. 2020 Dec;52(12):1303-1313.

doi: 10.1038/s41588-020-00725-7. Epub 2020 Nov 16.

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

Mark K Bakker¹, Rick A A van der Spek², Wouter van Rheenen², Sandrine Morel^{3

4}, Romain Bourcier^{5

6}, Isabel C Hostettler^{7

8}, Varinder S Alg⁷, Kristel R van Eijk², Masaru Koido^{9

10}, Masato Akiyama^{9

11

12}, Chikashi Terao⁹, Koichi Matsuda^{13

14}, Robin G Walters^{15

16}, Kuang Lin¹⁵, Liming Li¹⁷, Iona Y Millwood^{15

16}, Zhengming Chen^{15

16}, Guy A Rouleau¹⁸, Sirui Zhou¹⁹, Kristiina Rannikmäe²⁰, Cathie L M Sudlow^{20

21}, Henry Houlden²², Leonard H van den Berg², Christian Dina⁵, Olivier Naggara^{23

24}, Jean-Christophe Gentric²⁵, Eimad Shotar²⁶, François Eugène²⁷, Hubert Desal^{5

6}, Bendik S Winsvold^{28

29}, Sigrid Børte^{29

30

31}, Marianne Bakke Johnsen^{29

30

31}, Ben M Brumpton²⁹, Marie Søfteland Sandvei^{32

33}, Cristen J Willer³⁴, Kristian Hveem^{29

35}, John-Anker Zwart^{28

29

31}, W M Monique Verschuren^{36

37}, Christoph M Friedrich^{38

39}, Sven Hirsch⁴⁰, Sabine Schilling⁴⁰, Jérôme Dauvillier⁴¹, Olivier Martin⁴¹; 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); Gregory T Jones⁴², Matthew J Bown^{43

44}, Nerissa U Ko⁴⁵, Helen Kim^{46

47

48}, Jonathan R I Coleman^{49

50}, Gerome Breen^{49

50}, Jonathan G Zaroff⁵¹, Catharina J M Klijn⁵², Rainer Malik⁵³, Martin Dichgans^{54

55}, Muralidharan Sargurupremraj^{56

57}, Turgut Tatlisumak⁵⁸, Philippe Amouyel⁵⁹, Stéphanie Debette^{56

57}, Gabriel J E Rinkel², Bradford B Worrall⁶⁰, Joanna Pera⁶¹, Agnieszka Slowik⁶¹, Emília I Gaál-Paavola^{62

63}, Mika Niemelä⁶², Juha E Jääskeläinen^{64

65}, Mikael von Und Zu Fraunberg^{64

65}, Antti Lindgren^{64

65}, Joseph P Broderick⁶⁶, David J Werring⁷, Daniel Woo⁶⁶, Richard Redon⁵, Philippe Bijlenga⁴, Yoichiro Kamatani^{9

13}, Jan H Veldink², Ynte M Ruigrok⁶⁷

Collaborators, Affiliations

Affiliations

¹ Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands. m.k.bakker-25@umcutrecht.nl.
² Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands.
³ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁴ Neurosurgery Division, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
⁵ l'institut du thorax Université de Nantes, CHU Nantes, INSERM, CNRS, Nantes, France.
⁶ CHU Nantes, Department of Neuroradiology, Nantes, France.
⁷ Stroke Research Centre, University College London Queen Square Institute of Neurology, London, UK.
⁸ Department of Neurosurgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
⁹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁰ Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹¹ Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹² Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹³ Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁴ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁵ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁶ Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
¹⁷ Department of Epidemiology, School of Public Health, Peking University Health Science Center, Beijing, China.
¹⁸ Montréal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
¹⁹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
²⁰ Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK.
²¹ UK Biobank, Cheadle, Stockport, UK.
²² Neurogenetics Laboratory, The National Hospital of Neurology and Neurosurgery, London, UK.
²³ Pediatric Radiology, Necker Hospital for Sick Children, Université Paris Descartes, Paris, France.
²⁴ Department of Neuroradiology, Sainte-Anne Hospital and Université Paris Descartes, INSERM UMR, S894, Paris, France.
²⁵ Department of Neuroradiology, University Hospital of Brest, Brest, France.
²⁶ Department of Neuroradiology, Pitié-Salpêtrière Hospital, Paris, France.
²⁷ Department of Neuroradiology, University Hospital of Rennes, Rennes, France.
²⁸ Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
²⁹ K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
³⁰ Research and Communication Unit for Musculoskeletal Health (FORMI), Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
³¹ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
³² Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
³³ The Cancer Clinic, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
³⁴ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
³⁵ HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
³⁶ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
³⁷ National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
³⁸ Dortmund University of Applied Science and Arts, Dortmund, Germany.
³⁹ Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Essen, Germany.
⁴⁰ Zurich University of Applied Sciences, School of Life Sciences and Facility Management, Zurich, Switzerland.
⁴¹ SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁴² Department of Surgery, University of Otago, Dunedin, New Zealand.
⁴³ Department of Cardiovascular Sciences and National Institute for Health Research, University of Leicester, Leicester, UK.
⁴⁴ Leicester Biomedical Research Centre, University of Leicester, Glenfield Hospital, Leicester, UK.
⁴⁵ Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
⁴⁶ Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA.
⁴⁷ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
⁴⁸ Institute for Human Genetics, University of California, San Francisco, CA, USA.
⁴⁹ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵⁰ UK National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust, London, UK.
⁵¹ Division of Research, Kaiser Permanente of Northern California, Oakland, CA, USA.
⁵² Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
⁵³ Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-University, Munich, Germany.
⁵⁴ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁵⁵ Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich, Germany.
⁵⁶ INSERM U1219 Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.
⁵⁷ Department of Neurology, Institute for Neurodegenerative Disease, Bordeaux University Hospital, Bordeaux, France.
⁵⁸ Department of Clinical Neuroscience at Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
⁵⁹ Institut Pasteur de Lille, UMR1167 LabEx DISTALZ - RID-AGE Université de Lille, INSERM, Centre Hospitalier Université de Lille Lille, Lille Lille, France.
⁶⁰ Departments of Neurology and Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
⁶¹ Department of Neurology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
⁶² Department of Neurosurgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁶³ Clinical Neurosciences, University of Helsinki, Helsinki, Finland.
⁶⁴ Neurosurgery NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
⁶⁵ Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
⁶⁶ University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁶⁷ Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands. ij.m.ruigrok@umcutrecht.nl.

