Abstract P132: Genome-wide Linkage Analysis of Carotid Artery Traits in Exceptionally Long-Lived Families

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Abstract

The extent to which genetics plays a role in vascular health in exceptional aging has not been established. We performed genetic heritability and genome-wide linkage analysis of carotid artery ultrasound derived traits in 1931 individuals (3913 relative pairs) from the Long Life Family Study (LLFS). The LLFS is a longitudinal family-based cohort study that recruited long-lived individuals and at least 1 of their long-lived siblings, as well as, all offspring and offspring spouses. Participants had a home visit that included B-mode carotid artery ultrasound to assess inter-adventitial diameter (IAD), common carotid artery far wall (FW) intima-media thickness (IMT), lumen diameter (LD), and carotid plaque prevalence and burden. We conducted residual heritability analyses for each of these traits, adjusted for age, age2, sex, and field center (4 sites) using pedigree-based maximum-likelihood methods in SOLAR. Linkage markers were haplotypes generated from genotypes typed on the Human Omni Chip 2.5 v1 (Illumina, CA) and multipoint identity-by-descent estimates were calculated by Loki. Multipoint genome-wide (chr 1-22) linkage analysis was conducted in SOLAR. Chromosomal regions were considered significant if the logarithm of the odds (LOD) score was ≥3.0 (suggestive: LOD ≥2.0). Proband and offspring generations, respectively, were 59% and 55% female and had mean ages of 97.3 and 73.5 years. Carotid traits were significantly heritable, ranging from 0.37 for mean FW IMT to 0.67 for mean IAD. We found significant evidence of linkage on chromosome 3 at 125 cM (max LOD=3.57; Table). We also found 4 peaks suggestive of linkage with other carotid traits (Table). There are many genes of interest underlying these peaks with previous association with vascular disease, and fine-mapping the associations will require further refinement via sequence analysis. This is the first study to show that genetics appear to play a very strong role in determining variation in carotid artery traits in families with exceptionally long-lived members.

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