Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene
Rodrigo R.R. Duarte,
Oliver Pain,
Robert L. Furler,
Douglas F. Nixon,
Timothy R. Powell
Affiliations
Rodrigo R.R. Duarte
Department of Social, Genetic & Developmental Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, 16 De Crespigny Park, London, SE5 8AF, UK; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, 10021, USA; Corresponding author
Oliver Pain
Department of Social, Genetic & Developmental Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, 16 De Crespigny Park, London, SE5 8AF, UK
Robert L. Furler
Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, 10021, USA
Douglas F. Nixon
Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, 10021, USA
Timothy R. Powell
Department of Social, Genetic & Developmental Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, 16 De Crespigny Park, London, SE5 8AF, UK; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, 10021, USA
Summary: 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.
