biostudies-literatureDuarte RRRNIDA NIH HHSNIA NIH HHSNIAID NIH HHSNIDCD NIH HHSMedical Research CouncilNHGRI NIH HHS104854https://www.ebi.ac.uk/biostudies/studies/S-EPMC9403347biostudies-literatureUnknown25(9)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 <i>HERC1</i>, <i>UEVLD</i>, and <i>HISTiScienceTranscriptome-wide association study of HIV-1 acquisition identifies &lt;i&gt;HERC1&lt;/i&gt; as a susceptibility gene.PMC9403347R01 DC004212MC_PC_17228R01 AG004212HHSN268200782096CR21 AI154956R01 DA009532R01 DA026141MC_QA137853Furler RLPowell TRDuarte RRRNixon DFPain OfalseTranscriptome-wide association study of HIV-1 acquisition identifies &lt;i&gt;HERC1&lt;/i&gt; as a susceptibility gene.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 <i>HERC1</i>, <i>UEVLD</i>, and <i>HIST2022-01-01T00:00:00Z2022 Sep2026-05-09T03:16:41.972Z2024-10-16T04:13:10.876ZS-EPMC94033473603423210.1016/j.isci.2022.104854