Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity
Authors: Bakker Mark K. , Kanning Jos P. , Abraham Gad , Martinsen Amy E. , Winsvold Bendik S. , Zwart John-Anker , Bourcier Romain , Sawada Tomonobu , Koido Masaru , Kamatani Yoichiro , Morel Sandrine , Amouyel Philippe , Debette Stéphanie , Bijlenga Philippe , Berrandou Takiy , Ganesh Santhi K. , Bouatia-Naji Nabila , Jones Gregory , Bown Matthew , Rinkel Gabriel J.E. , Veldink Jan H. , Ruigrok Ynte M. , Hege Aamodt Anne , Heidi Skogholt Anne , Brumpton Ben M , Willer Cristen J , Sandset Else C , Kristoffersen Espen S , Ellekjær Hanne , Heuch Ingrid , Nielsen Jonas B , Hagen Knut , Hveem Kristian , Fritsche Lars G , Thomas Laurent F , Pedersen Linda M , Gabrielsen Maiken E , Holmen Oddgeir L , Børte Sigrid , Zhou Wei , Abboud Shérine , Pandolfo Massimo , Thijs Vincent , Leys Didier , Bodenant Marie , Louillet Fabien , Touzé Emmanuel , Mas Jean-Louis , Samson Yves , Leder Sara , Léger Anne , Deltour Sandrine , Crozier Sophie , Méresse Isabelle , Canaple Sandrine , Godefroy Olivier , Giroud Maurice , Béjot Yannick , Decavel Pierre , Medeiros Elizabeth , Montiel Paola , Moulin Thierry , Vuillier Fabrice , Dallongeville Jean , Metso Antti J , Metso Tiina , Tatlisumak Turgut , Grond-Ginsbach Caspar , Lichy Christoph , Kloss Manja , Werner Inge , Arnold Marie-Luise , Dos Santos Michael , Grau Armin , Dichgans Martin , Thomas-Feles Constanze , Weber Ralf , Brandt Tobias , Pezzini Alessandro , De Giuli Valeria , Caria Filomena , Poli Loris , Padovani Alessandro , Bersano Anna , Lanfranconi Silvia , Beretta Simone , Ferrarese Carlo , Giacolone Giacomo , Paolucci Stefano , Lyrer Philippe , Engelter Stefan , Fluri Felix , Hatz Florian , Gisler Dominique , Bonati Leo , Gensicke Henrik , Amort Margareth , Markus Hugh , Majersik Jennifer , Worrall Bradford , Southerland Andrew , Cole John , Kittner Steven , Evangelou Evangelos , Warren Helen R , Gao He , Ntritsos Georgios , Dimou Niki , Esko Tonu , Mägi Reedik , Milani Lili , Almgren Peter , Boutin Thibaud , Ding Jun , Giulianini Franco , Holliday Elizabeth G , Jackson Anne U , Li-Gao Ruifang , Lin Wei-Yu , Luan Jian’an , Mangino Massimo , Oldmeadow Christopher , Peter Prins Bram , Qian Yong , Sargurupremraj Muralidharan , Shah Nabi , Surendran Praveen , Thériault Sébastien , Verweij Niek , Willems Sara M , Zhao Jing-Hua , Connell John , de Mutsert Renée , Doney Alex SF , Farrall Martin , Menni Cristina , Morris Andrew D , Noordam Raymond , Paré Guillaume , Poulter Neil R , Shields Denis C , Stanton Alice , Thom Simon , Abecasis Gonçalo , Amin Najaf , Arking Dan E , Ayers Kristin L , Barbieri Caterina M , Batini Chiara , Bis Joshua C , Blake Tineka , Bochud Murielle , Boehnke Michael , Boerwinkle Eric , Boomsma Dorret I , Bottinger Erwin P , Braund Peter S , Brumat Marco , Campbell Archie , Campbell Harry , Chakravarti Aravinda , Chambers John C , Chauhan Ganesh , Ciullo Marina , Cocca Massimiliano , Collins Francis , Cordell Heather J , Davies Gail , de Borst Martin H , de