Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

Paul J. McLaren, Cedric Coulonges, István Bartha, Tobias L. Lenz, Aaron J. Deutsch, Arman Bashirova, Susan Buchbinder, Mary N. Carrington, Andrea Cossarizza, Judith Dalmau, Andrea De Luca, James J. Goedert, Deepti Gurdasani, David W. Haas, Joshua T. Herbeck, Eric O. Johnson, Gregory D. Kirk, Olivier Lambotte, Ma Luo, Simon MallalDaniëlle Van Manen, Javier Martinez-Picado, Laurence Meyer, José M. Miro, James I. Mullins, Niels Obel, Guido Poli, Manjinder S. Sandhu, Hanneke Schuitemaker, Patrick R. Shea, Ioannis Theodorou, Bruce D. Walker, Amy C. Weintrob, Cheryl A. Winkler, Steven M. Wolinsky, Soumya Raychaudhuri, David B. Goldstein, Amalio Telenti, Paul I.W. De Bakker, Jean François Zagury, Jacques Fellay

    Research output: Contribution to journalArticleResearchpeer-review

    78 Citations (Scopus)

    Abstract

    Previous genome-wide association studies (GWAS) of HIV-1Cinfected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ¡«8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5'32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation¡mostly in the HLA and CCR5 regions¡explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.
    Original languageEnglish
    Pages (from-to)14658-14663
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume112
    Issue number47
    DOIs
    Publication statusPublished - 24 Nov 2015

    Keywords

    • Genomics
    • GWAS
    • Heritability
    • HIV-1 control
    • Infectious disease

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