Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance.
BACKGROUND
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.


METHODS
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 naïve to the respective treatment.


RESULTS
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 GWAS's ability to identify variants outside classical candidate genes. Our results also suggest a polygenic component to DR.


CONCLUSIONS
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.
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa.
Robert A
RA
Power
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa.
Siva
S
Davaniah
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa.|Sorbonne Universités, UPMC Univ Paris 06, Inserm, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.
Anne
A
Derache
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa.
Eduan
E
Wilkinson
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa.
Frank
F
Tanser
Division of Infection and Immunity, University College London, London, United Kingdom.
Ravindra K
http://orcid.org/0000-0001-9751-1808
RK
Gupta
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa.|Division of Infection and Immunity, University College London, London, United Kingdom.
Deenan
D
Pillay
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa.
Tulio
T
de Oliveira
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