A genome-wide polygenic approach to HIV acquisition uncovers link to inflammatory bowel disease and identifies potential novel genetic variants

Abstract

Polygenic approaches using genome-wide data have been hugely successful in confirming and quantifying the heritability of complex human traits. Here, we highlight their ability to identify potential novel risk variants by looking for variants with pleiotropic effect in genetically overlapping phenotypes.We used LD Score Regression in a sample of 6,315 HIV+ European individuals and 7,247 controls to test for phenotypes genetically overlapping with susceptibility to HIV-1 infection. Using LD Hub, a web tool that performs LD Score Regression, identified two phenotypes with significant genetic overlap: schizophrenia (rG =0.19, p=0.0007 and ulcerative colitis (rG=0.22, p= 0.0061). We further showed that the genetic overlap between HIV acquisition and schizophrenia is likely driven in part by their shared overlap with cannabis use and sexual behavior. BUMHBOX analyses suggested that these genetic overlaps were driven by genome-wide pleiotropy with HIV acquisition rather than heterogeneity within the HIV acquisition sample. The two diseases identified as genetically overlapping with HIV-1 acquisition have >100 associated variants, and we tested if any of them significantly associated with HIV acquisition. We observed three variants that exceeded our threshold for statistical significance. Two of these were eQTLs in whole blood for genes coding for proteins suspected to be involved in HIV biology: rs1819333 in CCR6 (p=0.0002) and rs4932178 in FURIN (p=0.00033). However, no signal was found for these variants in two smaller African samples totaling 1015 cases and 963 controls, though the mode of acquisition and genetic architecture of these populations differed.These results highlight the ability to use polygenic methods to gain new insights into complex diseases and identify potential associations with individual variants. Crucially, the leveraging of existing, publically available data makes these methods a cost-effective approach. In this case, our results add to the evidence for the role of risk taking behavior and inflammation of the bowel in HIV acquisition.Author SummaryThe biology of what puts certain individuals at greater risk of HIV acquisition is poorly understood. Using several novel polygenic methods, we identify supporting evidence for two important factors leading to acquisition. First, the role of an individual’s genetic predisposition to risk taking behaviours such as number of sexual partners, age at first sexual intercourse drug use, and mental health problems. Second, the role of gut inflammation, in particular a genetic overlap between HIV acquisition with inflammatory bowel disease and the potential role of CCR6 during infection.

The behavioral, cellular and immune mediators of HIV-1 acquisition: New insights from population genetics

“…We estimated the SNP heritability (SNP h 2 ) of HIV-1 acquisition by analyzing these GWAS results using LD Hub (LDSC-based) 19 and SumHer-GC 20 (based on the LDAK model, correcting for possible hidden population structure). We observed that SNP h 2 = 0.28 ± 0.05 (standard deviation; SD) under the LDSC model, suggesting that HIV-1 acquisition is a heritable trait, replicating a previous analysis of the same dataset 21 . Analysis with SumHer-GC showed a higher estimate of SNP h 2 (0.42 ± 0.08), consistent with LDAK being able to capture a larger proportion of SNPs contributing to SNP h 2 , relative to LDSC.…”