Abstract P257: Between-pedigree Genome-wide Linkage Screen Identifies a Locus on Chromosome 9 Influencing Coronary Artery Calcification in the Family Heart Study

Abstract

Coronary artery calcification (CAC) is the buildup of calcium deposits in the arteries leading to the heart, and is an indicator of atherosclerosis. CAC is known to have a genetic component. To identify the genes underlying CAC, a genome-wide linkage screen was performed in the Family Heart Study. There are two established loci influencing CAC identified by genome-wide association scans, at chromosome 9p21 and 6p24. However, there may be rare variants on haplotypes in the population that influence CAC. These would not be able to be identified by genome-wide association scans, but linkage scans could detect them. From the study, 2,687 individuals of European descent from 508 pedigrees with CAC scores were genotyped on the Illumina Human 1M-DuoV3 single nucleotide polymorphisms (SNP) array. CAC scores were determined by cardiac CT scan and adjusted for age, sex, and principal components before analysis. Using 484,358 common SNPs (minor allele frequency greater than 5%), common ancestry across the genome was determined for all pairs of individuals in the study. A segment of the genome was considered to be inherited from a common ancestor (identical-by-descent, IBD) if it contained more than 1,000 matching SNP genotypes over a length of at least one megabase. To test the influence of IBD at a locus on CAC, a linear mixed effects model was fit, including random effects to account for covariance due to relatedness and IBD states at each locus. All pedigrees were considered jointly in the model. Statistical significance was determined by comparing this model to one without IBD covariance via the likelihood ratio test. This model was evaluated approximately every megabase across all 22 pairs of autosomes. Since IBD states are determined solely by dense genotype data, IBD can be detected both within and between pedigrees in the study. This allows the inclusion covariance due to IBD in individuals in different pedigrees. If there is a haplotype shared across pedigrees, power to detect linkage is increased. CAC was found to have a narrow-sense heritability of 37.4% in this sample. Significant evidence of linkage was encountered at rs13293430 (chromosome 9, 31,050,747bp, LOD=3.042). When considering IBD between pedigrees, 914 pairs of individuals from different pedigrees were IBD at this position. This locus is near DDX58. Mutations in DDX58 cause Singleton-Merton syndrome, a disease characterized by calcification of blood vessels, making it an intriguing candidate gene for influence on CAC.