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Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL.
[cadasil]
White
matter
hyperintensities
(
WMH
)
on
MRI
are
a
quantitative
marker
for
sporadic
cerebral
small
vessel
disease
and
are
highly
heritable
.
To
date
,
large
-scale
genetic
studies
have
identified
only
a
single
locus
influencing
WMH
burden
.
This
might
in
part
relate
to
biological
heterogeneity
of
sporadic
WMH
.
The
current
study
searched
for
genetic
modifiers
of
WMH
volume
in
cerebral
autosomal-dominant
arteriopathy
with
subcortical
infarcts
and
leukoencephalopathy
(
CADASIL
)
,
a
monogenic
small
vessel
disease
.
We
performed
a
genome-
wide
association
study
to
identify
quantitative
trait
loci
for
WMH
volume
by
combining
data
from
517
CADASIL
patients
collected
through
7
centers
across
Europe
.
WMH
volumes
were
centrally
analyzed
and
quantified
on
fluid
attenuated
inversion
recovery
images
.
Genotyping
was
performed
using
the
Affymetrix
6
.
0
platform
.
Individuals
were
assigned
to
2
distinct
genetic
clusters
(
cluster
1
and
cluster
2
)
based
on
their
genetic
background
.
Four
hundred
sixty-
six
patients
entered
the
final
genome-
wide
association
study
analysis
.
The
phenotypic
variance
of
WMH
burden
in
CADASIL
explained
by
all
single
nucleotide
polymorphisms
in
cluster
1
was
0
.
85
(
SE
=
0
.
21
)
,
suggesting
a
substantial
genetic
contribution
.
Using
cluster
1
as
derivation
and
cluster
2
as
a
validation
sample
,
a
polygenic
score
was
significantly
associated
with
WMH
burden
(
P
=
0
.
001
)
after
correction
for
age
,
sex
,
and
vascular
risk
factors
.
No
single
nucleotide
polymorphism
reached
genome-
wide
significance
.
We
found
a
polygenic
score
to
be
associated
with
WMH
volume
in
CADASIL
subjects
.
Our
findings
suggest
that
multiple
variants
with
small
effects
influence
WMH
burden
in
CADASIL
.
The
identification
of
these
variants
and
the
biological
pathways
involved
will
provide
insights
into
the
pathophysiology
of
white
matter
disease
in
CADASIL
and
possibly
small
vessel
disease
in
general
.
Diseases
Validation
Diseases presenting
"single nucleotide polymorphism"
symptom
cadasil
dystrophic epidermolysis bullosa
erythropoietic protoporphyria
esophageal adenocarcinoma
esophageal carcinoma
kabuki syndrome
monosomy 21
oligodontia
primary effusion lymphoma
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