PMID: 33199917
PMCID: PMC7116530
DOI: 10.1038/s41588-020-00725-7

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

Mark K Bakker et al. Nat Genet. 2020 Dec.

. 2020 Dec;52(12):1303-1313.

doi: 10.1038/s41588-020-00725-7. Epub 2020 Nov 16.

Authors

Affiliations

¹ Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands. m.k.bakker-25@umcutrecht.nl.
² Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands.
³ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁴ Neurosurgery Division, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
⁵ l'institut du thorax Université de Nantes, CHU Nantes, INSERM, CNRS, Nantes, France.
⁶ CHU Nantes, Department of Neuroradiology, Nantes, France.
⁷ Stroke Research Centre, University College London Queen Square Institute of Neurology, London, UK.
⁸ Department of Neurosurgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
⁹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁰ Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹¹ Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹² Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹³ Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁴ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁵ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁶ Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
¹⁷ Department of Epidemiology, School of Public Health, Peking University Health Science Center, Beijing, China.
¹⁸ Montréal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
¹⁹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
²⁰ Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK.
²¹ UK Biobank, Cheadle, Stockport, UK.
²² Neurogenetics Laboratory, The National Hospital of Neurology and Neurosurgery, London, UK.
²³ Pediatric Radiology, Necker Hospital for Sick Children, Université Paris Descartes, Paris, France.
²⁴ Department of Neuroradiology, Sainte-Anne Hospital and Université Paris Descartes, INSERM UMR, S894, Paris, France.
²⁵ Department of Neuroradiology, University Hospital of Brest, Brest, France.
²⁶ Department of Neuroradiology, Pitié-Salpêtrière Hospital, Paris, France.
²⁷ Department of Neuroradiology, University Hospital of Rennes, Rennes, France.
²⁸ Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
²⁹ K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
³⁰ Research and Communication Unit for Musculoskeletal Health (FORMI), Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
³¹ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
³² Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
³³ The Cancer Clinic, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
³⁴ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
³⁵ HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
³⁶ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
³⁷ National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
³⁸ Dortmund University of Applied Science and Arts, Dortmund, Germany.
³⁹ Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Essen, Germany.
⁴⁰ Zurich University of Applied Sciences, School of Life Sciences and Facility Management, Zurich, Switzerland.
⁴¹ SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁴² Department of Surgery, University of Otago, Dunedin, New Zealand.
⁴³ Department of Cardiovascular Sciences and National Institute for Health Research, University of Leicester, Leicester, UK.
⁴⁴ Leicester Biomedical Research Centre, University of Leicester, Glenfield Hospital, Leicester, UK.
⁴⁵ Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
⁴⁶ Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA.
⁴⁷ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
⁴⁸ Institute for Human Genetics, University of California, San Francisco, CA, USA.
⁴⁹ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵⁰ UK National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust, London, UK.
⁵¹ Division of Research, Kaiser Permanente of Northern California, Oakland, CA, USA.
⁵² Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
⁵³ Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-University, Munich, Germany.
⁵⁴ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁵⁵ Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich, Germany.
⁵⁶ INSERM U1219 Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.
⁵⁷ Department of Neurology, Institute for Neurodegenerative Disease, Bordeaux University Hospital, Bordeaux, France.
⁵⁸ Department of Clinical Neuroscience at Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
⁵⁹ Institut Pasteur de Lille, UMR1167 LabEx DISTALZ - RID-AGE Université de Lille, INSERM, Centre Hospitalier Université de Lille Lille, Lille Lille, France.
⁶⁰ Departments of Neurology and Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
⁶¹ Department of Neurology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
⁶² Department of Neurosurgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁶³ Clinical Neurosciences, University of Helsinki, Helsinki, Finland.
⁶⁴ Neurosurgery NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
⁶⁵ Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
⁶⁶ University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁶⁷ Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands. ij.m.ruigrok@umcutrecht.nl.

