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

Identifieur interne : 008201 ( Main/Merge ); précédent : 008200; suivant : 008202

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

Auteurs : Andrew J. Levine [États-Unis] ; Susan Service [États-Unis] ; Eric N. Miller [États-Unis] ; Sandra M. Reynolds [États-Unis] ; Elyse J. Singer [États-Unis] ; Paul Shapshak [États-Unis] ; Eileen M. Martin [États-Unis] ; Ned Sacktor [États-Unis] ; James T. Becker [États-Unis] ; Lisa P. Jacobson [États-Unis] ; Paul Thompson [États-Unis] ; Nelson Freimer [États-Unis]

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RBID : ISTEX:2E98F099317ED1D94AC1148EEE3A824168F0BF60

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English descriptors

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.

Url:
DOI: 10.1002/ajmg.b.32071

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ISTEX:2E98F099317ED1D94AC1148EEE3A824168F0BF60

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<term>Domain scores</term>
<term>Dominant model</term>
<term>Drug abuse</term>
<term>Eigenstrat analysis</term>
<term>Elli</term>
<term>Everall</term>
<term>Exec</term>
<term>Exec scores</term>
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<term>Further analysis</term>
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<term>Genetic</term>
<term>Genetic analysis</term>
<term>Genetic association studies</term>
<term>Genetic susceptibility loci</term>
<term>Genetics</term>
<term>Genomic control parameter</term>
<term>Genotype</term>
<term>Genotype data</term>
<term>Genotyped</term>
<term>Genotyped snps</term>
<term>Genotyping</term>
<term>Genotyping completeness</term>
<term>Grant number</term>
<term>Grant sponsor</term>
<term>Greater risk</term>
<term>Greatest impact</term>
<term>Gwas</term>
<term>Haplotype</term>
<term>Heaton</term>
<term>Heavy drinkers</term>
<term>Heritability</term>
<term>Heterogeneous syndrome</term>
<term>High levels</term>
<term>Human virus</term>
<term>Human virus infection</term>
<term>Impairment</term>
<term>Jacques fellay</term>
<term>Johns hopkins bloomberg school</term>
<term>Letendre</term>
<term>Levine</term>
<term>Lifestyle behaviors</term>
<term>Locus</term>
<term>Logistic regression</term>
<term>Mac</term>
<term>Macs participants</term>
<term>Males genotyped</term>
<term>Marcotte</term>
<term>Masliah</term>
<term>Maximally persons</term>
<term>Mcarthur</term>
<term>Medical charts</term>
<term>Medical genetics part</term>
<term>Meta analysis</term>
<term>Methamphetamine</term>
<term>More visits</term>
<term>Mullins data</term>
<term>Mullins samples</term>
<term>Multicenter</term>
<term>Multicenter aids cohort study</term>
<term>Mutant haplotype</term>
<term>Myriad immunologic</term>
<term>Nadir</term>
<term>National cancer institute</term>
<term>Ndings</term>
<term>Neurocognitive</term>
<term>Neurocognitive decline</term>
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<term>Neurocognitive domains</term>
<term>Neurocognitive impairment</term>
<term>Neurocognitive phenotypes</term>
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<term>Neurologic</term>
<term>Neurological exam</term>
<term>Neurological impairment</term>
<term>Neurology</term>
<term>Neuropsychol</term>
<term>Neuropsychological</term>
<term>Neuropsychological impairment</term>
<term>Neuropsychological performance</term>
<term>Neuropsychological testing</term>
<term>Normative data</term>
<term>Northern european ancestry</term>
<term>Opportunistic infection</term>
<term>Other factors</term>
<term>Participant</term>
<term>Phenotype</term>
<term>Phenotype data</term>
<term>Polymorphism</term>
<term>Positive indicator</term>
<term>Possible explanation</term>
<term>Prevalence</term>
<term>Previous studies</term>
<term>Principal components</term>
<term>Principal components analysis</term>
<term>Proc natl acad</term>
<term>Processing speed</term>
<term>Progression</term>
<term>Public health</term>
<term>Regimen</term>
<term>Risk allele</term>
<term>Risk allele homozygotes</term>
<term>Risk factors</term>
<term>Sample size</term>
<term>Singh</term>
<term>Single nucleotide polymorphism</term>
<term>Small sample size</term>
<term>Snp</term>
<term>Spector</term>
<term>Stroop</term>
<term>Stroop color</term>
<term>Study visit</term>
<term>Such genes</term>
<term>Susceptibility</term>
<term>Susceptibility loci</term>
<term>Symbol digit modalities test</term>
<term>Total number</term>
<term>True associations</term>
<term>Valcour</term>
<term>Wang</term>
<term>Wiley periodicals</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr">
<term>Génétique</term>
<term>Neurologie</term>
<term>Santé publique</term>
</keywords>
</textClass>
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<front>
<div type="abstract" xml:lang="en">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.</div>
</front>
</TEI>
</record>

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