Frontiers in Aging Neuroscience,
Год журнала:
2023,
Номер
15
Опубликована: Дек. 20, 2023
Objectives
To
explore
the
genetic
architecture
of
PD
in
Luxembourg
Parkinson’s
Study
including
cohorts
healthy
people
and
patients
with
disease
(PD)
atypical
parkinsonism
(AP).
Methods
809
controls,
680
103
AP
were
genotyped
using
Neurochip
array.
We
screened
validated
rare
single
nucleotide
variants
(SNVs)
copy
number
(CNVs)
within
seven
PD-causing
genes
(
LRRK2
,
SNCA
VPS35
PRKN
PARK7
PINK1
ATP13A2
).
Polygenic
risk
scores
(PRSs)
generated
latest
genome-wide
association
study
for
PD.
then
estimated
role
common
by
applying
gene-set-specific
PRSs.
Results
identified
60
SNVs
genes,
nine
which
pathogenic
.
Eleven
CNVs
detected
duplications
four
deletions.
The
majority
carriers
heterozygous
not
differentially
distributed
between
cases
controls.
PRSs
significantly
associated
specific
molecular
pathways
related
to
protein
metabolism
signal
transduction
as
drivers
risk.
Conclusion
performed
a
comprehensive
characterization
deep-phenotyped
individuals
Luxembourgish
Study.
Heterozygous
higher
In
particular,
we
reported
novel
digenic
patients.
Our
findings
will
help
future
studies
unravel
complexity
The American Journal of Human Genetics,
Год журнала:
2023,
Номер
110(5), С. 722 - 740
Опубликована: Апрель 14, 2023
Coronary
artery
disease
(CAD)
is
a
pandemic
where
up
to
half
of
the
risk
explained
by
genetic
factors.
Advanced
insights
into
basis
CAD
require
deeper
understanding
contributions
different
cell
types,
molecular
pathways,
and
genes
heritability.
Here,
we
investigate
biological
diversity
atherosclerosis-associated
states
interrogate
their
contribution
using
single-cell
bulk
RNA
sequencing
(RNA-seq)
mouse
human
lesions.
We
identified
12
disease-associated
that
characterized
further
gene
set
functional
profiling,
ligand-receptor
prediction,
transcription
factor
inference.
Importantly,
Vcam1+
smooth
muscle
state
contributed
most
SNP-based
heritability
CAD.
In
line
with
this,
variants
near
regulatory
elements
largest
fraction
CAD-risk
variance
between
individuals.
Using
this
information
for
variant
prioritization,
derived
hybrid
polygenic
score
(PRS)
demonstrated
improved
performance
over
classical
PRS.
Our
results
provide
mechanisms
associated
risk,
which
could
make
promising
precision
medicine
tailored
therapeutic
interventions
in
future.
Alzheimer s Research & Therapy,
Год журнала:
2024,
Номер
16(1)
Опубликована: Янв. 2, 2024
Recently,
single-nucleus
RNA-seq
(snRNA-seq)
analyses
have
revealed
important
cellular
and
functional
features
of
Alzheimer's
disease
(AD),
a
prevalent
neurodegenerative
disease.
However,
our
knowledge
regarding
intercellular
communication
mediated
by
dysregulated
ligand-receptor
(LR)
interactions
remains
very
limited
in
AD
brains.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Ноя. 30, 2023
Many
of
the
Alzheimer's
disease
(AD)
risk
genes
are
specifically
expressed
in
microglia
and
astrocytes,
but
how
when
genetic
localizing
to
these
cell
types
contributes
AD
pathophysiology
remains
unclear.
Here,
we
derive
cell-type-specific
polygenic
scores
(ADPRS)
from
two
extensively
characterized
datasets
uncover
impact
on
endophenotypes.
In
an
autopsy
dataset
spanning
all
stages
(n
=
1457),
astrocytic
ADPRS
affected
diffuse
neuritic
plaques
(amyloid-β),
while
microglial
plaques,
activation,
neurofibrillary
tangles
(tau),
cognitive
decline.
independent
neuroimaging
cognitively
unimpaired
elderly
2921),
was
associated
with
amyloid-β,
amyloid-β
tau,
connecting
pathology
even
before
symptom
onset.
Together,
our
study
provides
human
evidence
implicating
multiple
glial
pathophysiology,
starting
preclinical
stage.
Journal of Child Psychology and Psychiatry,
Год журнала:
2022,
Номер
63(10), С. 1111 - 1124
Опубликована: Март 30, 2022
The
increasing
availability
of
genotype
data
in
longitudinal
population‐
and
family‐based
samples
provides
opportunities
for
using
polygenic
scores
(PGS)
to
study
developmental
questions
child
adolescent
psychology
psychiatry.
Here,
we
aim
provide
a
comprehensive
overview
how
PGS
can
be
generated
implemented
psycho(patho)logy,
with
focus
on
designs.
As
such,
the
paper
is
organized
into
three
parts:
First,
formal
definition
related
concepts,
focusing
assumptions
limitations.
Second,
give
general
methods
used
compute
scores,
ranging
from
classic
approach
more
advanced
methods.
We
include
recommendations
reference
resources
available
researchers
aiming
conduct
analyses.
