Nuclear-Mitochondrial interactions influence susceptibility to HIV-associated neurocognitive impairment

Abstract

HIV-associated neurocognitive impairment (NCI) is a term established to capture a wide spectrum of HIV related neurocognitive deficits ranging in severity from asymptomatic to dementia. The genetic underpinnings of this complex phenotype are incompletely understood. Mitochondrial function has long been thought to play a role in neurodegeneration, along with iron metabolism and transport. In this work, we aimed to characterize the interplay of mitochondrial DNA (mtDNA) haplogroup and nuclear genetic associations to NCI phenotypes in the CHARTER cohort, encompassing 1025 individuals of European-descent, African-descent, or admixed Hispanic. We first employed a polygenic modeling approach to investigate the global effect of previous marginally associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. We see evidence of a significant interaction between nuclear SNPs en masse and mtDNA haplogroups within European-descent and African-descent individuals. Subsequently, we performed an analysis of each SNP by mtDNA haplogroup, and detected significant interactions between two nuclear SNPs (rs17160128 and rs12460243) and European haplogroups. These findings, which require validation in larger cohorts, indicate a potential new role for nuclear-mitochondrial DNA interactions in susceptibility to NCI and shed light onto the pathophysiology of this neurocognitive phenotype.

Keywords: Genomics; HIV; Haplogroups; Neurocognitive impairment; Nuclear mitochondrial interactions; Single nucleotide polymorphism.

Figure 1

Interaction of rs12460243 and Haplogroups. GDS (y-axis) is plotted by genotype/haplogroup combination in European-descent populations. Across all haplogroups, there is a recessive effect of SNP, with increased GDS in the GG genotype. Across all genotypes, all haplogroups have approximately the same median GDS. However, within the H haplogroup, heterozygotes (GA) have lower (better) GDS, compared to J, T, and UK haplogroups where heterozygotes show higher GDS (> 0.5) indicating greater impairment.

Figure 2

Interaction of rs978490 and Haplogroups. GDS (y-axis) is plotted by genotype/haplogroup combination in European-descent populations. There is increased GDS in the CT genotype within T haplogroup individuals relative to other haplogroups.

Figure 3

Interaction Box-Plots for expression of ELAVL1 (Geuvadis). Normalized gene expression (y-axis) is plotted by genotype/haplogroup combination in European-descent populations for rs12460243. We observe a significant interaction between genotype and haplogroup, and similar to GDS in figure 1, we osbserve higher expression in H homozygous (AA) individuals.

Figure 4

Interaction Box-Plots for expression of POLG2 (Geuvadis). Normalized gene expression (y-axis) is plotted by genotype/haplogroup combination in European-descent populations for rs978490. We observe a significant interaction between genotype and haplogroup, driven by a change in slope in the T haplogroup; for other groups, POLG2 expression is either equal to or slightly increasing with the number of copies of the C allele.