Abstract P109: Detection of Haplotypes Underlying a Coronary Artery Calcification Linkage Peak in the Family Heart Study
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, and a genome-wide linkage screen in the Family Heart Study identified significant evidence of linkage on chromosome 9 in the area near rs13293430, but no common variant in the linkage region showed significant evidence of association.
Linkage screens attempt to identify covariance due to common ancestry at a genomic locus. This is robust to the presence of rare variation or multiple variants in a region, but is unable to identify the genomic feature causing the signal and additional research is needed to identify potential causative variants.
Pairs of individuals who have inherited a locus from a common ancestor will share an identical sequence of alleles (a haplotype) within the region. To identify haplotypes influencing the trait in the region, a mixed effects model was used. CAC was modeled as a trait influenced by polygenic effects and locus-specific haplotype effects. This model has the benefit of jointly estimating the effect of each haplotype while separating the haplotype effect from the background polygenic effect.
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. Of these, 180 individuals from 23 pedigrees were for subsequent analysis due to membership in a pedigree contributing to the linkage signal. CAC scores were determined by cardiac CT scan and adjusted for age, sex, and principal components before analysis. Phased haplotypes were generated for 906,856 common SNPs across the genome using SHAPEIT. The region between 25Mb and 35Mb (3,500 SNPs) was divided into 250kb sections, and within each section haplotypes were created based on 24 evenly spaced SNPs. Statistical significance for each region was determined by likelihood ratio test.
Haplotype analysis identified two regions showing strong evidence of association (p<10-7) with CAC. The region 28-28.25Mb is located completely within the gene LINGO2, which has been associated with BMI and cholesterol. The region 27.5-27.75Mb contains MOBKL2B, IFNK and C9orf72. Additional work will be needed to validate haplotypes used in the model and identify the particular haplotype influencing the trait.
Author Disclosures: J.E. Hicks: None. M.A. Province: None.
- © 2017 by American Heart Association, Inc.