Instability of high polygenic risk classification and mitigation by integrative scoring
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Фев. 12, 2025
Polygenic
risk
scores
(PRS)
continue
to
improve
with
novel
methods
and
expanding
genome-wide
association
studies.
Healthcare
commercial
laboratories
are
increasingly
deploying
PRS
reports
patients,
but
it
is
unknown
how
the
classification
of
high
polygenic
changes
across
individual
PRS.
Here,
we
assess
performance
cataloged
for
three
complex
traits.
We
chronologically
order
all
trait-related
publications
(Pubn)
identify
single
Best(Pubn)
each
Pubn
that
has
strongest
target
outcome.
While
demonstrates
generally
consistent
population-level
strengths
associations,
individuals
in
top
10%
distribution
varies
widely.
Using
PRSmix
framework,
which
integrates
information
several
prediction,
generate
corresponding
ChronoAdd(Pubn)
combine
from
up
including
Pubn.
When
compared
Best(Pubn),
demonstrate
more
high-risk
amongst
themselves.
This
integrative
scoring
approach
provides
stable
reliable
an
adaptable
framework
into
new
can
be
incorporated
as
they
introduced,
integrating
easily
current
implementation
strategies.
Variability
exists
classifying
diseases.
Here
authors
show
improves
consistency
overall
toward
clinical
applications.
Язык: Английский
Cardiovascular Risk Predicts White Matter Hyperintensities, Brain Atrophy and Treatment Resistance in Major Depressive Disorder: Role of Genetic Liability
Acta Psychiatrica Scandinavica,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 27, 2025
ABSTRACT
Introduction
Depressive
disorders
are
a
leading
cause
of
global
disease
burden,
particularly
with
the
challenge
treatment‐resistant
depression
(TRD).
Research
points
to
complex
bidirectional
relationship
between
cardiovascular
(CV)
risk
factors
and
TRD,
CV
negatively
impacting
brain
structure
potentially
influencing
antidepressant
resistance.
Moreover,
association
genetic
vulnerability
suggests
shared
pathophysiological
process
two.
This
study
investigates
mediating
role
structural
alterations
in
cerebrovascular
(CeV)
treatment
resistance
depression.
Methods
We
assessed
165
inpatients
Major
depressive
disorder.
Each
patient's
was
via
QRISK
3
calculator.
For
subset
patients,
CeV
polygenic
scores
(PRS)
were
obtained.
All
patients
underwent
T
MRI
scan,
white
matter
hyperintensities
estimates
indicators
trophic
state
Results
Both
PRSs
associated
status,
hyperintensities,
atrophy.
Mediation
analyses
suggested
that
CV‐induced
might
underlie
relation
phenotypic
Conclusion
These
results
underscore
need
explore
management
as
part
strategies
for
depression,
pointing
toward
linking
heart
health
Язык: Английский
Human genetics of metabolic dysfunction–associated steatotic liver disease: from variants to cause to precision treatment
Journal of Clinical Investigation,
Год журнала:
2025,
Номер
135(7)
Опубликована: Март 31, 2025
Metabolic
dysfunction-associated
steatotic
liver
disease
(MASLD)
is
characterized
by
increased
hepatic
steatosis
with
cardiometabolic
and
a
leading
cause
of
advanced
disease.
We
review
here
the
genetic
basis
MASLD.
The
variants
most
consistently
associated
implicate
genes
involved
in
lipoprotein
input
or
output,
glucose
metabolism,
adiposity/fat
distribution,
insulin
resistance,
mitochondrial/ER
biology.
distinct
mechanisms
which
these
promote
result
effects
on
that
may
be
best
suited
to
precision
medicine.
Recent
work
gene-environment
interactions
has
shown
risk
not
fixed
exacerbated
attenuated
modifiable
(diet,
exercise,
alcohol
intake)
nonmodifiable
environmental
factors.
Some
steatosis-associated
variants,
notably
those
patatin-like
phospholipase
domain-containing
3
(PNPLA3)
transmembrane
6
superfamily
member
2
(TM6SF2),
are
developing
adverse
liver-related
outcomes
provide
information
beyond
clinical
stratification
tools,
especially
individuals
at
intermediate
high
for
Future
better
characterize
heterogeneity
combining
genetics
factors
holistically
predict
develop
therapies
based
required.
Язык: Английский
Performance and Agreement of Coronary Heart Disease Polygenic Risk Scores—Reply
JAMA,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 7, 2025
Язык: Английский
Performance and Agreement of Coronary Heart Disease Polygenic Risk Scores
JAMA,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 7, 2025
Язык: Английский
Polygenic Risk Scores for Personalized Cardiovascular Pharmacogenomics―A Scoping Review
Scientia Pharmaceutica,
Год журнала:
2025,
Номер
93(2), С. 18 - 18
Опубликована: Апрель 8, 2025
Cardiovascular
disease
(CVD)
is
the
leading
cause
of
mortality
worldwide,
often
involving
a
strong
genetic
background.
Polygenic
risk
scores
(PRSs)
combine
cumulative
effects
multiple
variants
to
quantify
an
individual’s
susceptibility
CVD.
Pharmacogenomics
(PGx)
can
further
personalize
treatment
by
tailoring
medication
choices
profile.
Even
with
these
potential
benefits,
extent
which
PRS
be
integrated
into
PGx
CVD
remains
unclear.
Our
review
provides
overview
current
evidence
on
application
in
CVD,
examining
clinical
utility
and
limitations
providing
directions
for
future
research.
