Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program
Authors: Klarin Derek , Verma Shefali Setia , Judy Renae , Dikilitas Ozan , Wolford Brooke N. , Paranjpe Ishan , Levin Michael G. , Pan Cuiping , Tcheandjieu Catherine , Spin Joshua M. , Lynch Julie , Assimes Themistocles L. , Åldstedt Nyrønning Linn , Mattsson Erney , Edwards Todd L. , Denny Josh , Larson Eric , Lee Ming Ta Michael , Carrell David , Zhang Yanfei , Jarvik Gail P. , Gharavi Ali G. , Harley John , Mentch Frank , Pacheco Jennifer A. , Hakonarson Hakon , Skogholt Anne Heidi , Thomas Laurent , Gabrielsen Maiken Elvestad , Hveem Kristian , Nielsen Jonas Bille , Zhou Wei , Fritsche Lars , Huang Jie , Natarajan Pradeep , Sun Yan V. , DuVall Scott L. , Rader Daniel J. , Cho Kelly , Chang Kyong-Mi , Wilson Peter W.F. , O’Donnell Christopher J. , Kathiresan Sekar , Scali Salvatore T. , Berceli Scott A. , Willer Cristen , Jones Gregory T. , Bown Matthew J. , Nadkarni Girish , Kullo Iftikhar J. , Ritchie Marylyn , Damrauer Scott M. , Tsao Philip S. , Gaziano J. Michael , Ramoni Rachel , Beckham Jean , Breeling Jim , Chang Kyong-Mi , Huang Grant , Muralidhar Sumitra , O’Donnell Christopher J. , Casas Romero J.P. , Tsao Philip S. , Muralidhar Sumitra , Moser Jennifer , Whitbourne Stacey B. , Brewer Jessica V. , Concato John , Warren Stuart , Argyres Dean P. , Tsao Philip S. , Gaziano J. Michael , Stephens Brady , Brophy Mary T. , Humphries Donald E. , Do Nhan , Shayan Shahpoor , Nguyen Xuan-Mai T. , O’Donnell Christopher J. , Pyarajan Saiju , Tsao Philip S. , Cho Kelly , Pyarajan Saiju , Hauser Elizabeth , Sun Yan , Zhao Hongyu , Wilson Peter , McArdle Rachel , Dellitalia Louis , Harley John , Zablocki Clement J. , Whittle Jeffrey , Beckham Jean , Wells John , Gutierrez Salvador , Gibson Gretchen , Kaminsky Laurence , Villareal Gerardo , Kinlay Scott , Xu Junzhe , Hamner Mark , Haddock Kathlyn Sue , Bhushan Sujata , Iruvanti Pran , Godschalk Michael , Ballas Zuhair , Buford Malcolm , Mastorides Stephen , Klein Jon , Ratcliffe Nora , Florez Hermes , Swann Alan , Murdoch Maureen , Sriram Peruvemba , Yeh Shing Shing , Washburn Ronald , Jhala Darshana , Aguayo Samuel , Cohen David , Sharma Satish , Callaghan John , Oursler Kris Ann , Whooley Mary , Ahuja Sunil , Gutierrez Amparo , Schifman Ronald , Greco Jennifer , Rauchman Michael , Servatius Richard , Oehlert Mary , Wallbom Agnes , Fernando Ronald , Morgan Timothy , Stapley Todd , Sherman Scott , Anderson Gwenevere , Tsao Philip , Sonel Elif , Boyko Edward , Meyer Laurence , Gupta Samir , Fayad Joseph , Hung Adriana , Lichy Jack , Hurley Robin , Robey Brooks , Striker Robert 
Published: September 2020

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 ratio
PRS
, 1.26 [95% CI, 1.18–1.36];
P
PRS
=2.7×10
−11
per SD increase in PRS), independent of family history and smoking risk factors (odds ratio
PRS+family history+smoking
, 1.24 [95% CI, 1.14–1.35];
P
PRS
=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.