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P2‐142: UTILIZING CRISPR TO INVESTIGATE AN ETHNIC SPECIFIC DELETION IN ABCA7
Author(s) -
Cukier Holly N.,
Nuytemans Karen,
Strong Thomas A.,
Laverde-Paz Juliana,
Eldabbas Rawan A.,
Pericak-Vance Margaret A.,
Dykxhoorn Derek M.
Publication year - 2019
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.2019.06.2549
Subject(s) - schizophrenia (object oriented programming) , cognition , psychosis , psychology , antipsychotic , effects of sleep deprivation on cognitive performance , disease , demographics , neuroscience , audiology , medicine , psychiatry , demography , sociology
Background: The ancestral heterogeneity (admixture) of Caribbean Hispanics (CHI) makes studies of CHI population critical in discovery of ancestry-specific genetic factors in Alzheimer disease (AD). In this study we analyzed twenty-five multiplex CHI Puerto Rican (PR) families using ancestral-aware genome-wide linkage analysis with the goal of identifying genomic regions and their ancestral backgrounds segregating with disease that are likely to contain risk or protective genes for PR AD. Methods: Genome-wide array genotyping of 95 individuals (69 affected) from 25 families was used for linkage analysis. Models assuming autosomal dominant inheritance included: 1) parametric two-point affecteds-only and age-dependent penetrance models, and 2) parametric multipoint affecteds-only and age-dependent penetrance models, and 3) nonparametric multipoint model. Linkage analyses were implemented in the MERLIN software. Local ancestry was estimated using SHAPEIT followed by RFMix. Results: Regions previously identified in AD linkage scan (PSEN1, PSEN2, APP, MAPT, APOE) showed no evidence of linkage in these data. A locus at 9q21.1-9p13.3 produced a linkage LOD score of 3.9 across all families in the parametric affectedonly dominant multipoint model. Two-point affecteds-only dominant parametric model results were also supportive for this region (HLOD1⁄42.6 at rs1408466). The region overlaps a previously reported linkage peak in an independent set of non-Hispanic White AD families (NHW). The haplotypes segregating with the disease in the PR families had European ancestral background, further supporting this linkage peak in the NHW population. The linkage region also includes several AD candidate genes, C9orf72, VCP, and CDKN2A. However, we did not observe the previously reported C9orf72 hexanucleotide (GGGGCC)n repeat expansion in the PR group. These data do not exclude a different variant in C9orf 72 contributing to the AD linkage signal.Conclusions: Linkage analysis of CHI PR families extended evidence for a LOAD susceptibility gene on chromosome 9 and confirmed a previously reported linkage to 9p21.3 in NHW families. Twenty-five families included in these study are undergoing whole-genome sequencing. To delineate the genetic effect at the linked region, variants located in the linkage region will be primary candidates for examination as potential risk or protective factors in AD.