Abstract
Millions are exposed to the human immunodeficiency virus type 1 (HIV-1) every year, but not all acquire the virus, suggesting a potential role for host genetics in the moderation of HIV-1 acquisition. Here, we analyzed summary statistics from the largest genome-wide association study of HIV-1 acquisition to-date, consisting of 6,334 infected patients and 7,247 population controls, to advance our understanding of the genetic mechanisms implicated in this trait. We found that HIV-1 acquisition is polygenic and heritable, with SNP heritability estimates explaining 28–42% of the variance in this trait at a population level. Genetic correlations alongside UK Biobank data revealed associations with smoking, prospective memory and socioeconomic traits. Gene-level enrichment analysis identified EF-hand calcium binding domain 14 as a novel susceptibility gene for HIV–1 acquisition. We also observed that susceptibility variants for HIV-1 acquisition were significantly enriched for genes expressed in T-cells, but also in striatal and hippocampal neurons. Finally, we tested how polygenic risk scores for HIV-1 acquisition influence blood levels of 35 inflammatory markers in 406 HIV-1-negative individuals. We found that higher genetic risk for HIV-1 acquisition was associated with lower levels of C-C motif chemokine ligand 17. Our findings corroborate a complex model for HIV-1 acquisition, whereby susceptibility is partly heritable and moderated by specific behavioral, cellular and immunological parameters.
Highlights
Analysis with SumHer-GC showed a higher estimate of single nucleotide polymorphism (SNP) h2 (0.42 ± 0.08), consistent with Linkage Disequilibrium Adjusted Kinships (LDAK) being able to capture a larger proportion of SNPs contributing to SNP h2, relative to Linkage Disequilibrium Score Regression (LDSC)
To better understand which behavioral parameters might be important in moderating human immunodeficiency virus type 1 (HIV-1) acquisition, we performed genetic correlation analyses leveraging on genome-wide association studies (GWAS) data from 516 heritable traits assessed in the UK Biobank via LD Hub, which contains genetic association results from up to 488,377 individuals
The genetic aspects of HIV-1 acquisition have been understudied, in part because no robust genome-wide significant variants were found in early studies[10,11,12,13,14,15,16], which led to the premature assumption that acquisition was not substantially moderated by common genetic variants
Summary
We aimed to investigate the cellular basis for the biological and behavioral parameters implicated in HIV-1 acquisition, and investigated the cell types enriched for variants associated with this trait. We aimed to assess how HIV-1 acquisition risk might be moderated by an individual’s immune profile prior to infection, and so we tested how polygenic risk for HIV-1 acquisition correlated with the expression of 35 inflammatory markers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
