Citations 3
Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program
Klarin, Derek , Judy, Renae , Dikilitas, Ozan , Wolford, Brooke N. , Paranjpe, Ishan , Levin, Michael G. , Pan, Cuiping , Tcheandjieu, Catherine , Spin, Joshua M. , Assimes, Themistocles L. , Nyrønning, Linn Åldstedt , Mattsson, Erney , Denny, Joshua C. , Zhang, Yanfei , Jarvik, Gail P. , Gharavi, Ali G. , Harley, John B. , Mentch, Frank , Håkonarson, Håkon , Skogholt, Anne Heidi , Thomas, Laurent F. , Gabrielsen, Maiken E. , Zhou, Wei , Fritsche, Lars G. , Huang, Jie , Natarajan, Pradeep , Sun, Yan V. , DuVall, Scott L. , Cho, Kelly , Chang, Kyong‐Mi , Wilson, Peter W.F. , O’Donnell, Christopher J., Kathiresan, Sekar , Scali, Salvatore T. , Jones, Gregory T. , Bown, Matthew J. , Nadkarni, Girish N. , Ritchie, Marylyn D. , Tsao, Philip S. , Gaziano, J. Michael , Ramoni, Rachel , Breeling, Jim, Huang, Grant D. , Muralidhar, Sumitra , O’Donnell, Christopher J. , Romero, Jonathan , Tsao, Philip S., Moser, Jennifer , Whitbourne, Stacey B. , Brewer, Jessica V., Warren, Stuart, Argyres, Dean P., Tsao, Philip S., Stephens, Brady, Brophy, Mary T. , Humphries, Donald E., Shayan, Shahpoor, O’Donnell, Christopher J., Pyarajan, Saiju , Tsao, Philip S., Dell’Italia, Louis J. , Zablocki, Clement J., Beckham, Jean, Wells, John A. , Gutierrez, Salvador, Kaminsky, Laurence S., Villareal, Gerardo, Xu, Junzhe, Hamner, Mark B. , Haddock, Kathlyn Sue, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Buford, Malcolm, Mastorides, Stephen , Ratcliffe, Nora, Flórez, Hermes , Swann, Alan C. , Murdoch, Maureen, Yeh, Shing Shing, Washburn, Ronald G., Jhala, Darshana , Aguayo, Samuel M., Cohen, David , Sharma, Satish, Callaghan, John, Oursler, Kris Ann, Ahuja, Sunil K. , Gutierrez, Amparo, Schifman, Ronald, Greco, Jennifer , Oehlert, Mary E. , Wallbom, Agnes, Fernando, Ronald, Morgan, Timothy R. , Stapley, Todd, Anderson, Gwenevere, Sonel, Elif, Fayad, Joseph, Hung, Adriana M. , Lichy, Jack, Hurley, Robin A. , Hakonarson, Hakon , Denny, Joshua C , Jarvik, Gail P , Dikilitas, Ozan , Assimes, Themistocles L , Natarajan, Pradeep , Wolford, Brooke N , Scali, Salvatore , Chang, Kyong-Mi , Tsao, Philip S , Verma, Shefali S. , Lynch, Julie A. , Edwards, Todd L. , Larson, Eric B. , Lee, Ming Ta Michael , Carrell, David , Pacheco, Jennifer A. , Hveem, Kristian , Nielsen, Jonas Bille , Rader, Daniel J , O’Donnell, Christopher J., Berceli, Scott A. , Willer, Cristen J , Kullo, Iftikhar J. , Damrauer, Scott M , Beckham, Jean C , Tsao, Philip S., Concato, John , Tsao, Philip S., Do, Nhan , Nguyen, Xuan‐Mai T. , O’Donnell, Christopher J., Tsao, Philip S., Hauser, Elizabeth R. , Zhao, Hongyu , McArdle, Rachel , Whittle, Jeff , Beckham, Jean, Wells, John, Gibson, Gretchen , Kinlay, Scott , Ballas, Zuhair K. , Klein, Jon , Sriram, Peruvemba , Washburn, Ronald, Whooley, Mary A. , Rauchman, Michael I. , Servatius, Richard J. , Sherman, Scott E. , Boyko, Edward J. , Meyer, Laurence , Gupta, Samir , Robey, R. Brooks , Striker, Rob
Circulation | September 28, 2020 | Volume: 142 | Issue: 17 | Pages: 1633-1646
10.1161/circulationaha.120.047544
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.
Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases
Haycock, Philip , Burgess, Stephen , Nounu, Aayah , Zheng, Jie , Okoli, George N. , Wade, Kaitlin H. , Timpson, Nicholas J. , Evans, David M. , Willeit, Peter , Aviv, Abraham , Gaunt, Tom R. , Hemani, Gibran , Mangino, Massimo , Ellis, Hayley, Kurian, Kathreena M. , Pooley, Karen A. , Eeles, Rosalind A. , Lee, Jeffrey E. , Fang, Shenying , Chen, Wei V., Law, Matthew H. , Bowdler, Lisa, Iles, Mark M. , Worrall, Bradford B. , Markus, Hugh S. , Hung, Rayjean J., Amos, Chris, Thompson, Deborah J. , O’Mara, Tracy A. , Wolpin, Brian M. , Ámundadóttir, Laufey T. , Trichopoulou, Antonia , Onland‐Moret, N. Charlotte , Lund, Eiliv , Canzian, Federico , Severi, Gianluca , Overvad, Kim , Gunter, Marc J. , Tumino, Rosario , Svenson, Ulrika, Rij, André van, Baas, Annette F., Bown, Matthew J. , Samani, Nilesh J. , t’Hof, Femke N.G. van, Tromp, Gerard , Jones, Gregory T. , Kuivaniemi, Helena , Elmore, James R. , Johansson, Mattias , McKay, James , Scélo, Ghislaine , Carreras‐Torres, Robert , Gaborieau, Valérie , Brennan, Paul , Bracci, Paige M. , Olson, Sara H. , Gallinger, Steven , Li, Donghui , Petersen, Gloria M. , Han, Jiali , Abnet, Christian C. , Freedman, Neal D. , Aben, Katja K.H. , Kiemeney, Lambertus A. , Vermeulen, Sita H. , Walsh, Kyle M. , Wrensch, Margaret , Rice, Terri, Turnbull, Clare , Litchfield, Kevin , Paternoster, Lavinia , Standl, Marie , Mijatovic, Vladan, Sapkota, Yadav , Zondervan, Krina T. , Nyholt, Dale R. , Heel, David A. van , Arking, Dan E. , Ashar, Foram N., Sotoodehnia, Nona, Woo, Daniel , Comeau, Mary E. , Brown, W. Mark , Silverman, Edwin K. , Hokanson, John E. , Hui, Jennie , Thompson, Philip J. , Morrison, Alanna C. , Smith, Nicholas L. , Christiano, Angela M. , Petukhova, Lynn , Betz, Regina C. , Zhang, Xuejun, Zhu, Caihong, Langefeld, Carl D. , Thompson, Susan D. , Wang, Feijie , Fingerlin, Tasha E. , Rotter, Jerome I. , Cotch, Mary Frances , Jensen, Richard A., Munz, Matthias , Dommisch, Henrik , Schäefer, Arne S. , Ollila, Hanna M. , Hillary, Ryan P. , Zeng, Chenjie , Zheng, Wei , Shu, Xiao-Ou , Reis, André , Uebe, Steffen , Hüffmeier, Ulrike , Kawamura, Yoshiya, Otowa, Takeshi , Sasaki, Tsukasa, Dávila, Sonia , Siminovitch, Katherine A. , Bei, Jin‐Xin , Zeng, Yi‐Xin , Chen, Bowang , Franke, Andre, Fischer, Annegret, Ellinghaus, David , Flores, Carlos , Noth, Imre , Ma, Shwu‐Fan , Foo, Jia Nee , Liu, Jianjun , Cox, David G. , Delattre, Olivier , Mirabeau, Olivier , Skibola, Christine F., Tang, Clara Sze-Man , Garcia-Barceló, Mercè, Su, Wen-Hui , Chang, Yu‐Sun , Wade, Tracey , Lee, Chaeyoung , Kubo, Michiaki , Cha, Pei-Chieng , Nakamura, Yusuke, Levy, Daniel , Hunt, S. E., Spector, Tim