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 singlenucleotide 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=4.1910-5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1910-3). 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.
Bibliographical noteFunding Information:
We thank the staff and participants of the ARIC study for their important contributions. We also thank the NINDS and WTCCC for giving us the use of their control data, used for the TAA GWAS. We are also grateful to the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We also thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database of the Rotterdam Study. The following clinical centers and collaborators contributed to the sample and data collection of the @neurIST project (in order of number of recruited patients): Hôpitaux Universitaire de Genève et Faculté de médecine de Genève, Geneva, Switzerland (Philippe Bijlenga, Max Jägersberg, Alister Rogers, Bawarjan Schatlo, Patrick Teta, Karl Schaller, Vitor Mendes-Pereira, Ana Marcos Gonzalez, Ana Paula Narata, Karl O Lovblad, Daniel A. Rüfenacht); John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom (Julia Yarnold, Paul Summers, Alison Clarke, Gulam Zilani, James Byrne); Hospital Clinic, Barcelona, Spain (Juan Macho, Jordi Blasco); University of Pècs Medical School, Pecs, Hungary (Peter Bukovics, Ferenc Kover, Istvan Hudak, Tamas Doczi); Erasmus University Medical Center, Rotterdam, The Netherlands (Roelof Risselada, Miriam CJM Sturkenboom); Royal Hallamshire Hospital, Sheffield, United Kingdom (Pankaj Singh, Alan Waterworth, Umang Patel, Stuart Coley, Patricia Lawford); and Hospital General de Catalunya, San Cugat del Valles, Spain (Teresa Sola, Elio Vivas).
© 2016 The Authors.
- Abdominal aortic aneurysm
- Genome wide association study
- Intracranial aneurysm
- Thoracic aortic aneurysm