Following
Preferred
Reporting
Items
Systematic
Reviews
Meta-Analyses
extension
Scoping
protocol,
we
conducted
comprehensive
literature
search
PubMed,
EMBASE,
Web
Science.
Studies
investigating
relationship
between
predicting
efficacy,
adverse
effects,
or
cost-effectiveness
cardiovascular
medications
were
selected.
Of
1894
articles
identified,
32
met
inclusion
criteria.
These
studies
predominantly
examined
lipid-lowering
therapies,
antihypertensives,
antiplatelets,
although
other
classes
(e.g.,
rate-control
drugs,
ibuprofen/acetaminophen,
diuretics,
antiarrhythmics)
also
included.
findings
showed
that
most
robustly
validated
especially
statins,
where
reported
individuals
higher
PRSs
derived
greatest
reduction
lipids
while
statins.
analyzing
antiarrhythmic
demonstrated
more
variable
outcomes,
though
certain
did
identify
subgroups
significantly
improved
response
rates
events.
Though
was
tool
many
cases,
found
some
key
its
applicability
research,
such
as
under-representation
non-European-ancestry
cohorts
lack
standardized
outcome
reporting.
In
conclusion,
offers
promise
improving
efficacy
enhancing
personalization
individual
level,
several
obstacles,
need
including
broader
ancestral
diversity
robust
data
remain.
Future
research
must
(i)
prioritize
validating
ethnically
diverse
populations,
(ii)
refine
derivation
methods
tailor
them
drug
phenotypes,
(iii)
establish
clear
attainable
guidelines
standardizing
reporting
outcomes.
Язык: Английский
Using Genomics to Develop Personalized Cardiovascular Treatments
Arteriosclerosis Thrombosis and Vascular Biology,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 17, 2025
Advances
in
genomic
technologies
have
significantly
enhanced
our
understanding
of
both
monogenic
and
polygenic
etiologies
cardiovascular
disease.
In
this
review,
we
explore
how
the
utilization
information
is
bringing
personalized
medicine
approaches
to
forefront
disease
management.
We
discuss
data
can
resolve
diagnostic
uncertainty,
support
cascade
screening,
inform
treatment
strategies.
The
role
that
genome-wide
association
studies
had
identifying
thousands
risk
variants
for
diseases,
these
insights,
harnessed
through
development
scores,
could
advance
prediction
beyond
traditional
clinical
algorithms.
detail
pharmacogenomics
leverage
genotype
guide
drug
selection
mitigate
adverse
events.
Finally,
present
paradigm-shifting
approach
gene
therapy,
which
holds
promise
being
a
curative
intervention
conditions.
Язык: Английский
Three Open Questions in Polygenic Score Portability
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 21, 2024
A
major
obstacle
hindering
the
broad
adoption
of
polygenic
scores
(PGS)
is
their
lack
"portability"
to
people
that
differ-in
genetic
ancestry
or
other
characteristics-from
GWAS
samples
in
which
effects
were
estimated.
Here,
we
use
UK
Biobank
measure
change
PGS
prediction
accuracy
as
a
continuous
function
individuals'
genome-wide
dissimilarity
sample
("genetic
distance").
Our
results
highlight
three
gaps
our
understanding
portability.
First,
extremely
noisy
at
individual
level
and
not
well
predicted
by
distance.
In
fact,
variance
explained
comparably
socioeconomic
measures.
Second,
trends
portability
vary
across
traits.
For
several
immunity-related
traits,
drops
near
zero
quickly
even
intermediate
levels
This
quick
drop
may
reflect
associations
being
more
ancestry-specific
traits
than
Third,
show
qualitative
can
depend
on
used.
instance,
for
white
blood
cell
count,
(reduction
mean
squared
error)
increases
with
Together,
cannot
be
understood
through
global
groupings
alone.
There
are
other,
understudied
factors
influencing
portability,
such
specifics
evolution
trait
its
architecture,
social
context,
construction
score.
Addressing
these
aid
development
application
inform
equitable
genomic
research.
Язык: Английский
Polygenic Risk Scores for Coronary Heart Disease
JAMA,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 16, 2024
Sarah
A.
Abramowitz,
BA;
Kristin
Boulier,
MD;
Karl
Keat,
BS;
Katie
M.
Cardone,
Manu
Shivakumar,
John
DePaolo,
MD,
PhD;
Renae
Judy,
MS;
Francisca
Bermudez,
Nour
Mimouni,
Christopher
Neylan,
Dokyoon
Kim,
Daniel
J.
Rader,
Marylyn
D.
Ritchie,
Benjamin
F.
Voight,
Bogdan
Pasaniuc,
Michael
G.
Levin,
Scott
Damrauer,
Penn
Medicine
BioBank;
J
Rader;
D
Ritchie;
JoEllen
Weaver;
Nawar
Naseer;
Giorgio
Sirugo;
Afiya
Poindexter;
Yi-An
Ko;
Kyle
P.
Nerz;
Meghan
Livingstone;
Fred
Vadivieso;
Stephanie
DerOhannessian;
Teo
Tran;
Julia
Stephanowski;
Salma
Santos;
Ned
Haubein;
Joseph
Dunn;
Anurag
Verma;
Colleen
Kripke;
Marjorie
Risman;
Judy;
Colin
Wollack;
Shefali
S.
M
Damrauer;
Yuki
Bradford;
Dudek;
Theodore
Drivas
Язык: Английский