Abstract 11805: Identifying Novel Genetic Variants Associated With an Increased Risk of Cerebrovascular Disease Using a Large-Scale Bio-Medical Database

Abstract

Introduction: Cerebrovascular disease occurs because of a complex interplay between vascular, environmental, and genetic factors. It is the second leading cause of disability worldwide. Understanding who may be genetically predisposed to cerebrovascular disease can help guide preventative efforts. We aim to utilize the UK Biobank to identify genetic variants associated with an increased risk of cerebrovascular disease. Methods: The UK Biobank is a prospective cohort containing clinical and genetic data gathered from over 500,000 individuals. We used Plink’s GLM options to analyze associations between genotypes and phenotypic manifestations of the disease. We defined cerebrovascular disease by selecting the ICD-10 codes G45, G46, I63-I67 and I69. We compared cases to age- and gender-matched controls with a case-to-control ratio of 20:1. Related individuals and those with confounding diagnoses such as coronary artery disease and other atherosclerotic conditions were excluded from the controls. Results: There were 9,726 and 6,699 instances of cerebrovascular disease as a primary or secondary diagnosis. We identified 189 variants in 8 different genes with p ≤ 1x 10 -6 . Identified genes have a minor allele frequency ≥ 0.5%. Variants with the highest significance were identified in close proximity to sequences encoding PITX2 (Paired like homeodomain 2; p = 2.4 x 10 -9 , OR = 1.1), LPA (Lipoprotein(a); p = 6.1 x 10 -9 , OR = 7.3), LRRTM4 (leucine rich repeat transmembrane neuronal 4; p = 1.8 x 10 -8 , OR = 1.08), and CDKN2B-AS1 (CDKN2B antisense RNA 1; p = 4.5 x 10 -8 , OR = 0.93). Conclusions: Through genome-wide analysis using ICD-10 codes as a phenotype for cerebrovascular diseases, we identified several novel genetic variants that are significantly associated with the incidence of cerebrovascular disease in the UK Biobank. Some of the associated genes were previously shown to be associated with atrial fibrillation ( PITX2 ), and atherosclerosis ( LPA and CDKN2B-AS1 ), solidifying the contribution of these two clinical risk factors to cerebrovascular accidents. LRRTM4 was previously associated with cognitive impairment, supporting a biologically plausible link to cerebrovascular disease. Future studies are warranted to confirm the findings of this analysis.