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Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.

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journal contribution
posted on 09.11.2016, 11:45 by F. N. van 't Hof, Y. M. Ruigrok, C. H. Lee, S. Ripke, G. Anderson, M. de Andrade, A. F. Baas, J. D. Blankensteijn, E. P. Böttinger, M. J. Bown, J. Broderick, P. Bijlenga, D. S. Carrell, D. C. Crawford, D. R. Crosslin, C. Ebeling, J. G. Eriksson, M. Fornage, T. Foroud, M. von Und Zu Fraunberg, C. M. Friedrich, E. I. Gaál, O. Gottesman, D. C. Guo, S. C. Harrison, J. Hernesniemi, A. Hofman, I. Inoue, J. E. Jääskeläinen, G. T. Jones, L. A. Kiemeney, R. Kivisaari, N. Ko, S. Koskinen, M. Kubo, I. J. Kullo, H. Kuivaniemi, M. I. Kurki, A. Laakso, D. Lai, S. M. Leal, H. Lehto, S. A. LeMaire, S. K. Low, J. Malinowski, C. A. McCarty, D. M. Milewicz, T. H. Mosley, Y. Nakamura, H. Nakaoka, M. Niemelä, J. Pacheco, P. L. Peissig, J. Pera, L. Rasmussen-Torvik, M. D. Ritchie, F. Rivadeneira, A. M. van Rij, R. L. Santos-Cortez, A. Saratzis, A. Slowik, A. Takahashi, G. Tromp, A. G. Uitterlinden, S. S. Verma, S. H. Vermeulen, G. T. Wang, Aneurysm Consortium; Vascular Research Consortium of New Zealand, B. Han, G. J. Rinkel, P. I. de Bakker
BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND RESULTS: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10(-3)). CONCLUSIONS: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.


van ’t Hof is supported by a grant of the Dutch Heart Foundation (NHS; Project No. 2008B004). Ruigrok is supported by a clinical fellowship grant of the Netherlands Organization for Scientific Research (NWO; Project No. 40‐00703‐98‐13533). Baas is supported by a grant from the Dr E. Dekker Program of the Netherlands Heart Foundation (2009T001). Bown is supported by a HEFCE Clinical Senior Lecturer Fellowship. Broderick is supported by a Familial Intracranial Aneurysm (FIA) grant (R01NS39512). Foroud is supported by an FIA grant (R03NS083468). Kubo is funded by the Instrumentarium Science Foundation, Finland, and by the Finnish Foundation for Cardiovascular Research, University of Eastern Finland. Saratzis is an NIHR Academic Clinical Lecturer. Milewicz is supported by grants from the National Institutes of Health (NIH; P50‐HL083794). The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, and RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS data sets are supported by the Netherlands Organization of Scientific Research NWO Investments (No. 175.010.2005.011, 911‐03‐012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014‐93‐015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO), Netherlands Consortium for Healthy Aging (NCHA; Project No. 050‐060‐810). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The Japanese IA GWAS (named “



Journal of the American Heart Association, 2016, 5 (7)

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/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences


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