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P2‐150: DEGREE OF INBREEDING IN MULTIPLEX CARIBBEAN HISPANIC FAMILIES LOADED FOR EARLY‐ONSET ALZHEIMER'S DISEASE
Author(s) -
Jean-Francois Melissa,
Johnson Francelethia S.,
Baez Penelope,
Martinez Izri,
Adams Larry D.,
Vance Jeffery M.,
Martin Eden R.,
Ayodele Temitope,
Pericak-Vance Margaret A.,
Cuccaro Michael L.,
Beecham Gary W.,
Reitz Christiane
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.2019.06.2557
Subject(s) - inbreeding , genetics , biology , consanguinity , single nucleotide polymorphism , population , gene , demography , genotype , sociology
Sequence data from the 1000 Genome project was used to identify all the variants that are significantly different between European (CEU) vs Yoruba (YRI), and JPT vs YRI on the ε4 but not the ε3 haplotype within the LGA. Methods: The ROADMAP data was used to predict functions of significantly different variants (p<0.05, Bonferroni corrected). Based on the predicted functions and location, two variants were prioritized for reporter gene assay: rs71352238 (promoter in the TOMM40 gene) and rs769449 (predicted enhancer in brain tissue, APOE gene). Neither variant was included in the GTEx database. DNA fragments containing the different alleles of rs71352238 (T, C) and rs769449 (G, A) were cloned into pGL4.10 (without promoter) and pGL4.24 (with minimal promoter) vector, respectively. The functional relevance of different alleles were evaluated in Astrocytes (U-118MG), Microglia (HMC3) and Neuronal (SH-SY5Y) cells. Results: In the SHSY5Y cells, the rs71352238 fragment demonstrated strong promoter activity (>200x higher than the empty vector, P<0.0001). Furthermore, the alternative allele C directs 2X higher transcriptional activity than the allele T (P1⁄40.0002). The rs769449 fragment demonstrated enhancer activity (1.5x higher than empty vector, P1⁄40.001), but there is no difference between the two alleles (P1⁄40.60). Similar patterns were observed in both U-118MG and HMC3. Conclusions: rs71352238 remains a potential candidate. Current work is focused on elucidating its gene target.