Genome-wide association study of neurocognitive impairment and dementia in HIV-infected adults

Abstract

The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. Candidate gene studies have implicated genetic susceptibility loci within immune-related genes; however, these have not been reliably validated. Here, we employed genome-wide association (GWA) methods to discover novel genetic susceptibility loci associated with HAND, and validate susceptibility loci implicated in prior candidate gene studies. Data from 1,287 participants enrolled in the Multicenter AIDS Cohort Study between 1985 and 2010 were used. Genotyping was conducted with Illumina 1M, 1MDuo, or 550K platform. Linear mixed models determined subject-specific slopes for change over time in processing speed and executive functioning, considering all visits including baseline and the most recent study visit. Covariates modeled as fixed effects included: time since the first visit, depression severity, nadir CD4+ T-cell count, hepatitis C co-infection, substance use, and antiretroviral medication regimen. Prevalence of HIV-associated dementia (HAD) and neurocognitive impairment (NCI) was also examined as neurocognitive phenotypes in a case-control analysis. No genetic susceptibility loci were associated with decline in processing speed or executive functioning among almost 2.5 million single nucleotide polymorphisms (SNPs) directly genotyped or imputed. No association between the SNPs and HAD or NCI were found. Previously reported associations between specific genetic susceptibility loci, HIV-associated NCI, and HAD were not validated. In this first GWAS of HAND, no novel or previously identified genetic susceptibility loci were associated with any of the phenotypes examined. Due to the relatively small sample size, future collaborative efforts that incorporate this dataset may still yield important findings.

Figure 1

First two principal components (PC) from an engine-analysis of the IBS matrix, based on samples from HapMap (www.hapmap.org). CEU is a sample of Northern European origin, YRI are Yorubans from Nigeria, JPT_CHB are samples of Japanese and Han Chinese, respectively. In our PC analysis, data for CEU are completely obscured by data from CHAVI, LGD and Mullins, in the bottom let corner of the plot Samples of Northern European (NE) ancestry were defined as samples with PC1<0.01 and PC2<0.01. Samples of African (A) ancestry were defined as samples with PC1>0.025.

Figure 2

Distribution of subject-specific slopes for SPEED and EXEC. The x-axis represents the change in SPEED or EXEC per year.