TY - JOUR
T1 - Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene
AU - Rafagnin Duarte, Rodrigo R
AU - Pain, Ollie
AU - Furler, Robert L
AU - Nixon, Douglas F
AU - Powell, Timothy
N1 - Funding Information:
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R21 AI154956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. OP received funding from the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London. TRP is supported by an MRC (UKRI) New Investigator Research Grant (MR/W028018/1). According to UK research councils’ Common Principles on Data Policy, all data supporting this study is openly available, see key resources table. We acknowledge and thank the participants and investigators from McLaren et al. (2013), Johnson et al. (2015), FinnGen (2021), and UK Biobank (Neale Lab, 2018). We acknowledge use of the research computing facility at King's College London, Rosalind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the NIHR Maudsley BRC, and was part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy's & St. Thomas’ Charity (TR130505). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. We also acknowledge the contribution of data from CIDR-NIDA Study of HIV Host Genetics (dbGAP: phs000454.v1.p1). Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by X01 HG005275-01A1. CIDR is fully funded through a contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Funding support for collection of datasets and samples was provided by National Institute on Drug Abuse grants R01 DA026141, R01 DA004212, U01 DA006908, R01 DA009532, as well as the San Francisco Department of Public Health, The Substance Abuse and Mental Health Services Administration, and Health Resources and Services Administration. Study design, performed the analyses: R.R.R.D. and T.R.P. Statistical support: O.P. Wrote the paper: R.R.R.D. and T.R.P. Contributed knowledge, revised the manuscript: all authors. The authors declare no competing interests.
Funding Information:
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R21 AI154956 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. OP received funding from the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London. TRP is supported by an MRC (UKRI) New Investigator Research Grant (MR/W028018/1). According to UK research councils’ Common Principles on Data Policy, all data supporting this study is openly available, see key resources table . We acknowledge and thank the participants and investigators from McLaren et al. (2013) , Johnson et al. (2015) , FinnGen (2021) , and UK Biobank ( Neale Lab, 2018 ). We acknowledge use of the research computing facility at King’s College London, Rosalind ( https://rosalind.kcl.ac.uk ), which is delivered in partnership with the NIHR Maudsley BRC, and was part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy’s & St. Thomas’ Charity (TR130505). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. We also acknowledge the contribution of data from CIDR- NIDA Study of HIV Host Genetics (dbGAP: phs000454.v1.p1). Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by X01 HG005275-01A1. CIDR is fully funded through a contract from the National Institutes of Health to The Johns Hopkins University , contract number HHSN268200782096C . Funding support for collection of datasets and samples was provided by National Institute on Drug Abuse grants R01 DA026141 , R01 DA004212 , U01 DA006908 , R01 DA009532 , as well as the San Francisco Department of Public Health , The Substance Abuse and Mental Health Services Administration , and Health Resources and Services Administration .
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/9/16
Y1 - 2022/9/16
N2 - The host genetic factors conferring protection against HIV type 1 (HIV-1) acquisition remain elusive, and in particular the contributions of common genetic variants. Here, we performed the largest genome-wide association meta-analysis of HIV-1 acquisition, which included 7,303 HIV-1-positive individuals and 587,343 population controls. We identified 25 independent genetic loci with suggestive association, of which one was genome-wide significant within the major histocompatibility complex (MHC) locus. After exclusion of the MHC signal, linkage disequilibrium score regression analyses revealed a SNP heritability of 21% and genetic correlations with behavioral factors. A transcriptome-wide association study identified 15 susceptibility genes, including HERC1, UEVLD, and HIST1H4K. Convergent evidence from conditional analyses and fine-mapping identified HERC1 downregulation in immune cells as a robust mechanism associated with HIV-1 acquisition. Functional studies on HERC1 and other identified candidates, as well as larger genetic studies, have the potential to further our understanding of the host mechanisms associated with protection against HIV-1.
AB - The host genetic factors conferring protection against HIV type 1 (HIV-1) acquisition remain elusive, and in particular the contributions of common genetic variants. Here, we performed the largest genome-wide association meta-analysis of HIV-1 acquisition, which included 7,303 HIV-1-positive individuals and 587,343 population controls. We identified 25 independent genetic loci with suggestive association, of which one was genome-wide significant within the major histocompatibility complex (MHC) locus. After exclusion of the MHC signal, linkage disequilibrium score regression analyses revealed a SNP heritability of 21% and genetic correlations with behavioral factors. A transcriptome-wide association study identified 15 susceptibility genes, including HERC1, UEVLD, and HIST1H4K. Convergent evidence from conditional analyses and fine-mapping identified HERC1 downregulation in immune cells as a robust mechanism associated with HIV-1 acquisition. Functional studies on HERC1 and other identified candidates, as well as larger genetic studies, have the potential to further our understanding of the host mechanisms associated with protection against HIV-1.
UR - http://www.scopus.com/inward/record.url?scp=85136596069&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.104854
DO - 10.1016/j.isci.2022.104854
M3 - Article
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 9
M1 - 104854
ER -
