P2‐140: Genome‐wide Linkage Analysis of Caribbean Hispanic Puerto Rican Families Supports Evidence of Linkage to C9orf72 Region of Chromosome 9
Year: 2019
Type: article
Study design: Observational Study
Abstract: 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. 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. 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 affected-only dominant multipoint model. Two-point affecteds-only dominant parametric model results were also supportive for this region (HLOD=2.6 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. 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.
Source: Alzheimer s & Dementia
Authors: Farid Rajabli, Briseida E. Feliciano-Astacio, Katrina Celis, Kara L. Hamilton-Nelson, Larry D. Adams, Vanessa C. Rodriguez, Pedro Ramon Mena, Patrice L. Whitehead, Natalia K. Hofmann, Parker Bussies, Michael Prough, Carolina B. Sierra-Lopez, Heriberto Acosta, Angel Chinea, Nereida I. Feliciano, Jeffery M. Vance, Michael L. Cuccaro, Gary W. Beecham, Margaret A. Pericak-Vance
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980639360