu-Natal, South Africa
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Abstract

Genome-wide association studies (GWAS) have considerably advanced our understanding of human traits and diseases. With the increasing availability of whole genome sequences (WGS) for pathogens, it is important to establish whether GWAS of viral genomes could reveal important biological insights. Here we perform the first proof of concept viral GWAS examining drug resistance (DR), a phenotype with well understood genetics.

We performed a GWAS of DR in a sample of 343 HIV subtype C patients failing 1st line antiretroviral treatment in rural KwaZulu-Natal, South Africa. The majority and minority variants within each sequence were called using PILON, and GWAS was performed within PLINK. HIV WGS from patients failing on different antiretroviral treatments were compared to sequences derived from individuals naive to the respective treatment.

GWAS methodology was validated by identifying five associations on a genetic level that led to amino acid changes known to cause DR. Further, we highlighted the ability of GWAS to identify epistatic effects, identifying two replicable variants within amino acid 68 of the reverse transcriptase protein previously described as potential fitness compensatory mutations. A possible additional DR variant within amino acid 91 of the matrix region of the Gag protein was associated with tenofovir failure, highlighting the ability of GWAS to identify variants outside classical candidate genes. Our results also suggest a polygenic component to DR.

These results validate the applicability of GWAS to HIV WGS data even in relative small samples, and emphasise how high throughput sequencing can provide novel and clinically relevant insights. Further they suggested that for viruses like HIV, population structure was only minor concern compared to that seen in bacteria or parasite GWAS. Given the small genome length and reduced burden for multiple testing, this makes HIV an ideal candidate for GWAS.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 20, 2016.
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Genome-wide association study of HIV whole genome sequences validated using drug resistance
Robert A. Power, Siva Davaniah, Anne Derache, Eduan Wilkinson, Frank Tanser, Ravindra K. Gupta, Deenan Pillay, Tulio de Oliveira
bioRxiv 076216; doi: https://doi.org/10.1101/076216
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Genome-wide association study of HIV whole genome sequences validated using drug resistance
Robert A. Power, Siva Davaniah, Anne Derache, Eduan Wilkinson, Frank Tanser, Ravindra K. Gupta, Deenan Pillay, Tulio de Oliveira
bioRxiv 076216; doi: https://doi.org/10.1101/076216

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