title: Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load.
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.
authors.affiliation: Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland;
authors.forename: Paul J
authors.identifier: http://orcid.org/0000-0001-6019-7018
authors.initials: PJ
authors.lastname: McLaren
authors.affiliation: Laboratoire Génomique, Bioinformatique, et Applications, EA4627, Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, 75003 Paris, France; ANRS Genomic Group (French Agency for Research on AIDS and Hepatitis), 75013 Paris, France;
authors.forename: Cedric
authors.initials: C
authors.lastname: Coulonges
authors.affiliation: Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland;
authors.forename: István
authors.initials: I
authors.lastname: Bartha
authors.affiliation: Evolutionary Immunogenomics, Department of Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, 24306 Ploen, Germany;
authors.forename: Tobias L
authors.initials: TL
authors.lastname: Lenz
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology and Harvard Medical School, Harvard University, Boston, MA 02115; Division of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Deutsch
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA 02129;
authors.forename: Arman
authors.initials: A
authors.lastname: Bashirova
authors.affiliation: Bridge HIV-1, San Francisco Department of Public Health, San Francisco, CA 94102;
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA 02129; Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702;
authors.forename: Mary N
authors.initials: MN
authors.lastname: Carrington
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia School of Medicine, 41121 Modena, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Cossarizza
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain;
authors.forename: Judith
authors.initials: J
authors.lastname: Dalmau
authors.affiliation: University Division of Infectious Diseases, Siena University Hospital, 53100 Siena, Italy; Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850;
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, CB10 1SA Hinxton, United Kingdom; Department of Medicine, University of Cambridge, CB2 2QQ Cambridge, United Kingdom;
authors.forename: Deepti
authors.initials: D
authors.lastname: Gurdasani
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN 37212;
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA 98195;
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Herbeck
authors.affiliation: Behavioral Health Epidemiology, RTI International, Research Triangle Park, NC 27709;
authors.forename: Eric O
authors.initials: EO
authors.lastname: Johnson
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Baltimore, MD 21205;
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirk
authors.affiliation: INSERM U1012, 94270 Bicêtre, France; University Paris-Sud, 94270 Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Department of Internal Medicine and Infectious Diseases, Bicêtre Hospital, 94270 Bicêtre, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Lambotte
authors.affiliation: Department of Medical Microbiology, University of Manitoba, R3E 0J6 Winnipeg, MB, Canada; National Microbiology Laboratory, R3E 3P6 Winnipeg, MB, Canada;
authors.forename: Ma
authors.initials: M
authors.lastname: Luo
authors.affiliation: Institute for Immunology & Infectious Diseases, Murdoch University and Pathwest, 6150 Perth, Australia;
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.affiliation: Center for Infectious Diseases and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Daniëlle
authors.initials: D
authors.lastname: van Manen
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; Institució Catalana de Recerca i Estudis Avançats, 08916 Barcelona, Spain;
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
authors.affiliation: ANRS Genomic Group (French Agency for Research on AIDS and Hepatitis), 75013 Paris, France; Inserm, Centre de Recherche en Épidémiologie et Santé des Populations, U1018, Le Kremlin 94270 Bicêtre, France; Faculté de Médecine Paris-Sud, Université Paris-Sud, UMRS 1018, Le Kremlin 94270 Bicêtre, France; Epidemiology and Public Health Service, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin 94270 Bicêtre, France;
authors.forename: Laurence
authors.initials: L
authors.lastname: Meyer
authors.affiliation: Infectious Diseases Service, Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, 08036 Barcelona, Spain;
authors.forename: José M
authors.initials: JM
authors.lastname: Miro
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195;
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.affiliation: Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark;
authors.forename: Niels
authors.initials: N
authors.lastname: Obel
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University School of Medicine, 20132 Milan, Italy;
authors.forename: Guido
authors.initials: G
authors.lastname: Poli
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, CB10 1SA Hinxton, United Kingdom; Department of Medicine, University of Cambridge, CB2 2QQ Cambridge, United Kingdom;
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Sandhu
authors.affiliation: Center for Infectious Diseases and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Hanneke
authors.initials: H
authors.lastname: Schuitemaker
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032;
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Shea
authors.affiliation: ANRS Genomic Group (French Agency for Research on AIDS and Hepatitis), 75013 Paris, France; INSERM UMRS 945, 75014 Paris, France;
authors.forename: Ioannis
authors.initials: I
authors.lastname: Theodorou
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA 02129; Howard Hughes Medical Institute, Chevy Chase, MD 20815;
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
authors.forename: Amy C
authors.initials: AC
authors.lastname: Weintrob
authors.affiliation: Basic Research Laboratory, Molecular Genetic Epidemiology Section, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.affiliation: Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolinsky
authors.affiliation: Division of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142; Faculty of Medical and Human Sciences, University of Manchester, M13 9PL Manchester, United Kingdom;
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032;
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.affiliation: The J. Craig Venter Institute, La Jolla, CA 92037;
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Department of Epidemiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Laboratoire Génomique, Bioinformatique, et Applications, EA4627, Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, 75003 Paris, France; ANRS Genomic Group (French Agency for Research on AIDS and Hepatitis), 75013 Paris, France;
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Zagury
authors.affiliation: Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Jacques.Fellay@epfl.ch.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
mesh_terms: D000328:Adult; D000483:Alleles; D000596:Amino Acids / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015497:HIV-1 / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019713:Receptors, CCR5 / Q000235:genetics; D019562:Viral Load / Q000235:genetics*
chemical_list: D000596:Amino Acids; C584933:CCR5 protein, human; D015235:HLA-B Antigens; D019713:Receptors, CCR5
keywords: GWAS; HIV-1 control; genomics; heritability; infectious disease