Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. RinkelJan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M. Brumpton, Cristen J. Willer, Else C. Sandset, Espen S. Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B. Nielsen, Knut Hagen, Kristian Hveem, Lars G. Fritsche, Laurent F. Thomas, Linda M. Pedersen, Maiken E. Gabrielsen, Oddgeir L. Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J. Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R. Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G. Holliday, Anne U. Jackson, Ruifang Li-Gao, Wei Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M. Willems, Jing Hua Zhao, John Connell, Renée De Mutsert, Alex S.F. Doney, Martin Farrall, Cristina Menni, Andrew D. Morris, Raymond Noordam, Guillaume Paré, Neil R. Poulter, Denis C. Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E. Arking, Kristin L. Ayers, Caterina M. Barbieri, Chiara Batini, Joshua C. Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I. Boomsma, Erwin P. Bottinger, Peter S. Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C. Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J. Cordell, Gail Davies, Martin H. De Borst, Eco J. De Geus, Ian J. Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B. Ehret, Roberto Elosua, Stefan Enroth, A. Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H. Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J. Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B. Harris, Sarah E. Harris, Catharina A. Hartman, Aki S. Havulinna, Andrew A. Hicks, Edith Hofer, Albert Hofman, Jouke Jan Hottenga, Jennifer E. Huffman, Shih Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D. Johnson, Peter K. Joshi, Pekka Jousilahti, J. Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D. Keavney, Kay Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S. Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J. Launer, Benjamin Lehne, Terho Lehtimäki, David C.M. Liewald, Li Lin, Lars Lind, Cecilia M. Lindgren, Yong Mei Liu, Ruth J.F. Loos, Lorna M. Lopez, Yingchang Lu, Leo Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P. Morris, Alanna C. Morrison, Peter J. Munson, Mike A. Nalls, Priyanka Nandakumar, Christopher P. Nelson, Teemu Niiranen, Ilja M. Nolte, Teresa Nutile, Albertine J. Oldehinkel, Ben A. Oostra, Paul F. O'reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P. Pramstaller, Quang Tri Nguyen, Olli T. Raitakari, Rainer Rettig, Kenneth Rice, Paul M. Ridker, Janina S. Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M. Rose, Jerome I. Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F. Sala, Veikko Salomaa, Nilesh J. Samani, Antti Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V. Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M. Starr, David J. Stott, David P. Strachan, Rona J. Strawbridge, Johan Sundström, Morris A. Swertz, Kent D. Taylor, Alexander Teumer, Martin D. Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G. Uitterlinden, Ahmad Vaez, Peter J. Van Der Most, Cornelia M. Van Duijn, Germaine C. Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H. Wild, Gonneke Willemsen, James F. Wilson, Alan F. Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R. Attia, Adam S. Butterworth, Daniel I. Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna M.M. Howson, Markku Laakso, Edward G. Lakatta, Claudia Langenberg, Olle Melander, Dennis O. Mook-Kanamori, Colin N.A. Palmer, Lorenz Risch, Robert A. Scott, Rodney J. Scott, Peter Sever, Tim D. Spector, Pim Van Der Harst, Nicholas J. Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B. Munroe, Christopher Newton-Cheh, Morris J. Brown, Andres Metspalu, Bruce M. Psaty, Louise V. Wain, Paul Elliott, Mark J. Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H. Pers, Kai How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A. Furlotte, Tobias Kurth, Andres Ingason, George Mcmahon, Lannie Ligthart, Gisela M. Terwindt, Mikko Kallela, Tobias M. Freilinger, Caroline Ran, Scott G. Gordon, Anine H. Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H.H. Adams, Terho Lehtimäki, Antti Pekka Sarin, Juho Wedenoja, David A. Hinds, Julie E. Buring, Markus Schürks, Paul M. Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M. Ring, Jouke Jan Hottenga, Brenda W.J.H. Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C. Heath, Pamela A.F. Madden, Nicholas G. Martin, Grant W. Montgomery, Mitja I. Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E. Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H. Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G. Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G. Uitterlinden, Cornelia M. Van Duijn, Lynn Cherkas, Linda M. Pedersen, Audun Stubhaug, Christopher S. Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J. Aromaa, Olli Raitakari, M. Arfan Ikram, Tim Spector, Marjo Riitta Järvelin, Christian Kubisch, David P. Strachan, Michel D. Ferrari, Andrea C. Belin, Maija Wessman, Arn M.J.M. Van Den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J. Daly, Benjamin M. Neale, Jes Olesen, Daniel I. Chasman, Dale R. Nyholt, Masato Akiyama, Varinder S. Alg, Sigrid Børte, Joseph P. Broderick, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Kristian Hveem, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M.Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10-3per year [95% CI, -6.49×10-3to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Original languageEnglish (US)
Pages (from-to)810-818
Number of pages9
JournalStroke
Volume54
Issue number3
DOIs
StatePublished - Mar 1 2023
Externally publishedYes

Keywords

  • aneurysmal subarachnoid hemorrhage
  • genetic heterogeneity
  • genetics
  • intracranial aneurysm
  • risk assessment

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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