Genome‐wide association study of neurocognitive impairment and dementia in HIV‐infected adults
- 24 May 2012
- journal article
- research article
- Published by Wiley in American Journal Of Medical Genetics Part B-Neuropsychiatric Genetics
- Vol. 159B (6), 669-683
- https://doi.org/10.1002/ajmg.b.32071
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.Keywords
This publication has 108 references indexed in Scilit:
- Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: Antagonistic pleiotropy and premature brain agingNeuroImage, 2011
- The Search for Host Genetic Factors of HIV/AIDS Pathogenesis in the Post-Genome Era: Progress to Date and New Avenues for DiscoveryCurrent HIV/AIDS Reports, 2011
- HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictorsJournal of NeuroVirology, 2010
- Investigation of 15 of the top candidate genes for late-onset Alzheimer’s diseaseHuman Genetics, 2010
- MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypesGenetic Epidemiology, 2010
- Genome-wide Analysis of Genetic Loci Associated With Alzheimer DiseaseJama-Journal Of The American Medical Association, 2010
- Gene Expression Profiles of HIV-1-Infected Glia and Brain: Toward Better Understanding of the Role of Astrocytes in HIV-1-Associated Neurocognitive DisordersJournal of Neuroimmune Pharmacology, 2009
- Drug Abuse and Hepatitis C Infection as Comorbid Features of HIV Associated Neurocognitive Disorder: Neurocognitive and Neuroimaging FeaturesNeuropsychology Review, 2009
- Cognitive Neuropsychology of HIV-Associated Neurocognitive DisordersNeuropsychology Review, 2009
- Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration Into the Central Nervous SystemArchives of Neurology, 2008