Genome-wide association study of HIV-associated neurocognitive disorder (HAND): A CHARTER group study

Abstract

HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive, and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded. Neurocognitive outcomes included GDS-defined neurocognitive impairment (NCI; binary GDS, 366 cases with GDS ≥ 0.5 and 684 controls with GDS < 0.5, and GDS as a continuous variable) and Frascati HAND definitions that incorporate assessment of functional impairment by self-report and performance-based criteria. Genotype data were obtained using the Affymetrix Human SNP Array 6.0 platform. Multivariable logistic or linear regression-based association tests were performed for GDS-defined NCI and HAND. GWAS results did not reveal SNPs meeting the genome-wide significance threshold (5.0 × 10^-8 ) for GDS-defined NCI or HAND. For binary GDS, the most significant SNPs were rs6542826 (P = 8.1 × 10^-7 ) and rs11681615 (1.2 × 10^-6 ), both located on chromosome 2 in SH3RF3. The most significant SNP for continuous GDS was rs11157436 (P = 1.3 × 10^-7 ) on chromosome 14 in the T-cell-receptor alpha locus; three other SNPs in this gene were also associated with binary GDS (P ≤ 2.9 × 10^-6 ). This GWAS, conducted among ART-era participants from a single cohort with robust neurological phenotyping, suggests roles for several biologically plausible loci in HAND that deserve further exploration. © 2017 Wiley Periodicals, Inc.

Keywords: CHARTER study; GWAS; HIV-associated neurocognitive disorder; genotype; global deficit score; neurocognitive impairment.

Figure 1

Distribution of Global Deficit Score (GDS) in the CHARTER study population. GDS as a continuous (quantitative) variable (A) or as a binary variable (B) in different population subgroups. GDS as a continuous variable (C) or as a binary variable (D) in different HAND sub-categories.

Figure 2

Genetic ancestry (by principal components, PC) in the CHARTER population compared to HapMap samples.

Figure 3

Population distribution as predicted by genome-wide genotype data versus self-reported race/ethnicity.

Figure 4

Q-Q plot of the genome-wide association study (GWAS) results for GDS as a binary phenotype (left) or GDS as a quantitative phenotype (right). The grey area indicates 95% confidence interval (CI).

Figure 5

Manhattan plot of GWAS results for GDS as a binary phenotype (top) or GDS as a quantitative phenotype (bottom).

Figure 6

Examples of top SNPs associated with GDS as a quantitative phenotype or binary phenotype in the CHARTER Study. Note in the region on chromosome 14, the gene TRAα had many transcripts and was not shown in the figure.

Figure 7

Comparison of top SNPs associated with GDS as a quantitative phenotype and GDS as a binary phenotype at different cut-off values and overlap of associations between phenotypes.