Heritability and Genome-Wide Association Analyses of Intracranial Carotid Artery Calcification The Rotterdam Study

Background and Purpose Intracranial carotid artery calcification (ICAC) is one of the most important risk factors for stroke. Although several environmental risk factors for ICAC have been identified, its genetic background remains unclear. Methods Between 2003 and 2006, 2034 participants from the prospective population-based Rotterdam study (mean age: 69.66.8 years; 51.7% female) underwent computed tomography to quantify vascular calcification in the intracranial internal carotid artery. Blood samples were drawn for genotyping. Genotypes of the participants were imputed to the 1000 Genomes reference panel to generate genetic relationship matrices for the estimation of the heritability of ICAC volume. Adjustments were made for age and sex. Subsequently, genome-wide association analyses were performed to identify specific variants. Results The age- and sex-adjusted heritability (h(2)) of ICAC was 47% [standard error (SE): 19%; P=0.009]. Genome-wide association analyses identified a variant on chromosome 9p21.3 (rs1537372; N=2034; P=4.75x10(-9)) and 1 variant on chromosome 11p11.2 (rs11038042, N=2034; P=3.27x10(-8)) that were significantly associated with ICAC volume. Rs1537372 replicated in an independent sample of 716 stroke patients (P-combined=1.38x10(-10)). Conclusions ICAC volume is a heritable trait, which is partly explained by common genetic variation. We identified specific genetic variants associated with ICAC, which given the importance of ICAC in stroke risk, needs replication in larger-scale studies to further elucidate its genetic basis.