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Am J Med Genet B Neuropsychiatr Genet. 2017 Jun;174(4):413-426. doi: 10.1002/ajmg.b.32530. Epub 2017 Apr 26.

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

Author information

1
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas.
2
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
3
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
4
Department of Epidemiology and Biostatistics, and Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio.
5
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.
6
Department of Psychiatry, University of California San Diego, San Diego, California.
7
Department of Neurology, University of California San Diego, San Diego, California.
8
Department of Neurology, University of Washington, Seattle, Washington.
9
Department of Medicine, University of Washington, Seattle, Washington.
10
Department of Neurology, Washington University, St. Louis, Missouri.
11
Department of Pathology, University of Texas Medical Branch, Galveston, Texas.
12
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
13
Department of Neurology, Icahn School of Medicine of Mount Sinai, New York, New York.
14
Department of Medicine, University of California San Diego, San Diego, California.
15
Department of Genomic Medicine, Lerner Research Institute and Department of Medicine, Cleveland Clinic, Cleveland, Ohio.
16
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.

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.

KEYWORDS:

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

PMID:
28447399
PMCID:
PMC5435520
DOI:
10.1002/ajmg.b.32530
[Indexed for MEDLINE]
Free PMC Article

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