Geus Eco J , Deary Ian J , Deelen Joris , Del Greco M Fabiola , Yusuf Demirkale Cumhur , Dörr Marcus , Ehret Georg B , Elosua Roberto , Enroth Stefan , Mesut Erzurumluoglu A , Ferreira Teresa , Frånberg Mattias , Franco Oscar H , Gandin Ilaria , Gasparini Paolo , Giedraitis Vilmantas , Gieger Christian , Girotto Giorgia , Goel Anuj , Gow Alan J , Gudnason Vilmundur , Guo Xiuqing , Gyllensten Ulf , Hamsten Anders , Harris Tamara B , Harris Sarah E , Hartman Catharina A , Havulinna Aki S , Hicks Andrew A , Hofer Edith , Hofman Albert , Hottenga Jouke-Jan , Huffman Jennifer E , Hwang Shih-Jen , Ingelsson Erik , James Alan , Jansen Rick , Jarvelin Marjo-Riitta , Joehanes Roby , Johansson Åsa , Johnson Andrew D , Joshi Peter K , Jousilahti Pekka , Wouter Jukema J , Jula Antti , Kähönen Mika , Kathiresan Sekar , Keavney Bernard D , Khaw Kay-Tee , Knekt Paul , Knight Joanne , Kolcic Ivana , Kooner Jaspal S , Koskinen Seppo , Kristiansson Kati , Kutalik Zoltan , Laan Maris , Larson Marty , Launer Lenore J , Lehne Benjamin , Lehtimäki Terho , Liewald David CM , Lin Li , Lind Lars , Lindgren Cecilia M , Liu YongMei , Loos Ruth JF , Lopez Lorna M , Lu Yingchang , Lyytikäinen Leo-Pekka , Mahajan Anubha , Mamasoula Chrysovalanto , Marrugat Jaume , Marten Jonathan , Milaneschi Yuri , Morgan Anna , Morris Andrew P , Morrison Alanna C , Munson Peter J , Nalls Mike A , Nandakumar Priyanka , Nelson Christopher P , Niiranen Teemu , Nolte Ilja M , Nutile Teresa , Oldehinkel Albertine J , Oostra Ben A , O’Reilly Paul F , Org Elin , Padmanabhan Sandosh , Palmas Walter , Palotie Aarno , Pattie Alison , WJH Penninx Brenda , Perola Markus , Peters Annette , Polasek Ozren , Pramstaller Peter P , Tri Nguyen Quang , Raitakari Olli T , Rettig Rainer , Rice Kenneth , Ridker Paul M , Ried Janina S , Riese Harriëtte , Ripatti Samuli , Robino Antonietta , Rose Lynda M , Rotter Jerome I , Rudan Igor , Ruggiero Daniela , Saba Yasaman , Sala Cinzia F , Salomaa Veikko , Samani Nilesh J , Sarin Antti-Pekka , Schmidt Reinhold , Schmidt Helena , Shrine Nick , Siscovick David , Smith Albert V , Snieder Harold , Sõber Siim , Sorice Rossella , Starr John M , Stott David J , Strachan David P , Strawbridge Rona J , Sundström Johan , Swertz Morris A , Taylor Kent D , Teumer Alexander , Tobin Martin D , Tomaszewski Maciej , Toniolo Daniela , Traglia Michela , Trompet Stella , Tuomilehto Jaakko , Tzourio Christophe , Uitterlinden André G , Vaez Ahmad , van der Most Peter J , van Duijn Cornelia M , Verwoert Germaine C , Vitart Veronique , Völker Uwe , Vollenweider Peter , Vuckovic Dragana , Watkins Hugh , Wild Sarah H , Willemsen Gonneke , Wilson James F , Wright Alan F , Yao Jie , Zemunik Tatijana , Zhang Weihua , Attia John R , Butterworth Adam S , Chasman Daniel I , Conen David , Cucca Francesco , Danesh John , Hayward Caroline , Howson Joanna MM , Laakso Markku , Lakatta Edward G , Langenberg Claudia , Melander Olle , Mook-Kanamori Dennis O , Palmer Colin NA , Risch Lorenz , Scott Robert A , Scott Rodney J , Sever