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

P.J. McLaren; C. Coulonges; I. Bartha; T.L. Lenz; A.J. Deutsch; A. Bashirova; S. Buchbinder; M.N. Carrington; A. Cossarizza; J. Dalmau; A. De Luca; J.J. Goedert; D. Gurdasani; D.W. Haas; J.T. Herbeck; E.O. Johnson; G.D. Kirk; O. Lambotte; M. Luo; S. Mallal; D. van Manen; J. Martinez-Picado; L. Meyer; J.M. Miro; J.I. Mullins; N. Obel; G. Poli; M.S. Sandhu; H. Schuitemaker; P.R. Shea; I. Theodorou; B.D. Walker; A.C. Weintrob; C.A. Winkler; S.M. Wolinsky; S. Raychaudhuri; D.B. Goldstein; A. Telenti; P.I.W. de Bakker; J-F Zagury; J. Fellay

doi:10.1073/pnas.1514867112

Back

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

Journal article

Open access

Peer reviewed

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

P.J. McLaren, C. Coulonges, I. Bartha, T.L. Lenz, A.J. Deutsch, A. Bashirova, S. Buchbinder, M.N. Carrington, A. Cossarizza, J. Dalmau, …

Proceedings of the National Academy of Sciences, Vol.112(47), pp.14658-14663

2015

DOI: https://doi.org/10.1073/pnas.1514867112

Files and links (2)

pdf

polymorphisms_of_large_effect.pdfDownload View

Published (Version of Record) Open Access

url

Link to Published Version *Subscription may be requiredView

Abstract

Previous genome-wide association studies (GWAS) of HIV-1–infected 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 CCR5Δ32 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.

Details

Title: Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load
Authors/Creators: P.J. McLaren (Author/Creator)
C. Coulonges (Author/Creator) - Génomique Bioinformatique et Applications
I. Bartha (Author/Creator) - École Polytechnique Fédérale de Lausanne
T.L. Lenz (Author/Creator) - Max Planck Institute for Evolutionary Biology
A.J. Deutsch (Author/Creator) - Brigham and Women's Hospital
A. Bashirova (Author/Creator) - Massachusetts Institute of Technology
S. Buchbinder (Author/Creator) - San Francisco Department of Public Health
M.N. Carrington (Author/Creator) - Massachusetts Institute of Technology
A. Cossarizza (Author/Creator) - University of Modena and Reggio Emilia
J. Dalmau (Author/Creator) - Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol
A. De Luca (Author/Creator) - University of Siena
J.J. Goedert (Author/Creator) - National Cancer Institute
D. Gurdasani (Author/Creator) - Wellcome Sanger Institute
D.W. Haas (Author/Creator) - sVanderbilt University School of Medicine, Nashville, TN 37212;
J.T. Herbeck (Author/Creator) - University of Washington
E.O. Johnson (Author/Creator) - RTI International
G.D. Kirk (Author/Creator) - Johns Hopkins University
O. Lambotte (Author/Creator) - wINSERM U1012, 94270 Bicêtre, France;
M. Luo (Author/Creator) - University of Manitoba
S. Mallal (Author/Creator) - Murdoch University
D. van Manen (Author/Creator) - University of Amsterdam
J. Martinez-Picado (Author/Creator) - Institució Catalana de Recerca i Estudis Avançats
L. Meyer (Author/Creator) - Agence Nationale de Recherches sur le Sida et les Hépatites Virales
J.M. Miro (Author/Creator) - Universitat de Barcelona
J.I. Mullins (Author/Creator) - University of Washington
N. Obel (Author/Creator) - Copenhagen University Hospital
G. Poli (Author/Creator) - Vita-Salute San Raffaele University
M.S. Sandhu (Author/Creator) - Wellcome Sanger Institute
H. Schuitemaker (Author/Creator) - University of Amsterdam
P.R. Shea (Author/Creator) - Columbia University
I. Theodorou (Author/Creator) - Agence Nationale de Recherches sur le Sida et les Hépatites Virales
B.D. Walker (Author/Creator) - Massachusetts Institute of Technology
A.C. Weintrob (Author/Creator) - Uniformed Services University of the Health Sciences
C.A. Winkler (Author/Creator) - Leidos (United States)
S.M. Wolinsky (Author/Creator) - Northwestern University
S. Raychaudhuri (Author/Creator) - Brigham and Women's Hospital
D.B. Goldstein (Author/Creator) - Columbia University
A. Telenti (Author/Creator) - J. Craig Venter Institute
P.I.W. de Bakker (Author/Creator) - Utrecht University
J-F Zagury (Author/Creator) - Génomique Bioinformatique et Applications
J. Fellay (Author/Creator) - École Polytechnique Fédérale de Lausanne
Publication Details: Proceedings of the National Academy of Sciences, Vol.112(47), pp.14658-14663
Publisher: National Academy of Sciences
Identifiers: 991005540785907891
Copyright: © 2015 National Academy of Sciences
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Metrics

199 File views/ downloads

94 Record Views

141 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.66 HIV; 1.66.46 HIV Pathogenesis
Web Of Science research areas: Multidisciplinary Sciences
ESI research areas: Molecular Biology & Genetics