PMID: 33199917
PMCID: PMC7116530
DOI: 10.1038/s41588-020-00725-7

Erratum in

Author Correction: Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.
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; 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 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, Ruigrok YM. Bakker MK, et al. Nat Genet. 2021 Feb;53(2):254. doi: 10.1038/s41588-020-00760-4. Nat Genet. 2021. PMID: 33353957 No abstract available.

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.

Trial registration: ClinicalTrials.gov NCT02848495.

PubMed Disclaimer

Conflict of interest statement

Competing Interests

When this study was conducted, C.L.M.S. was chief scientist for the UK Biobank study.

Figures

**Figure 1. GWAS meta-analysis association results.**
SAIGE logistic mixed model association P-values of the Stage 1 (upwards direction) and Stage 2 (downwards direction) GWAS meta-analyses. The horizontal axis indicates chromosomal position. The vertical axis indicates -log₁₀(P-value) of the association. The dotted lines indicate the genome-wide significance threshold of P=5·10^-8. Lead SNPs of each locus are highlighted with a diamond, and SNPs in close proximity (±500Kbp) are colored in pink or purple, depending on chromosome index parity. Labels are gene or locus names annotated using SMR, eCAVIAR and TWAS, or prior information of intracranial aneurysm-associated genes. Labels or loci identified only in the Stage 2 GWAS are shown in red.

**Figure 2. Heritability and functional enrichment analyses.**
a) Partitioned LDSR enrichment of regulatory elements. Labels indicate type of regulatory element or histone mark. On the horizontal axis, the enrichment is shown. Enrichment=1 indicates no enrichment. Statistical significance was defined as P-value below 0.05 divided by the number of annotations (52). Effective N varies per SNP (see data availability statement). Points are estimates and error bars denote one standard error in the direction of no effect. Statistics derived from two-sided, weighted linear regression. No P-value adjustment. b) Partitioned LDSR heritability analysis per chromosome. On the horizontal axis the proportion of SNPs on each chromosome is shown. On the vertical axis the proportion of SNP-based heritability. The linear regression line is shown in blue. Data is presented as point estimate ± standard error. Statistics the same as used for 2a. c) Partitioned LDSR enrichment analysis of scRNAseq brain cell types. Format and statistics are the same as used for 2a. d) GARFIELD analysis of tissues. On the horizontal axis, the enrichment of annotations is shown; on the vertical axis, the corresponding -log₁₀(P-value). Dashed line indicates the significance threshold of P=0.05 divided by the number of annotations. Odds ratios are derived by logistic regression. P-values are unadjusted, derived from two-sided test. e) GARFIELD analysis of regulatory regions defined by histone modifications. Format and statistics are the same as used for 2d).

**Figure 3. Cross-trait analyses.**
a) GSMR analysis of UK Biobank predictors on the Stage 1 intracranial aneurysm GWAS, conditioned on traits depicted by column labels with mtCOJO. Numeric values are the GSMR effect sizes. The top 13 traits are blood pressure-related traits. The bottom three traits are smoking-related. Statistical significance was defined as P-value below 0.05 divided by the number of traits that passed quality control (376). Square fill colors indicate -log₁₀(P-value) of the GSMR effect. All 16 traits that pass the multiple testing threshold for significance in the unconditioned analysis are shown. BP: blood pressure. Presented N is sample size in UK Biobank GWAS. For intracranial aneurysms, effective N per SNP was used. P-values from two-sided linear regression, unadjusted. b) Causality diagram further explaining the analyses of 2a: GSMR analysis showed that genetic risk for smoking and BP are causative of intracranial aneurysms. Using mtCOJO, it was found that the genetic factors associated with BP and smoking cause intracranial aneurysms through independent mechanisms. Statistics the same as used for 3a. BP N=317,754 samples, smoking N=101,726 samples. c) Genetic correlation analysis with LDSR. Genetic correlation estimates are indicated by color and numeric value. Axis labels on the left denote the trait correlated with intracranial aneurysms. Labels on the top denote the trait for which the Stage 1 intracranial aneurysm GWAS was conditioned using mtCOJO. More details in Supplementary Table 3. Presented N is effective sample size for trait on the left. Except for IS and ICH+IS, where an N per SNP was used and average N is shown. IS: ischemic stroke. ICH: intracerebral hemorrhage. AAA: abdominal aortic aneurysm.

See this image and copyright information in PMC

References

1. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol. 2011;10:626–36. - PubMed
1. Nieuwkamp DJ, et al. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009;8:635–42. - PubMed
1. Korja M, et al. Genetic epidemiology of spontaneous subarachnoid hemorrhage: Nordic Twin Study. Stroke. 2010;41:2458–62. - PubMed
1. Kurki MI, et al. High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms. PLoS Genet. 2014;10:e1004134. - PMC - PubMed
1. Yasuno K, et al. Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracranial aneurysm risk. Proc Natl Acad Sci U S A. 2011;108:19707–12. - PMC - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical