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This retrospective study included the CHARTER cohort participants, excluding those with severe neuropsychiatric comorbidities. Genome-wide data previously obtained for 1047 participants and targeted sequencing of 992 participants with available genomic DNA were utilized to interrogate the association of three noncoding and three coding <jats:italic>EIF2AK3<\/jats:italic> SNVs with the continuous global deficit score (GDS) and global neurocognitive impairment (NCI; GDS\u2009\u2265\u20090.5) using univariable and multivariable methods, with demographic, disease-associated, and treatment characteristics as covariates. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4\u2009+\u2009T cell counts, 175\/\u00b5L (nadir) and 428\/\u00b5L (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA levels\u2009\u2264\u2009200 copies\/mL. All three noncoding <jats:italic>EIF2AK3<\/jats:italic> SNVs were associated with GDS and NCI (all <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Additionally, 30.9%, 30.9%, and 41.2% of participants had at least one risk allele for the coding SNVs rs1805165 (G), rs867529 (G), and rs13045 (A), respectively. Homozygosity for all three coding SNVs was associated with significantly worse GDS (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and more NCI (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II value\u2009&gt;\u200913 were independently associated with GDS and NCI (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) whereas the other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding <jats:italic>EIF2AK3<\/jats:italic> SNVs were associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of <jats:italic>EIF2AK3<\/jats:italic> were associated with global NC and domain-specific performance. The effects were small-to-medium in size but present in multivariable analyses, raising the possibility of specific SNVs in <jats:italic>EIF2AK3<\/jats:italic> as an important component of genetic vulnerability to neurocognitive complications in PWH.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s11481-024-10125-x","type":"journal-article","created":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T03:31:57Z","timestamp":1716607917000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV"],"prefix":"10.1007","volume":"19","author":[{"given":"Cagla","family":"Akay-Espinoza","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah E.B.","family":"Newton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beth A.","family":"Dombroski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asha","family":"Kallianpur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ajay","family":"Bharti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald R.","family":"Franklin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerard D.","family":"Schellenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert K.","family":"Heaton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Grant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald J.","family":"Ellis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott L.","family":"Letendre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly L.","family":"Jordan-Sciutto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,5,25]]},"reference":[{"issue":"2","key":"10125_CR2","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1111\/j.1365-2990.2011.01215.x","volume":"38","author":"C Akay","year":"2012","unstructured":"Akay C, Lindl KA, Shyam N, Nabet B, Goenaga-Vazquez Y, Ruzbarsky J, Jordan-Sciutto KL (2012) Activation status of integrated stress response pathways in neurones and astrocytes of HIV-associated neurocognitive disorders (HAND) cortex. 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