Multiancestry sex-stratified genomic associations with HIV viral load and controller status from the ICGH
Candelaria Vergara, Jeffrey F. Tuff, International Collaboration for the Genomics of HIV (ICGH), Jacques Fellay, Priya Duggal, Eileen P. Scully, Paul J. McLaren
Candelaria Vergara, Jeffrey F. Tuff, International Collaboration for the Genomics of HIV (ICGH), Jacques Fellay, Priya Duggal, Eileen P. Scully, Paul J. McLaren
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Research Article AIDS/HIV Genetics

Multiancestry sex-stratified genomic associations with HIV viral load and controller status from the ICGH

Abstract

Biological sex and host genetics influence HIV pathogenesis. Females have a higher likelihood of spontaneous viral control and lower set point viral load (spVL). No prior studies have assessed sex-specific genetics of HIV. To address this, we performed a sex-stratified genome-wide association study using data from the ICGH. Although it is the largest collection of genomic data in HIV, this multiethnic sample of 9,705 people is 81.3% male. We sought to identify sex-specific genetic variants and genes associated with HIV spVL and control. We confirmed associations in the HLA and CCR5 regions in males and HLA in females. Gene-based analyses detected associations between HIV spVL and PET100, PCP2, XAB2, and STXBP2 only in males. We detected variants with a significant sex-differential effect on spVL in SDC3 and PUM1 (rs10914268) and PSORS1C2 (rs1265159) and on HIV control in SUB1 (rs687659), AL158151.3, PTPA, and IER5L (rs4387067). Those variants have epigenetic and genetic interactions with relevant genes with both cis and trans effects. In summary, we identified sex-shared associations at the single-variant level, sex-specific associations at the gene-based level, and genetic variants with significant differential effects between the sexes.

Authors

Candelaria Vergara, Jeffrey F. Tuff, International Collaboration for the Genomics of HIV (ICGH), Jacques Fellay, Priya Duggal, Eileen P. Scully, Paul J. McLaren

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Figure 3

Variants on chr1p35.2 and chr6p21.33 regions showing strong heterogeneity in direction and size of effect on HIV spVL in males compared with females.

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Variants on chr1p35.2 and chr6p21.33 regions showing strong heterogeneit...
(A and B) Effect size (β) point estimates (diamonds) and standard error (whiskers) for variants showing strong differences between females (red) and males (blue). The x axis shows genomic positions (GRChg38/hg38) in mega-bases. The y axis denotes betas from linear regression models in units of HIV RNA copies/mL of plasma. Protein coding genes in the region are included at the bottom in green. (C and D) Effect sizes (beta) and standard error of the variant with the most significantly different effects between males and females in each region. The rs number and effect allele are listed above each plot. P values were calculated using 2-tailed Student’s t test. (E and F) Circos plots of chromatin interactions and eQTLs for chr1p35.2 and chr6p21.33 loci, respectively. In the most outer layer is a Manhattan plot, showing only SNPs with P < 0.05. SNPs in genomic risk loci are color coded as a function of their maximum r2 to the 1 of the independent significant SNPs in the locus, as follows: red (r2 > 0.8), orange (r2 > 0.6), green (r2 > 0.4), and blue (r2 > 0.2). SNPs that are not in LD with any of the independent significant SNPs (with r2 ≤ 0.2) are gray. The rs number of the top SNPs in each risk locus are displayed in the most outer layer. The y axis (represented by the expanding rings around the central circular locus map) is ranged between 0 to the maximum –log10(P value) of the SNPs. The second layer displays the chromosome ring, where genomic risk loci are highlighted in blue. Inside this ring are the acronyms of the genes mapped by chromatin interactions or eQTLs. Links to genes and genes mapped only by chromatin interactions or only by eQTLs are colored orange or green. Links for genes and genes mapped by both are colored in red. PSORS1C2, psoriasis susceptibility 1 candidate 2; SDC3, syndecan 3; PUM1, pumilio RNA binding family member 1.