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

Author

Bakker MK, van der Spek RAA, van Rheenen W, Morel S, Bourcier R, Hostettler IC, Alg VS, van Eijk KR, Koido M, Akiyama M, Terao C, Matsuda K, Walters RG, Lin K, Li L, Millwood IY, Chen Z, Rouleau GA, Zhou S, Rannikmäe K, Sudlow CLM, Houlden H, van den Berg LH, Dina C, Naggara O, Gentric JC, Shotar E, Eugène F, Desal H, Winsvold BS, Børte S, Johnsen MB, Brumpton BM, Sandvei MS, Willer CJ, Hveem K, Zwart JA, Verschuren WMM, Friedrich CM, Hirsch S, Schilling S, Dauvillier J, Martin O, Jones GT, Bown MJ, Ko NU, Kim H, Coleman JRI, Breen G, Zaroff JG, Klijn CJM, Malik R, Dichgans M, Sargurupremraj M, Tatlisumak T, Amouyel P, Debette S, Rinkel GJE, Worrall BB, Pera J, Slowik A, Gaál-Paavola EI, Niemelä M, Jääskeläinen JE, von Und Zu Fraunberg M, Lindgren A, Broderick JP, Werring DJ, Woo D, Redon R, Bijlenga P, Kamatani Y, Veldink JH, and Ruigrok YM

Subjects
Asian People genetics, Blood Pressure genetics, Case-Control Studies, Endothelial Cells pathology, Genome-Wide Association Study, Humans, Hypertension physiopathology, Intracranial Aneurysm pathology, Polymorphism, Single Nucleotide genetics, Risk Factors, Smoking adverse effects, White People genetics, Genetic Predisposition to Disease genetics, Hypertension genetics, Intracranial Aneurysm genetics, Smoking genetics, Subarachnoid Hemorrhage genetics, Subarachnoid Hemorrhage pathology
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.

Published
2020
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2. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Author

Bakker, Mark K, van der Spek, Rick AA, van Rheenen, Wouter, Morel, Sandrine, Bourcier, Romain, Hostettler, Isabel C, Alg, Varinder S, van Eijk, Kristel R, 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, Rannikmäe, Kristiina, Sudlow, Cathie LM, Houlden, Henry, van den Berg, Leonard H, Dina, Christian, Naggara, Olivier, Gentric, Jean-Christophe, Shotar, Eimad, Eugène, François, Desal, Hubert, Winsvold, Bendik S, Børte, Sigrid, Johnsen, Marianne Bakke, Brumpton, Ben M, Sandvei, Marie Søfteland, Willer, Cristen J, Hveem, Kristian, Zwart, John-Anker, Verschuren, WM Monique, Friedrich, Christoph M, Hirsch, Sven, Schilling, Sabine, Dauvillier, Jérôme, Martin, Olivier, HUNT All-In Stroke, China Kadoorie Biobank Collaborative Group, BioBank Japan Project Consortium, ICAN Study Group, CADISP Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators, International Stroke Genetics Consortium (ISGC), Jones, Gregory T, Bown, Matthew J, Ko, Nerissa U, Kim, Helen, Coleman, Jonathan RI, Breen, Gerome, Zaroff, Jonathan G, Klijn, Catharina JM, Malik, Rainer, Dichgans, Martin, Sargurupremraj, Muralidharan, Tatlisumak, Turgut, Amouyel, Philippe, Debette, Stéphanie, Rinkel, Gabriel JE, Worrall, Bradford B, Pera, Joanna, Slowik, Agnieszka, Gaál-Paavola, Emília I, Niemelä, Mika, Jääskeläinen, Juha E, von Und Zu Fraunberg, Mikael, Lindgren, Antti, Broderick, Joseph P, Werring, David J, Woo, Daniel, Redon, Richard, Bijlenga, Philippe, Kamatani, Yoichiro, Veldink, Jan H, and Ruigrok, Ynte M

Subjects
BioBank Japan Project Consortium, Blood Pressure, Cardiovascular, Medical and Health Sciences, International Stroke Genetics Consortium, White People, Asian People, Risk Factors, Clinical Research, Genetics, ICAN Study Group, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, China Kadoorie Biobank Collaborative Group, CADISP Group, Prevention, Smoking, Human Genome, Neurosciences, Endothelial Cells, Intracranial Aneurysm, Single Nucleotide, Subarachnoid Hemorrhage, Biological Sciences, Brain Disorders, Stroke, Case-Control Studies, Hypertension, HUNT All-In Stroke, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators, Genome-Wide Association Study, Developmental Biology
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.

Published
2020

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