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Admixture mapping of cognitive function in diverse Hispanic and Latino adults: Results from the Hispanic Community Health Study/Study of Latinos.

TitleAdmixture mapping of cognitive function in diverse Hispanic and Latino adults: Results from the Hispanic Community Health Study/Study of Latinos.
Publication TypePublication
Year2024
AuthorsXia R, Jian X, Rodrigue AL, Bressler J, Boerwinkle E, Cui B, Daviglus ML, DeCarli C, Gallo LC, Glahn DC, Knowles EEM, Moon J-Y, Mosley TH, Satizabal CL, Sofer T, Tarraf W, Testai F, Blangero J, Seshadri S, González HM, Fornage M
JournalAlzheimers Dement
Volume20
Issue9
Pagination6070-6081
Date Published2024 Sep
ISSN1552-5279
KeywordsAdult, Aged, Cognition, Female, genome-wide association study, Hispanic or Latino, Humans, Male, Middle Aged, Neuropsychological Tests, Polymorphism, Single Nucleotide
Abstract

INTRODUCTION: We conducted admixture mapping and fine-mapping analyses to identify ancestry-of-origin loci influencing cognitive abilities.METHODS: We estimated the association of local ancestry intervals across the genome with five neurocognitive measures in 7140 diverse Hispanic and Latino adults (mean age 55 years). We prioritized genetic variants in associated loci and tested them for replication in four independent cohorts.RESULTS: We identified nine local ancestry-associated regions for the five neurocognitive measures. There was strong biological support for the observed associations to cognitive function at all loci and there was statistical evidence of independent replication at 4q12, 9p22.1, and 13q12.13.DISCUSSION: Our study identified multiple novel loci harboring genes implicated in cognitive functioning and dementia, and uncovered ancestry-relevant genetic variants. It adds to our understanding of the genetic architecture of cognitive function in Hispanic and Latino adults and demonstrates the power of admixture mapping to discover unique haplotypes influencing cognitive function, complementing genome-wide association studies.HIGHLIGHTS: We identified nine ancestry-of-origin chromosomal regions associated with five neurocognitive traits. In each associated region, we identified single nucleotide polymorphisms (SNPs) that explained, at least in part, the admixture signal and were tested for replication in independent samples of Black, non-Hispanic White, and Hispanic/Latino adults with the same or similar neurocognitive tests. Statistical evidence of independent replication of the prioritized SNPs was observed for three of the nine associations, at chr4q12, chr9p22.1, and chr13q12.13. At all loci, there was strong biological support for the observed associations to cognitive function and dementia, prioritizing genes such as KIT, implicated in autophagic clearance of neurotoxic proteins and on mast cell and microglial-mediated inflammation; SLC24A2, implicated in synaptic plasticity associated with learning and memory; and MTMR6, implicated in phosphoinositide lipids metabolism.

DOI10.1002/alz.14082
Alternate JournalAlzheimers Dement
PubMed ID38946675
PubMed Central IDPMC11497725
Grant ListHHSN268201300005C / HL / NHLBI NIH HHS / United States
U01AG052409 / / HCHS/SOL /
N01-HC-65237 / / San Diego State University /
N01-HC-65235 / / Albert Einstein College of Medicine /
/ NS / NINDS NIH HHS / United States
N01-HC-65234 / / University of Miami /
HHSN268201300005I / / San Diego State University /
/ / NIH Institution-Office of Dietary Supplements /
R01AG075758 / / HCHS/SOL /
/ MD / NIMHD NIH HHS / United States
HHSN268201300004C / HL / NHLBI NIH HHS / United States
/ DC / NIDCD NIH HHS / United States
HHSN268201300001C / HL / NHLBI NIH HHS / United States
/ DE / NIDCR NIH HHS / United States
HHSN268201300003I / HL / NHLBI NIH HHS / United States
HHSN268201300001I / / University of North Carolina /
HHSN268201300004I / / University of Miami /
N01-HC-65233 / / University of North Carolina /
N01-HC-65236 / / University of Illinois at Chicago /
HHSN268201300003C / HL / NHLBI NIH HHS / United States
R01 AG075758 / AG / NIA NIH HHS / United States
U01 AG052409 / AG / NIA NIH HHS / United States
/ DK / NIDDK NIH HHS / United States
HHSN268201300002I / / Albert Einstein College of Medicine /
MS#: 
1306
Manuscript Lead/Corresponding Author Affiliation: 
Affiliated Investigator - Not at HCHS/SOL site
ECI: 
Manuscript Affiliation: 
HCHS/SOL Baseline Visit - Neurocognitive Reading Center
Manuscript Status: 
Published