D. , Soranzo, Nicole , Barr, R. Graham, Kahali, Bratati , Speliotes, Elizabeth K. , Yerges-Armstrong, Laura M. , Cheng, Ching‐Yu , Wong, Tien Yin , Fogh, Isabella , Powell, John , Rice, Kenneth , Relton, Caroline L. , Martin, Richard M. , Smith, George Davey , Hung, Rayjean J. , Bowden, Jack , Yang, Qiong , Spurdle, Amanda B. , Stolzenberg‐Solomon, Rachael Z. , Duell, Eric J. , Neale, Rachel Ε. , Risch, Harvey A. , Klein, Alison P. , Taylor, Philip R. , Maris, John M. , Wiencke, John K. , Abecasis, Gonçalo R. , SanGiovanni, John Paul , Li, Yong , Low, Siew‐Kee , Montgomery, Grant W. , Hunt, Karen A. , Rosand, Jonathan M. , Cho, Michael H. , Ferreira, Manuel A. R. , Felix, Janine F. , Fan, Xing Hua , Xu, Lin , Schwartz, David A. , Han, Fang , Albagha, Omar , Ralston, Stuart H. , Sasaki, Tsukasa, Hibberd, Martin Lloyd , Xie, Gang , Försti, Asta , Landi, Stefano , Ellinghaus, David , Kim, Jong‐Won , Chang, Kai‐Ping , Martin, Nicholas G. , Gordon, Scott D. , Kimura, Masayuki , Hwang, Shih‐Jen , Manichaikul, Ani , Barr, R. Graham, Jonas, Jost B , Lin, Kuang , Amundadottir, Laufey , Kiemeney, Lambertus A , Eeles, Rosalind A , van Heel, David A , Gunter, Marc J , Canzian, Federico , Hung, Rayjean J , O'Mara, Tracy A , Abnet, Christian C , Haycock, Philip , Tumino, Rosario , Han, Jiali , Martin, Richard M , Severi, Gianluca , Reis, André , Zheng, Wei , Rotter, Jerome I , Carreras-Torres, Robert , Law, Matthew H , Davey Smith, George , Johansson, Mattias , Iles, Mark M , Morrison, Alanna C , Rice, Ken , Freedman, Neal D , Foo, Jia Nee , Levy, Daniel , Rice, Kenneth , Sapkota, Yadav , Wong, Tien Y , Liu, Jing
JAMA Oncology | February 27, 2017 | Volume: 3 | Issue: 5 | Pages: 636
Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms
Hof, Femke N. G. van ’t, Ruigrok, Ynte M. , Lee, Cue Hyunkyu , Ripke, Stephan , Anderson, Graig, Baas, Annette F., Blankensteijn, Jan D. , Böttinger, Erwin P. , Bown, Matthew J. , Broderick, Joseph P., Bijlenga, Philippe , Crosslin, David R. , Ebeling, Christian , Eriksson, Johan G. , Fornage, Myriam , Foroud, Tatiana, Fraunberg, Mikael von und zu , Friedrich, Christoph M. , Gaál, Emília Ilona, Gottesman, Omri, Guo, Dongchuan , Harrison, Seamus C. , Hernesniemi, Juha , Hofman, Albert , Inoue, Ituro , Jääskeläinen, Juha E. , Kiemeney, Lambertus A. , Kivisaari, Riku , Ko, Nerissa , Koskinen, Seppo, Kubo, Michiaki , Kuivaniemi, Helena , Laakso, Aki , Lehto, Hanna, LeMaire, Scott A. , Malinowski, Jennifer , McCarty, Catherine A. , Mosley, Thomas H., Nakaoka, Hirofumi , Peissig, Peggy , Pera, Joanna , Rasmussen‐Torvik, Laura J. , Ritchie, Marylyn D. , Rivadeneira, Fernando , Rij, André M. van , Santos‐Cortez, Regie Lyn