Genome-wide linkage analysis of carotid artery traits in exceptionally long-lived families. (December 2019)

• Record Type: Journal Article
• Authors: Kuipers, Allison L.; Wojczynski, Mary K.; Barinas-Mitchell, Emma; Minster, Ryan L.; Wang, Lihua; Feitosa, Mary F.; Kulminski, Alexander; Thyagarajan, Bharat; Lee, Joseph H.; Province, Michael A.; Newman, Anne B.; Zmuda, Joseph M.
• Is Part Of: Atherosclerosis. Volume 291(2019)
• Page Start: 19
• Page End: 26
• Publication Date: 2019-12
• Subjects: Carotid ultrasound -- Atherosclerosis -- Genome-wide study -- Linkage analysis -- Aging; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2019.10.008
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Atherosclerosis develops with age and is partially controlled by genetics. Research to date has identified common variants with small effects on atherosclerosis related traits. We aimed to use family-based genome-wide linkage analysis to identify chromosomal regions potentially harboring rare variants with larger effects for atherosclerosis related traits. Methods: Participants included 2205 individuals from the Long Life Family Study (LLFS), which recruited families with exceptional longevity from Boston, New York, Pittsburgh, and Denmark. Participants underwent B-mode ultrasonography of the carotid arteries to measure intima-media thickness (IMT), inter-adventitial diameter (IAD), and plaque presence and severity. We conducted residual heritability and genome-wide linkage analyses adjusted for age, age 2, sex, and field center using pedigree-based maximum-likelihood methods in SOLAR. Results: All carotid traits were significantly heritable with a range of 0.68 for IAD to 0.38 for IMT. We identified three chromosomal regions with linkage to IAD (3q13; max LOD 5.3), plaque severity (17q22-q23, max LOD 3.2), and plaque presence (17q24, max LOD 3.1). No common allelic variants within these linkage peaks were associated with the carotid artery traits. Conclusions: We identified three chromosomal regions with evidence of linkage to carotid artery diameter and atherosclerotic plaque in exceptionally long-lived families. Since common allelic variants within our linkage peaks did not account for our findings, future follow-up resequencing of these regions in LLFS families should help advance our understanding of atherosclerosis, CVD, and healthy vascular aging. Graphical abstract: Image 1 Highlights: Measures of carotid atherosclerosis assessed via ultrasound were significantly heritable. We identified 3 discrete chromosomal regions with significant linkage to carotid atherosclerosis. These regions contain genes with previous evidence of association with atherosclerotic traits. Common SNPs in these regions were not associated with atherosclerosis; thus, these families may harbor rare genetic variants.