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Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program

2020; Lippincott Williams & Wilkins; Volume: 142; Issue: 17 Linguagem: Inglês

10.1161/circulationaha.120.047544

1524-4539

Derek Klarin, Shefali S. Verma, Renae Judy, Ozan Dikilitas, Brooke N. Wolford, Ishan Paranjpe, Michael G. Levin, Cuiping Pan, Catherine Tcheandjieu, Joshua M. Spin, Julie A. Lynch, Themistocles L. Assimes, Linn Åldstedt Nyrønning, Erney Mattsson, Todd L. Edwards, Joshua C. Denny, Eric B. Larson, Ming Ta Michael Lee, David Carrell, Yanfei Zhang, Gail P. Jarvik, Ali G. Gharavi, John B. Harley, Frank Mentch, Jennifer A. Pacheco, Hákon Hákonarson, Anne Heidi Skogholt, Laurent F. Thomas, Maiken E. Gabrielsen, Kristian Hveem, Jonas B. Nielsen, Wei Zhou, Lars G. Fritsche, Jie Huang, Pradeep Natarajan, Yan V. Sun, Scott L. DuVall, Daniel J. Rader, Kelly Cho, Kyong–Mi Chang, Peter W.F. Wilson, Christopher J. O’Donnell, Sekar Kathiresan, Salvatore T. Scali, Scott A. Berceli, Cristen J. Willer, Gregory T. Jones, Matthew J. Bown, Girish N. Nadkarni, Iftikhar J. Kullo, Marylyn D. Ritchie, Scott M. Damrauer, Philip S. Tsao, J. Michael Gaziano, Rachel Ramoni, Jean C. Beckham, Jim Breeling, Kyong–Mi Chang, Grant D. Huang, Sumitra Muralidhar, Christopher J. O’Donnell, Jonathan Romero, Philip S. Tsao, Sumitra Muralidhar, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, John Concato, Stuart Warren, Dean P. Argyres, Philip S. Tsao, J. Michael Gaziano, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Nhan Do, Shahpoor Shayan, Xuan‐Mai T. Nguyen, Christopher J. O’Donnell, Saiju Pyarajan, Philip S. Tsao, Kelly Cho, Saiju Pyarajan, Elizabeth R. Hauser, Yan V. Sun, Hongyu Zhao, Peter W.F. Wilson, Rachel McArdle, Louis J. Dell’Italia, John B. Harley, Clement J. Zablocki, Jeff Whittle, Jean C. Beckham, John A. Wells, Salvador Gutierrez, Gretchen Gibson, Laurence S. Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark B. Hamner, Kathlyn Sue Haddock, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair K. Ballas, Malcolm Buford, Stephen Mastorides, Jon Klein, Nora Ratcliffe, Hermes Flórez, Alan C. Swann, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Ronald G. Washburn, Darshana Jhala, Samuel M. Aguayo, David Cohen, Satish Sharma, John Callaghan, Kris Ann Oursler, Mary A. Whooley, Sunil K. Ahuja, Amparo Gutierrez, Ronald Schifman, Jennifer Greco, Michael Rauchman, Richard J. Servatius, Mary E. Oehlert, Agnes Wallbom, Ronald Fernando, Timothy R. Morgan, Todd Stapley, Scott E. Sherman, Gwenevere Anderson, Philip S. Tsao, Elif Sonel, Edward J. Boyko, Laurence Meyer, Samir Gupta, Joseph Fayad, Adriana M. Hung, Jack Lichy, Robin A. Hurley, R. Brooks Robey, Rob Striker,

Connective tissue disorders research

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.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.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=2.7×10-11 per 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.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.