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

Authors

  • Andrew J. Levine,

    Corresponding author
    1. National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles
    • 11645 Wilshire Blvd., Ste 770, Los Angeles, CA 90025.
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  • Susan Service,

    1. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at the University of California, Los Angeles
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  • Eric N. Miller,

    1. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California, Los Angeles
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  • Sandra M. Reynolds,

    1. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore
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  • Elyse J. Singer,

    1. National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles
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  • Paul Shapshak,

    1. Departments of Medicine and Psychiatry and Behavioral Medicine, University of South Florida, College of Medicine, Tampa
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  • Eileen M. Martin,

    1. Departments of Psychiatry and Neurology, University of Illinois, Chicago
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  • Ned Sacktor,

    1. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore
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  • James T. Becker,

    1. Departments of Psychiatry and Neurology and Psychology, University of Pittsburgh Medical Center, Pittsburgh
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  • Lisa P. Jacobson,

    1. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore
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  • Paul Thompson,

    1. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California, Los Angeles
    2. Laboratory of Neuro-Imaging, Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles
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  • Nelson Freimer

    1. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at the University of California, Los Angeles
    2. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California, Los Angeles
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  • How to Cite this Article: Levine AJ, Service S, Miller EN, Reynolds SM, Singer EJ, Shapshak P, Martin EM, Sacktor N, Becker JT, Jacobson LP, Thompson, P, Freimer N. 2012. Genome-Wide Association Study of Neurocognitive Impairment and Dementia in HIV-Infected Adults. Am J Med Genet Part B 159B:669–683.

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. © 2012 Wiley Periodicals, Inc.

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