Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study

Year: 2022

Type: article

Abstract: Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of abdominal aortic aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in 10 cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects [Partners Biobank cohort 1 (PBIO)] as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In genome-wide association study (GWAS) on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, P-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (P-value = 8.19 × 10-4). In exome-array single-variant analysis (P-value threshold = 9 × 10-7), the lowest P-value was found for rs239259 located in SLC22A20 (beta = 0.007, P-value = 1.2 × 10-5). In the gene-based analysis (P-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (P-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, P-value = 0.02), triglycerides (beta = -0.16, P-value = 0.008) and height (beta = 0.03, P-value < 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.

Source: Human Molecular Genetics

DOI: 10.1093/hmg/ddac051

Institutions: Erasmus MC, Erasmus University Rotterdam, Broad Institute, Harvard University, Massachusetts General Hospital, National Institutes of Health, National Heart, Lung, and Blood Institute, Framingham Heart Study, National Heart, Lung, and Blood Institute Division of Intramural Research, University of Washington, Universitätsmedizin Greifswald, Universität Greifswald, German Centre for Cardiovascular Research, Helmholtz Munich, Brigham and Women's Hospital, Stanford Medicine, Stanford University, Weill Cornell Medicine, University of California San Diego, University of Michigan, The Lundquist Institute, Harbor–UCLA Medical Center, University of Freiburg, Utrecht University, University Medical Center Utrecht, Philadelphia VA Medical Center, University of Pennsylvania, German Center for Diabetes Research, Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz, Institut für Humangenetik, Technical University of Munich, VA Boston Healthcare System, MRC Centre for Environment and Health, Imperial College London

Language: English

Topic: Aortic aneurysm repair treatments

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,181

Funders: U.S. Department of Veterans Affairs, Medical Research Council, National Heart, Lung, and Blood Institute

Awards: G1502031688, G1554891411, G4429312988, Genomic and Functional Studies of Dysplasia-Associated Arterial Diseases

OpenAlex ID: W4214592039