Peter , Spector Tim D , van der Harst Pim , Wareham Nicholas J , Zeggini Eleftheria , Levy Daniel , Munroe Patricia B , Newton-Cheh Christopher , Brown Morris J , Metspalu Andres , Psaty Bruce M. , Wain Louise V , Elliott Paul , Caulfield Mark J , Gormley Padhraig , Anttila Verneri , Palta Priit , Esko Tonu , Pers Tune H , Farh Kai-How , Cuenca-Leon Ester , Muona Mikko , Furlotte Nicholas A , Kurth Tobias , Ingason Andres , McMahon George , Ligthart Lannie , Terwindt Gisela M , Kallela Mikko , Freilinger Tobias M , Ran Caroline , Gordon Scott G , Stam Anine H , Steinberg Stacy , Borck Guntram , Koiranen Markku , Quaye Lydia , Adams Hieab H H , Lehtimäki Terho , Sarin Antti-Pekka , Wedenoja Juho , Hinds David A , Buring Julie E , Schürks Markus , Ridker Paul M , Gudlaug Hrafnsdottir Maria , Stefansson Hreinn , Ring Susan M , Hottenga Jouke-Jan , Penninx Brenda W J H , Färkkilä Markus , Artto Ville , Kaunisto Mari , Vepsäläinen Salli , Malik Rainer , Heath Andrew C , Madden Pamela A F , Martin Nicholas G , Montgomery Grant W , Kurki Mitja I , Kals Mart , Mägi Reedik , Pärn Kalle , Hämäläinen Eija , Huang Hailiang , Byrnes Andrea E , Franke Lude , Huang Jie , Stergiakouli Evie , Lee Phil H , Sandor Cynthia , Webber Caleb , Cader Zameel , Muller-Myhsok Bertram , Schreiber Stefan , Meitinger Thomas , Eriksson Johan G , Salomaa Veikko , Heikkilä Kauko , Loehrer Elizabeth , Uitterlinden Andre G , Hofman Albert , van Duijn Cornelia M , Cherkas Lynn , Pedersen Linda M , Stubhaug Audun , Nielsen Christopher S , Männikkö Minna , Mihailov Evelin , Milani Lili , Göbel Hartmut , Esserlind Ann-Louise , Francke Christensen Anne , Folkmann Hansen Thomas , Werge Thomas , Kaprio Jaakko , Aromaa Arpo J , Raitakari Olli , Arfan Ikram M , Spector Tim , Järvelin Marjo-Riitta , Metspalu Andres , Kubisch Christian , Strachan David P , Ferrari Michel D , Belin Andrea C , Dichgans Martin , Wessman Maija , van den Maagdenberg Arn M J M , Boomsma Dorret I , Davey Smith George , Stefansson Kari , Eriksson Nicholas , Daly Mark J , Neale Benjamin M , Olesen Jes , Chasman Daniel I , Nyholt Dale R , Palotie Aarno , Akiyama Masato , Alg Varinder S. , Børte Sigrid , Broderick Joseph P. , Brumpton Ben M. , Dauvillier Jérôme , Desal Hubert , Dina Christian , Friedrich Christoph M. , Gaál-Paavola Emília I. , Gentric Jean-Christophe , Hirsch Sven , Hostettler Isabel C. , Houlden Henry , Hveem Kristian , Jääskeläinen Juha E. , Johnsen Marianne Bakke , Li Liming , Lin Kuang , Lindgren Antti , Martin Olivier , Matsuda Koichi , Millwood Iona Y. , Naggara Olivier , Niemelä Mika , Pera Joanna , Redon Richard , Rouleau Guy A. , Sandvei Marie Søfteland , Schilling Sabine , Shotar Eimad , Slowik Agnieszka , Terao Chikashi , Verschuren W. M. Monique , Walters Robin G. , Werring David J. , Willer Cristen J. , Woo Daniel , Worrall Bradford B. , Zhou Sirui 
Published: January 2023

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
−3
per year [95% CI, −6.49×10
−3
to −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.