Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls

Paul J McLaren; Cédric Coulonges; Stephan Ripke; Leonard van den Berg; Susan Buchbinder; Mary Carrington; Andrea Cossarizza; Judith Dalmau; Steven G Deeks; Olivier Delaneau; Andrea De Luca; James J Goedert; David Haas; Joshua T Herbeck; Sekar Kathiresan; Gregory D Kirk; Olivier Lambotte; Ma Luo; Simon Mallal; Daniëlle van Manen; Javier Martinez-Picado; Laurence Meyer; José M Miro; James I Mullins; Niels Obel; Stephen J O'Brien; Florencia Pereyra; Francis A Plummer; Guido Poli; Ying Qi; Pierre Rucart; Manj S Sandhu; Patrick R Shea; Hanneke Schuitemaker; Ioannis Theodorou; Fredrik Vannberg; Jan Veldink; Bruce D Walker; Amy Weintrob; Cheryl A Winkler; Steven Wolinsky; Amalio Telenti; David B Goldstein; Paul I W de Bakker; Jean-François Zagury; Jacques Fellay

doi:10.1371/journal.ppat.1003515

Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls

Paul J McLaren, Cédric Coulonges, Stephan Ripke, Leonard van den Berg, Susan Buchbinder, Mary Carrington, Andrea Cossarizza, Judith Dalmau, Steven G Deeks, Olivier Delaneau, Andrea De Luca, James J Goedert, David Haas, Joshua T Herbeck, Sekar Kathiresan, Gregory D Kirk, Olivier Lambotte, Ma Luo, Simon Mallal, Daniëlle van ManenJavier Martinez-Picado, Laurence Meyer, José M Miro, James I Mullins, Niels Obel, Stephen J O'Brien, Florencia Pereyra, Francis A Plummer, Guido Poli, Ying Qi, Pierre Rucart, Manj S Sandhu, Patrick R Shea, Hanneke Schuitemaker, Ioannis Theodorou, Fredrik Vannberg, Jan Veldink, Bruce D Walker, Amy Weintrob, Cheryl A Winkler, Steven Wolinsky, Amalio Telenti, David B Goldstein, Paul I W de Bakker, Jean-François Zagury, Jacques Fellay

72 Citations (Scopus)

Abstract

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10^-11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

Original language	English
Journal	P L o S Pathogens (Online)
Volume	9
Issue number	7
Pages (from-to)	e1003515
Number of pages	9
ISSN	1553-7374
DOIs	https://doi.org/10.1371/journal.ppat.1003515
Publication status	Published - Jul 2013

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10.1371/journal.ppat.1003515

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McLaren, P. J., Coulonges, C., Ripke, S., van den Berg, L., Buchbinder, S., Carrington, M., Cossarizza, A., Dalmau, J., Deeks, S. G., Delaneau, O., De Luca, A., Goedert, J. J., Haas, D., Herbeck, J. T., Kathiresan, S., Kirk, G. D., Lambotte, O., Luo, M., Mallal, S., ... Fellay, J. (2013). Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls. P L o S Pathogens (Online), 9(7), e1003515. https://doi.org/10.1371/journal.ppat.1003515

McLaren, PJ, Coulonges, C, Ripke, S, van den Berg, L, Buchbinder, S, Carrington, M, Cossarizza, A, Dalmau, J, Deeks, SG, Delaneau, O, De Luca, A, Goedert, JJ, Haas, D, Herbeck, JT, Kathiresan, S, Kirk, GD, Lambotte, O, Luo, M, Mallal, S, van Manen, D, Martinez-Picado, J, Meyer, L, Miro, JM, Mullins, JI, Obel, N, O'Brien, SJ, Pereyra, F, Plummer, FA, Poli, G, Qi, Y, Rucart, P, Sandhu, MS, Shea, PR, Schuitemaker, H, Theodorou, I, Vannberg, F, Veldink, J, Walker, BD, Weintrob, A, Winkler, CA, Wolinsky, S, Telenti, A, Goldstein, DB, de Bakker, PIW, Zagury, J-F & Fellay, J 2013, 'Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls', P L o S Pathogens (Online), vol. 9, no. 7, pp. e1003515. https://doi.org/10.1371/journal.ppat.1003515

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title = "Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls",

abstract = "Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10-11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.",

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AU - McLaren, Paul J

AU - Coulonges, Cédric

AU - Ripke, Stephan

AU - van den Berg, Leonard

AU - Buchbinder, Susan

AU - Carrington, Mary

AU - Cossarizza, Andrea

AU - Dalmau, Judith

AU - Deeks, Steven G

AU - Delaneau, Olivier

AU - De Luca, Andrea

AU - Goedert, James J

AU - Haas, David

AU - Herbeck, Joshua T

AU - Kathiresan, Sekar

AU - Kirk, Gregory D

AU - Lambotte, Olivier

AU - Luo, Ma

AU - Mallal, Simon

AU - van Manen, Daniëlle

AU - Martinez-Picado, Javier

AU - Meyer, Laurence

AU - Miro, José M

AU - Mullins, James I

AU - Obel, Niels

AU - O'Brien, Stephen J

AU - Pereyra, Florencia

AU - Plummer, Francis A

AU - Poli, Guido

AU - Qi, Ying

AU - Rucart, Pierre

AU - Sandhu, Manj S

AU - Shea, Patrick R

AU - Schuitemaker, Hanneke

AU - Theodorou, Ioannis

AU - Vannberg, Fredrik

AU - Veldink, Jan

AU - Walker, Bruce D

AU - Weintrob, Amy

AU - Winkler, Cheryl A

AU - Wolinsky, Steven

AU - Telenti, Amalio

AU - Goldstein, David B

AU - de Bakker, Paul I W

AU - Zagury, Jean-François

AU - Fellay, Jacques

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N2 - Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10-11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

AB - Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10-11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

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DO - 10.1371/journal.ppat.1003515

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JO - PLoS Pathogens

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Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls

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