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

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Title: Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.
Authors: Van 't Hof, FNG
Ruigrok, YM
Lee, CH
Ripke, S
Anderson, G
De Andrade, M
Baas, AF
Blankensteijn, JD
Böttinger, EP
Bown, MJ
Broderick, J
Bijlenga, P
Carrell, DS
Crawford, DC
Crosslin, DR
Ebeling, C
Eriksson, JG
Fornage, M
Foroud, T
Von Und Zu Fraunberg, M
Friedrich, CM
Gaál, EI
Gottesman, O
Guo, D-C
Harrison, SC
Hernesniemi, J
Hofman, A
Inoue, I
Jääskeläinen, JE
Jones, GT
Kiemeney, LALM
Kivisaari, R
Ko, N
Koskinen, S
Kubo, M
Kullo, IJ
Kuivaniemi, H
Kurki, MI
Laakso, A
Lai, D
Leal, SM
Lehto, H
LeMaire, SA
Low, S-K
Malinowski, J
McCarty, CA
Milewicz, DM
Mosley, TH
Nakamura, Y
Nakaoka, H
Niemelä, M
Pacheco, J
Peissig, PL
Pera, J
Rasmussen-Torvik, L
Ritchie, MD
Rivadeneira, F
Van Rij, AM
Santos-Cortez, RLP
Saratzis, A
Slowik, A
Takahashi, A
Tromp, G
Uitterlinden, AG
Verma, SS
Vermeulen, SH
Wang, GT
Aneurysm Consortium; Vascular Research Consortium of New Zealand
Han, B
Rinkel, GJE
De Bakker, PIW
Item Type: Journal Article
Abstract: 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.
Issue Date: 14-Jul-2016
Date of Acceptance: 16-Mar-2016
URI: http://hdl.handle.net/10044/1/62781
DOI: https://dx.doi.org/10.1161/JAHA.115.002603
ISSN: 2047-9980
Publisher: Wiley
Journal / Book Title: Journal of the American Heart Association
Volume: 5
Issue: 7
Copyright Statement: © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properl y cited and is not used for commercial purposes.
Keywords: abdominal aortic aneurysm
genome wide association study
intracranial aneurysm
thoracic aortic aneurysm
Aortic Aneurysm, Abdominal
Aortic Aneurysm, Thoracic
Case-Control Studies
Cohort Studies
Genetic Predisposition to Disease
Genome-Wide Association Study
Intracranial Aneurysm
Linkage Disequilibrium
Middle Aged
Odds Ratio
Polymorphism, Single Nucleotide
Risk Factors
Aneurysm Consortium; Vascular Research Consortium of New Zealand
Publication Status: Published
Conference Place: England
Online Publication Date: 2016-07-14
Appears in Collections:Department of Surgery and Cancer