P., Saratzis, Athanasios , Słowik, Agnieszka , Tromp, Gerard , Uitterlinden, André G. , Vermeulen, Sita H. , Wang, Gao T., Han, Buhm , Bakker, Paul I. W. de , Verissimo, Ana Raquel, Wright, Benjamin J., Bumpstead, Suzannah, Grétarsdóttir, Sólveig , Badger, Stephen A., Child, Anne H. , Cockerill, Gillian, Hafez, Hany , Futers, Simon , Sohrabi, Soroush, Smith, Alberto, Thompson, Matthew M., Bockxmeer, Frank M. van, Matthíasson, Stefán E., Þorsteinsdóttir, Unnur , Graaf, Jacqueline de , Palmen, Jutta, Lindholt, Jes S. , Bradley, Declan , Waltham, Matthew, Gwilliam, Rhian, Golledge, Jonathan , Eriksson, Per , Stefánsson, Kāri , Thompson, John R., Humphries, Steve E. , Sayers, Robert D., Deloukas, Panos , Samani, Nilesh J. , Phillip, L. Victoria, Hill, Geraldine B., Williams, Michael , Thomson, Ian , Krysa, Jo, Wilkins, Gerard , Vasudevan, Thodor M., Lewis, David R. , Blair, Ross D., Hill, Andrew A., de Andrade, Mariza, Ripke, Stephan , Andrade, Mariza de , Broderick, Joseph, Carrell, David , Crawford, Dana C. , Jones, Gregory T. , Kullo, Iftikhar J. , Kurki, Mitja , Lai, Dongbing , Leal, Suzanne M. , Low, Siew‐Kee , Milewicz, Dianna M. , Nakamura, Yusuke , Niemela, Mika R. , Pacheco, Jennifer A. , Takahashi, Atsushi , Verma, Shefali S. , Rinkel, Gabriël J.E. , Clough, Rachel E. , Scott, D. Julian A., Þorleifsson, Guðmar , Teijink, Joep A.W. , Wijmenga, Cisca , Smith, Andrew J P , Edkins, Sarah , Hunt, Sarah E , Potter, Simon , Norman, Paul E , Powell, Janet T. , Merriman, Tony Raymond , Kiemeney, Lambertus A , Bijlenga, Philippe , Lindholt, Jes Sanddal , Malinowski, Jennnifer , Rasmussen-Torvik, Laura J , Eriksson, Per
Journal of the American Heart Association | July 15, 2016 | Volume: 5 | Issue: 7 | Pages: No page available
Background Intracranial aneurysms ( IAs ), abdominal aortic aneurysms ( AAAs ), and thoracic aortic aneurysms ( TAAs ) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs , AAAs, and TAAs . Methods and Results We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study ( GWAS ) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA , AAA , and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA ‐, AAA ‐, and TAA ‐associated SNP s and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls ( IA ) and 4391 cases and 37 904 controls ( AAA ), and found nominally significant associations for IA risk locus 18q11 near RBBP 8 to AAA (odds ratio [ OR ]=1.11; P =4.1×10 −5 ) and for TAA risk locus 15q21 near FBN 1 to AAA ( OR =1.07; P =1.1×10 −3 ). Conclusions Although there was no evidence for polygenic overlap between IAs , AAAs , and TAAs , we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs . These two loci will require further replication.