Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Bakker, Mark K.; Spek, Rick A. A. van der; Rheenen, Wouter van; Morel, Sandrine; Bourcier, Romain; Hostettler, Isabel C.; Alg, Varinder S.; Eijk, Kristel R. van; Koido, Masaru; Akiyama, Masato; Terao, Chikashi; Matsuda, Koichi; Walters, Robin G.; Lin, Kuang; Li, Liming; Millwood, Iona Y.; Chen, Zhengming; Rouleau, Guy A.; Zhou, Sirui; Rannikmae, Kristiina; Sudlow, Cathie L. M.; Houlden, Henry; Berg, Leonard H. van den; Dina, Christian; Naggara, Olivier; Gentric, Jean-Christophe; Shotar, Eimad; Eugene, Francois; Desal, Hubert; Winsvold, Bendik S.; Borte, Sigrid; Johnsen, Marianne Bakke; Brumpton, Ben M.; Sandvei, Marie Softeland; Willer, Cristen J.; Hveem, Kristian; Zwart, John-Anker; Verschuren, W. M. Monique; Friedrich, Christoph M.; Hirsch, Sven; Schilling, Sabine; Dauvillier, Jerome; Martin, Olivier; Winsvold, Bendik S.; Winsvold, Bendik S.; Borte, Sigrid; Johnsen, Marianne Bakke; Brumpton, Ben M.; Sandvei, Marie Softeland; Willer, Cristen J.; Hveem, Kristian; Zwart, John-Anker; Bian, Zheng; Chen, Junshi; Chen, Yiping; Chen, Zhengming; Clarke, Robert; Collins, Rory; Guo, Yu; Han, Xiao; Hill, Michael; Li, Liming; Lin, Kuang; Liu, Depei; Lv, Jun; Millwood, Iona; Peto, Richard; Sansome, Sam; Walters, Robin; Yang, Xiaoming; Yu, Canqing; Koido, Masaru; Koido, Masaru; Akiyama, Masato; Terao, Chikashi; Matsuda, Koichi; Kamatani, Yoichiro; Desal, Hubert; Desal, Hubert; Bourcier, Romain; Redon, Richard; Dina, Christian; Naggara, Olivier; Eugene, Francois; Gentric, Jean-Christophe; Shotar, Eimad; Sargurupremraj, Muralidharan; Tatlisumak, Turgut; Debette, Stephanie; Werring, David J.; Houlden, Henry; Alg, Varinder S.; Hostettler, Isabel C.; Bonner, Stephen; Walsh, Daniel; Bulters, Diederik; Kitchen, Neil; Brown, Martin; Grieve, Joan; Bakker, Mark K.; Bourcier, Romain; Walters, Robin G.; Malik, Rainer; Dichgans, Martin ; Sargurupremraj, Muralidharan; Tatlisumak, Turgut; Debette, Stephanie; Rinkel, Gabriel J. E.; Worrall, Bradford B.; Pera, Joanna; Slowik, Agnieszka; Broderick, Joseph P.; Werring, David J.; Woo, Daniel; Bijlenga, Philippe; Kamatani, Yoichiro; Ruigrok, Ynte M.; Jones, Gregory T.; Bown, Matthew J.; Ko, Nerissa U.; Kim, Helen; Coleman, Jonathan R. I.; Breen, Gerome; Zaroff, Jonathan G.; Klijn, Catharina J. M.; Malik, Rainer; Dichgans, Martin ; Sargurupremraj, Muralidharan; Tatlisumak, Turgut; Amouyel, Philippe; Debette, Stephanie; Rinkel, Gabriel J. E.; Worrall, Bradford B.; Pera, Joanna; Slowik, Agnieszka; Gaal-Paavola, Emilia I.; Niemela, Mika; Jaaskelainen, Juha E.; Fraunberg, Mikael von und zu; Lindgren, Antti; Broderick, Joseph P.; Werring, David J.; Woo, Daniel; Redon, Richard; Bijlenga, Philippe; Kamatani, Yoichiro; Veldink, Jan H. und Ruigrok, Ynte M. (2020): Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. In: Nature Genetics, Bd. 52, Nr. 12: S. 1303-1313

Abstract

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits. Cross-ancestry genome-wide association analyses in individuals of European and East Asian ancestry identify 11 new risk loci for intracranial aneurysms and highlight a polygenic architecture explaining a substantial fraction of disease heritability.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Institut für Schlaganfall- und Demenzforschung (ISD)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1061-4036
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198