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[O1–03–04]: CHROMOSOME X‐WIDE ASSOCIATION STUDY IDENTIFIES A NEW LOCUS FOR LATE‐ONSET ALZHEIMER's DISEASE ON XQ25
Author(s) -
Napolioni Valerio,
Khan Raiyan R.,
Greicius Michael D.
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.048
Subject(s) - haplotype , logistic regression , genetics , locus (genetics) , genome wide association study , disease , cohort , biology , genetic association , chromosome , medicine , oncology , gene , genotype , single nucleotide polymorphism
Background: Neurocognitive disorders, including Alzheimer’s Disease (AD), are major public health problems that disproportionately affect Latinos. Measures of neurocognitive function, such as reasoning, spatial ability, memory, verbal ability, and information processing speed, are correlated and heritable. However, few genes other than APOE have been reproducibly associated with neurocognitive measures in non-demented communitydwelling adults. Methods:We conducted a genome-wide association study (GWAS) of neurocognitive function in Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Measures of neurocognitive function included global mental status (Six-item Screener), verbal learning and memory (Spanish English Verbal Learning Test, SEVLT), executive function and expressive language (Word Fluency Test, WFT), and psychomotor speed (Digit Symbol Substitution Test, DSST). Genotypes were imputed to 1000 Genomes phase 3 reference panel. We estimated linear mixed models for each trait. Fixed effects included sex, age, recruitment center, individual sampling weights, and top five principal components accounting for ancestry. Random effects included pairwise empirical kinship coefficients accounting for familial relatedness, household membership, and membership in a census block group. We further adjusted for “genetic analysis group” to account for additional group-associated effects. A pvalue <5x10was considered genome-wide significant. Results: In total 7,369 Hispanic/Latino individuals (61% female; age: 5568 years) were included in the analysis. Common variants (minor allele frequency (MAF) >0.05) were associated with neurocognitive measures: A locus at chromosome 4p14 associated with SEVLT (MAF: 6.1%, p 1⁄4 3.7x10) and a locus at chromosome 3p14.1 associated with WFT (MAF: 18.6%, p 1⁄4 5.09 x10-). Variants at 4p14 are located within the RBM47 gene, which encodes a RNA-binding protein implicated in RNA editing and critical for head formation during zebrafish embryogenesis. Variants at 3p14.1 lie 2KB upstream of the gene FRMD4B, a hub gene in the myelination network which has been implicated in late-onset AD. Additionally, several rare variants were also identified for each of the neurocognitive measures. Conclusions:We have performed the first GWAS of neurocognitive function among Hispanic/Latinos and identified several genetic variants associated with measures of neurocognitive function. Replication is underway in an independent Hispanic American sample. We are also investigating whether these findings are generalizable in other ancestries including European Americans and African Americans.