Genetic, transcriptomic, and epigenetic studies of HIV-associated neurocognitive disorder

Abstract

The Human Genome Project, coupled with rapidly evolving high-throughput technologies, has opened the possibility of identifying heretofore unknown biological processes underlying human disease. Because of the opaque nature of HIV-associated neurocognitive disorder (HAND) neuropathogenesis, the utility of such methods has gained notice among NeuroAIDS researchers. Furthermore, the merging of genetics with other research areas has also allowed for application of relatively nascent fields, such as neuroimaging genomics, and pharmacogenetics, to the context of HAND. In this review, we detail the development of genetic, transcriptomic, and epigenetic studies of HAND, beginning with early candidate gene association studies and culminating in current "omics" approaches that incorporate methods from systems biology to interpret data from multiple levels of biological functioning. Challenges with this line of investigation are discussed, including the difficulty of defining a valid phenotype for HAND. We propose that leveraging known associations between biology and pathology across multiple levels will lead to a more reliable and valid phenotype. We also discuss the difficulties of interpreting the massive and multitiered mountains of data produced by current high-throughput omics assays and explore the utility of systems biology approaches in this regard.

Figure 1

Co-expressed genes tend to cluster into modules corresponding to major biological divisions (cell type, molecular function, etc), as well as disease-relevant changes. Module summaries are presented for frontal cortex (top), neostriautm (middle), and white matter (bottom). The dendrograms group genes into distinct modules using hierarchical clustering. The y-axis corresponds to distance determined by the extent of topological overlap (1-TO). Top color band (Module label): dynamic tree cutting was used to identify highly parsimonious module definitions, generally dividing modules at significant branch points in the dendrogram. Second color band (CT vs. HIV): plotted T values of control (group A) vs. HIV+ samples (group B,C,D). Third color band (Encephalitis): plotted T values of HIV without encephalitis (groups B,C) vs. HIV with encephalitis (group D) samples. Fourth color band (Impairment): plotted correlations of GCR scores, our measure of neurocognitive impairment, across all HIV subjects. Fifth color band (CPE score): plotted correlations of CPE scores across all HIV+ subjects. NOTE: Red corresponds to genes with higher expression in HIV, impairment score (GCR), HIVE, and CPE score for color bands two through five, respectively. Note that the most significant correlations with disease tend to occur in FC. Arrows within top color band indicate that these modules are enriched for genes showing increased or decreased expression in hippocampus of Alzheimer’s disease (Blalock et al. 2004; p<0.00002). Figure from Levine et al .