Whole-genome linkage scan combined with exome sequencing identifies novel candidate genes for carotid intima-media thickness

Vojinovic, D. and Kavousi, M. and Ghanbari, M. and Brouwer, R. W. W. and Van Rooij, J. G. J. and Van Den Hout, M. C. G. N. and Kraaij, R. and Van Ijcken, W. F. J. and Uitterlinden, A. G. and Van Duijn, C. M. and Amin, N. (2018) Whole-genome linkage scan combined with exome sequencing identifies novel candidate genes for carotid intima-media thickness. Frontiers in Genetics, 9 (OCT).

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Abstract

Carotid intima-media thickness (cIMT) is an established heritable marker for subclinical atherosclerosis. In this study, we aim to identify rare variants with large effects driving differences in cIMT by performing genome-wide linkage analysis of individuals in the extremes of cIMT trait distribution (>90th percentile) in a large family-based study from a genetically isolated population in the Netherlands. Linked regions were subsequently explored by fine-mapping using exome sequencing. We observed significant evidence of linkage on chromosomes 2p16.3 rs1017418, heterogeneity LOD (HLOD) = 3.35, 19q1343 (rs3499, HLOD = 9.09), 20p13 (rs1434789, HLOD = 4.10), and 21q22.12 (rs2834949, HLOD = 3.59). Fine-mapping using exome sequencing data identified a non-coding variant (rs62165235) in PNPT1 gene under the linkage peak at chromosome 2 that is likely to have a regulatory function. The variant was associated with quantitative cIMT in the family-based study population (effect = 0.27, p-value = 0.013). Furthermore, we identified several genes under the linkage peak at chromosome 21 highly expressed in tissues relevant for atherosclerosis. To conclude, our linkage analysis identified four genomic regions significantly linked to cIMT. Further analyses are needed to demonstrate involvement of identified candidate genes in development of atherosclerosis. © 2018 Vojinovic, Kavousi, Ghanbari, Brouwer, van Rooij, van den Hout, Kraaij, van Ijcken, Uitterlinden, van Duijn and Amin.

Item Type: Article
Additional Information: Export Date: 16 February 2020 Correspondence Address: Amin, N.; Department of Epidemiology, Erasmus MC University Medical CenterNetherlands; email: n.amin@erasmusmc.nl
Uncontrolled Keywords: Atherosclerosis Exome sequencing Genetics Intima-media thickness Linkage genomic DNA adult arterial wall thickness Article autosome cardiovascular risk chromosome 2p16.3 clinical examination DNA extraction female genetic linkage genetic variability genotyping technique human linkage analysis major clinical study male Netherlands phenotype whole exome sequencing
Subjects: QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: lib2 lib2 lib2
Date Deposited: 27 Apr 2020 06:48
Last Modified: 27 Apr 2020 06:48
URI: http://eprints.mums.ac.ir/id/eprint/17572

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