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J Am Heart Assoc. 2016 Jul 14;5(7). pii: e002603. doi: 10.1161/JAHA.115.002603.

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

Author information

1
Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
2
Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences Asan Medical Center, Seoul, Korea Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
3
Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA Department of Psychiatry and Psychotherapy, Charité, Universitätsmedizin Berlin, Berlin, Germany.
4
The George Institute for International Health, University of Sydney, Australia.
5
Mayo Clinic, Rochester, NY.
6
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
7
Department of Vascular Surgery, VU Medical Center, Amsterdam, The Netherlands.
8
Icahn School of Medicine Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY.
9
Department of Cardiovascular Sciences and the NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, United Kingdom.
10
Department of Neurology, University of Cincinnati School of Medicine, Cincinnati, OH.
11
Hôpitaux Universitaire de Genève et Faculté de médecine de Genève, Geneva, Switzerland.
12
Group Health Research Institute, Seattle, WA.
13
Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH Center for Human Genetics Research, Vanderbilt University, Nashville, TN.
14
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA.
15
Fraunhofer Institut Algorithmen und Wissenschaftliches Rechnen, Sankt Augustin, Germany.
16
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland Folkhälsan Research Center, Helsinki, Finland Department of General Practice and Primary Health Care, and Helsinki University Hospital, University of Helsinki, Finland.
17
Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX.
18
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
19
Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
20
Department of Computer Science, University of Applied Science and Arts, Dortmund, Germany.
21
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
22
Department of Internal Medicine, The University of Texas Medical School at Houston, TX.
23
Department of Cardiovascular Science, University of Leicester, United Kingdom.
24
Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
25
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
26
Division of Human Genetics, National Institute of Genetics, Mishima, Japan.
27
Surgery Department, University of Otago, Dunedin, New Zealand.
28
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
29
Department of Neurology, University of California, San Francisco, CA.
30
Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, Helsinki, Finland.
31
Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan.
32
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA Department of Surgery, Temple University School of Medicine, Philadelphia, PA Department of Biomedical Sciences, Stellenbosch University, Tygerberg, South Africa.
33
Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA Medical and Population Genetics Program, Broad Institute, Boston, MA.
34
Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
35
Center for Statistical Genetics, Baylor College of Medicine, Houston, TX.
36
Michael E. DeBakey Department of Surgery, Baylor College of Medicine and the Texas Heart Institute, Houston, TX.
37
Center for Human Genetics Research, Vanderbilt University, Nashville, TN Department of Surgery, Yale School of Medicine, New Haven, CT.
38
Research Division, Essentia Institute of Rural Health, Duluth, MN.
39
Department of Medicine, University of Mississippi Medical Center, Jackson, MS.
40
Section of Hematology and Oncology, Department of Medicine, University of Chicago, IL.
41
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
42
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI.
43
Department of Neurology, Jagiellonian University, Krakow, Poland.
44
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
45
Center for Systems Genomics, The Pennsylvania State University, Pennsylvania, PA.
46
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
47
The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA Department of Biomedical Sciences, Stellenbosch University, Tygerberg, South Africa.
48
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
49
Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences Asan Medical Center, Seoul, Korea.
50
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands pdebakker@umcutrecht.nl.

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.

KEYWORDS:

abdominal aortic aneurysm; genome wide association study; intracranial aneurysm; thoracic aortic aneurysm

PMID:
27418160
PMCID:
PMC5015357
DOI:
10.1161/JAHA.115.002603
[Indexed for MEDLINE]
Free PMC Article

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