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], 19q13.43 (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.
Highlights
Cardiovascular diseases, including heart and cerebrovascular diseases, are listed among the leading causes of death in developed countries (Xu et al, 2016)
We only considered variants with minor allele frequency (MAF) < 5% or absent in 1000 Genome Project (1kG) and MAF < 5% in the Erasmus Rucphen Family (ERF) controls which were defined as individuals who scored below the mean of the distribution of the residuals from the regression of Carotid intima-media thickness (cIMT) onto age, age2, sex, smoking status, body mass index (BMI), waist–hip ratio (WHR), diabetes, dyslipidemia, and hypertension
Significant evidence of linkage for cIMT was observed to chromosomes 2p16.3, 19q13.43, 20p13, and 21q22.12 in the parametric linkage analysis
Summary
Cardiovascular diseases, including heart and cerebrovascular diseases, are listed among the leading causes of death in developed countries (Xu et al, 2016). Several genome-wide linkage studies of quantitative cIMT published up to date reported significant and suggestive evidence of linkage on chromosomes 2q33-q35, 6p12-p22, 7p, 11q23, 12q24, 13q32q33, and 14q31 (Fox et al, 2004; Wang et al, 2005; Sacco et al, 2009; Kuipers et al, 2013). The largest genome-wide association study (GWAS) of cIMT, including 42,484 individuals, identified only three genomic regions of common non-coding genetic variation on 8q24 (near ZHX2), 19q13 (near APOC1), and 8q23.1 (PINX1) and an additional suggestive region on 6p22 (near SLC17A4; Bis et al, 2011). An exome-wide association study in 52,869 individuals identified the association of protein-coding variants in APOE with cIMT (Natarajan et al, 2016). The chances of success for family-based studies are even higher in genetic isolates since rare variants become more frequent due to founder effect, genetic drift, and inbreeding (Stacey et al, 2011; Gudmundsson et al, 2012; Auer and Lettre, 2015)
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