A large-scale multi-ancestry genome-wide study accounting for smoking bahavior identifies multiple genome-wide significant loci for systolic and diastolic blood pressure
Author(s)
Type
Journal Article
Abstract
Genome-
wide association analysis advanced understanding of blood pressure (BP), a major risk
factor
for vascular conditions such as coronary heart disease and stroke. Accounting for smoking
behavior may help identify novel BP loci and extend
our knowledge of its genetic architecture. We performed genome
-wide association meta
-analys
es
of systolic and diastolic BP
incorporating
gene
-smoking interactions
in 610,091 individuals
.
Stage 1 analysis
examined
~18.8 million SNPs and
small insertion/deletion
variants
in
129,913
individuals from four ancestries (European, African, Asian, and Hispanic)
with
follow
-up
analysis
of promising variants
in
480
,178 additional individuals from
fiv
e ancestr
ies
. We
identifie
d
15
new loci
that were genome-
wide significant (P < 5
×10
-8
) in Stage 1
and
formally
replicated in Stage 2
. A combined Stage 1 and 2 meta
-analysis identified
66 additional genome
-
wide significant
loci
( 13, 35, and 18 loci in European, African and trans
-ancestry, respectively
).
A total of 5
6 k
nown
BP loci were also
identified
by our results
(P < 5
×10
-8
).
O f the newly
identified
loci
, 10
sho
wed
significant interaction
with smoking
status
, but
none of them
were
replicated in Stage 2
. Several
loci were identified in African ancestry
, highlighting the
importance of genetic studies in diverse populations.
The identified
loci
show
strong evidence
for regulatory features and
support
shared pathophysiology
with c
ardiometabolic
and addiction
traits
. They
also
highlight a role in BP regulation
for
biological candidates
such as
modulators of
vascular structure and function
(
CDKN1B
,
BCAR1
-CFDP1
,
PXDN
,
EEA1
), ciliopathies
(
SDCCAG8,
RPGRIP1L
), telomere maintenance
(
TNKS
,
PINX1
,
AKTIP
)
, and cen
tral
dopaminergic signaling
(
MSRA
,
EBF2
)
wide association analysis advanced understanding of blood pressure (BP), a major risk
factor
for vascular conditions such as coronary heart disease and stroke. Accounting for smoking
behavior may help identify novel BP loci and extend
our knowledge of its genetic architecture. We performed genome
-wide association meta
-analys
es
of systolic and diastolic BP
incorporating
gene
-smoking interactions
in 610,091 individuals
.
Stage 1 analysis
examined
~18.8 million SNPs and
small insertion/deletion
variants
in
129,913
individuals from four ancestries (European, African, Asian, and Hispanic)
with
follow
-up
analysis
of promising variants
in
480
,178 additional individuals from
fiv
e ancestr
ies
. We
identifie
d
15
new loci
that were genome-
wide significant (P < 5
×10
-8
) in Stage 1
and
formally
replicated in Stage 2
. A combined Stage 1 and 2 meta
-analysis identified
66 additional genome
-
wide significant
loci
( 13, 35, and 18 loci in European, African and trans
-ancestry, respectively
).
A total of 5
6 k
nown
BP loci were also
identified
by our results
(P < 5
×10
-8
).
O f the newly
identified
loci
, 10
sho
wed
significant interaction
with smoking
status
, but
none of them
were
replicated in Stage 2
. Several
loci were identified in African ancestry
, highlighting the
importance of genetic studies in diverse populations.
The identified
loci
show
strong evidence
for regulatory features and
support
shared pathophysiology
with c
ardiometabolic
and addiction
traits
. They
also
highlight a role in BP regulation
for
biological candidates
such as
modulators of
vascular structure and function
(
CDKN1B
,
BCAR1
-CFDP1
,
PXDN
,
EEA1
), ciliopathies
(
SDCCAG8,
RPGRIP1L
), telomere maintenance
(
TNKS
,
PINX1
,
AKTIP
)
, and cen
tral
dopaminergic signaling
(
MSRA
,
EBF2
)
Date Issued
2018-02-15
Date Acceptance
2018-01-18
Citation
American Journal of Human Genetics, 2018, 102 (3), pp.375-400
ISSN
0002-9297
Publisher
Elsevier (Cell Press)
Start Page
375
End Page
400
Journal / Book Title
American Journal of Human Genetics
Volume
102
Issue
3
Copyright Statement
© 2018 American Society of Human Genetics. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
British Heart Foundation
Medical Research Council (MRC)
Wellcome Trust
Medical Research Council (MRC)
Action on Hearing Loss
Home Office
British Heart Foundation
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Grant Number
SP/04/02
G0700931
084723/Z/08/Z
G0601966
G51_Chambers
7370192
SP/13/2/30111
MR/L01632X/1
MR/L01341X/1
RTJ6219303-1
RDF03
Subjects
GWAS
GxE interactions
blood pressure
lifestyle
multi-ancestry
smoking
06 Biological Sciences
11 Medical And Health Sciences
Genetics & Heredity
Publication Status
Published
Article Number
AJHG-D-17-00640R4