Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program

• Type of Material: Article
• Authors: Derek Klarin, Malcolm Randall VA Medical Center; Shefali Setia Verma, University of Pennsylvania; Renae Judy, University of Pennsylvania; Ozan Dikilitas, Mayo Clinic; Brooke N. Wolford, University of Michigan; Ishan Paranjpe, Icahn School of Medicine at Mount Sinai; Yan Sun, Emory University; Peter Wilson, Emory University; Scott M. Damrauer, University of Pennsylvania; Philip S. Tsao, Stanford University
• Language: English
• Date: 2020-10-27
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047544
• Title of Journal or Parent Work: CIRCULATION
• Volume: 142
• Issue: 17
• Start Page: 1633
• End Page: 1646
• Grant/Funding Information: This work was supported by funding from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant MVP000; Department of Veterans Affairs awards I01-01BX03340 (Drs Cho and Wilson), I01-BX003362 (Drs Chang and Tsao), and IK2-CX001780 (Dr Damrauer); Veterans Affairs Informatics and Computing Infrastructure (VINCI) grant VA HSR RES 130457 (Dr DuVall); and National Institutes of Health grant K08HL140203 (Dr Natarajan). Phase III of the eMERGE Network (electronic Medical Records and Genomics) was initiated and funded by the National Human Genome Research Institute through the following grants: U01HG8657 (Kaiser Washington/University of Washington), U01HG8685 (Brigham and Women’s Hospital), U01HG8672 (Vanderbilt University Medical Center), U01HG8666 (Cincinnati Children’s Hospital Medical Center), U01HG6379 (Mayo Clinic), U01HG8679 (Geisinger Clinic), U01HG8680 (Columbia University Health Sciences), U01HG8684 (Children’s Hospital of Philadelphia), U01HG8673 (Northwestern University), U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center), U01HG8676 (Partners Healthcare/Broad Institute), and U01HG8664 (Baylor College of Medicine). Phase I and II of the eMERGE Network was initiated and funded by the National Human Genome Research Institute through the following grants: U01HG006828 (Cincinnati Children’s Hospital Medical Center/Boston Children’s Hospital), U01HG006830 (Children’s Hospital of Philadelphia), U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University), U01HG006382 (Geisinger Clinic), U01HG006375 (Group Health Cooperative/University of Washington), U01HG006379 (Mayo Clinic), U01HG006380 (Icahn School of Medicine at Mount Sinai), U01HG006388 (Northwestern University), U01HG006378 (Vanderbilt University Medical Center), U01HG006385 (Vanderbilt University Medical Center, serving as the Coordinating Center), U01HG004438 (Center for Inherited Disease Research, serving as a Genotyping Center), and U01HG004424 (the Broad Institute, serving as a Genotyping Center).
• Keywords: aortic diseases; BLOOD-PRESSURE; METAANALYSIS; BIOBANK; Cardiovascular System & Cardiology; Science & Technology; aneurysm; VARIANT; Cardiac & Cardiovascular Systems; Life Sciences & Biomedicine; GENOME-WIDE ASSOCIATION; humans; Peripheral Vascular Disease; genome-wide association study; INFERENCE; MENDELIAN RANDOMIZATION; HEALTH; DISEASES; MORTALITY
• Research Categories: Biology, Neuroscience; Health Sciences, Public Health; Biology, Genetics; Health Sciences, Medicine and Surgery

Abstract

Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; P=1.6×10-6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=1.27×10-6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.