Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms
Authors: van ’t Hof Femke N. G. , Ruigrok Ynte M. , Lee Cue Hyunkyu , Ripke Stephan , Anderson Graig , de Andrade Mariza , Baas Annette F. , Blankensteijn Jan D. , Böttinger Erwin P. , Bown Matthew J. , Broderick Joseph , Bijlenga Philippe , Carrell David S. , Crawford Dana C. , Crosslin David R. , Ebeling Christian , Eriksson Johan G. , Fornage Myriam , Foroud Tatiana , von und zu Fraunberg Mikael , Friedrich Christoph M. , Gaál Emília I. , Gottesman Omri , Guo Dong‐Chuan , Harrison Seamus C. , Hernesniemi Juha , Hofman Albert , Inoue Ituro , Jääskeläinen Juha E. , Jones Gregory T. , Kiemeney Lambertus A. L. M. , Kivisaari Riku , Ko Nerissa , Koskinen Seppo , Kubo Michiaki , Kullo Iftikhar J. , Kuivaniemi Helena , Kurki Mitja I. , Laakso Aki , Lai Dongbing , Leal Suzanne M. , Lehto Hanna , LeMaire Scott A. , Low Siew‐Kee , Malinowski Jennifer , McCarty Catherine A. , Milewicz Dianna M. , Mosley Thomas H. , Nakamura Yusuke , Nakaoka Hirofumi , Niemelä Mika , Pacheco Jennifer , Peissig Peggy L. , Pera Joanna , Rasmussen‐Torvik Laura , Ritchie Marylyn D. , Rivadeneira Fernando , van Rij Andre M. , Santos‐Cortez Regie Lyn P. , Saratzis Athanasios , Slowik Agnieszka , Takahashi Atsushi , Tromp Gerard , Uitterlinden André G. , Verma Shefali S. , Vermeulen Sita H. , Wang Gao T. ,   Aneurysm Consortium; Vascular Research Consortium of New Zealand, Han Buhm , Rinkel Gabriël J. E. , de Bakker Paul I. W. , Bown Matthew J. , Harrison Seamus C. , Saratzis Athanasios , Verissimo Ana , Wright Benjamin J. , Bumpstead Suzannah , Baas Annette F. , Gretarsdottir Solveig , Badger Stephen A. , Child Anne H. , Clough Rachel E. , Cockerill Gillian , Hafez Hany , Scott D. Julian A. , Futers Simon , Sohrabi Soroush , Smith Alberto , Thompson Matthew M. , van Bockxmeer Frank M. , Matthiasson Stefan E. , Thorleifsson Gudmar , Thorsteinsdottir Unnur , Blankensteijn Jan D. , Teijink Joep A. W. , Wijmenga Cisca , de Graaf Jacqueline , Kiemeney Lambertus A. , Palmen Jutta , Smith Andrew J. , Lindholt Jes S. , Bradley Declan T. , Waltham Matthew , Edkins Sarah , Gwilliam Rhian , Hunt Sarah E. , Potter Simon , Golledge Jonathan , Eriksson Per , Norman Paul E. , Powell Janet T. , Stefansson Kari , Thompson John R. , Humphries Steve E. , Sayers Robert D. , Deloukas Panos , Samani Nilesh J. , Jones Gregory T. , Phillip L. Victoria , van Rij Andre M. , Hill Geraldine B. , Williams Michael J. A. , Thomson Ian A. , Krysa Jo , Wilkins Gerard T. , Merriman Tony R. , Vasudevan Thodor M. , Lewis David R. , Blair Ross D. , Hill Andrew A. 
Published: July 2016

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
SNP
s 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

RBBP
8

to
AAA
(odds ratio [
OR
]=1.11;
P
=4.1×10
−5
) and for
TAA
risk locus 15q21 near

FBN
1

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.