Finally,
practical
applications
analysis
data.
describe
have
been
research
outcomes,
they
applied
address
questions.
Brain,
Год журнала:
2023,
Номер
147(3), С. 887 - 899
Опубликована: Окт. 6, 2023
Abstract
There
are
78
loci
associated
with
Parkinson’s
disease
in
the
most
recent
genome-wide
association
study
(GWAS),
yet
specific
genes
driving
these
associations
mostly
unknown.
Herein,
we
aimed
to
nominate
top
candidate
gene
from
each
locus
and
identify
variants
pathways
potentially
involved
disease.
We
trained
a
machine
learning
model
predict
disease-associated
GWAS
using
genomic,
transcriptomic
epigenomic
data
brain
tissues
dopaminergic
neurons.
nominated
identified
novel
disease,
such
as
inositol
phosphate
biosynthetic
pathway
(INPP5F,
IP6K2,
ITPKB
PPIP5K2).
Specific
common
coding
SPNS1
MLX
may
be
burden
tests
of
rare
further
support
that
CNIP3,
LSM7,
NUCKS1
polyol/inositol
Functional
studies
needed
analyse
involvements
Alzheimer s & Dementia,
Год журнала:
2024,
Номер
20(9), С. 6146 - 6160
Опубликована: Июль 29, 2024
Abstract
INTRODUCTION
Unraveling
how
Alzheimer's
disease
(AD)
genetic
risk
is
related
to
neuropathological
heterogeneity,
and
whether
this
occurs
through
specific
biological
pathways,
a
key
step
toward
precision
medicine.
METHODS
We
computed
pathway‐specific
scores
(GRSs)
in
non‐demented
individuals
investigated
AD
variants
predict
cerebrospinal
fluid
(CSF)
imaging
biomarkers
reflecting
pathology,
cardiovascular,
white
matter
integrity,
brain
connectivity.
RESULTS
CSF
amyloidbeta
phosphorylated
tau
were
most
GRSs.
Inflammatory
pathways
associated
with
cerebrovascular
disease,
whereas
quantitative
measures
of
lesion
microstructure
integrity
predicted
by
clearance
migration
pathways.
Functional
connectivity
alterations
involved
signal
transduction
synaptic
communication.
DISCUSSION
This
study
reveals
distinct
profiles
association
pathophysiological
aspects
predementia
stages
AD,
unraveling
the
substrates
heterogeneity
AD‐associated
endophenotypes
promoting
forward
understanding
development
personalized
therapies.
Highlights
Polygenic
for
encompasses
six
that
can
be
quantified
scores,
differentially
relate
biomarkers.
are
mostly
burden.
White
health
membrane
functional
communication
Molecular Psychiatry,
Год журнала:
2024,
Номер
29(8), С. 2389 - 2398
Опубликована: Март 15, 2024
A
primary
goal
of
psychiatry
is
to
better
understand
the
pathways
that
link
genetic
risk
psychiatric
symptoms.
Here,
we
tested
association
diagnosis
and
endophenotypes
with
overall
neurotransmitter
pathway-specific
polygenic
in
patients
early-stage
psychosis.
Subjects
included
205
demographically
diverse
cases
a
psychotic
disorder
who
underwent
comprehensive
neurological
phenotyping
115
matched
controls.
Following
genotyping,
calculated
scores
(PGSs)
for
schizophrenia
(SZ)
bipolar
(BP)
using
Psychiatric
Genomics
Consortium
GWAS
summary
statistics.
To
test
if
can
be
partitioned
into
affected
pathways,
pathway
PGSs
(pPGSs)
SZ
affecting
each
four
major
systems:
glutamate,
GABA,
dopamine,
serotonin.
Psychosis
subjects
had
elevated
PGS
versus
controls;
or
BP
diagnoses
stronger
risk,
respectively.
There
was
no
significant
within
psychosis
between
individual
symptom
measures
PGS.
However,
neurotransmitter-specific
pPGSs
were
moderately
associated
specific
endophenotypes;
notably,
glutamate
deficits
cognitive
control
during
task-based
fMRI,
while
dopamine
global
functioning.
Finally,
unbiased
endophenotype-driven
clustering
identified
three
diagnostically
mixed
case
groups
separated
on
positive
symptoms,
negative
functioning,
control.
All
clusters
showed
strong
genome-wide
risk.
Cluster
2,
characterized
by
additionally
concentrated
glutamatergic
GABAergic
pathways.
Due
intensive
characterization
our
subjects,
present
study
limited
relatively
small
cohort.
As
such,
results
should
followed
up
additional
research
at
population
mechanism
level.
Our
suggests
pathway-based
analysis
may
powerful
path
forward
mechanisms
driving
endophenotypes.
Neuroscience Applied,
Год журнала:
2024,
Номер
3, С. 104070 - 104070
Опубликована: Янв. 1, 2024
The
canonical
Wnt
signaling
pathway
plays
a
vital
role
in
the
developmental
processes
of
Central
Nervous
System
throughout
both
prenatal
and
postnatal
stages,
as
well
maintaining
homeostasis
during
adulthood.
Its
complex
intracellular
cascade
involves
participation
key
proteins
(i.e.,
GSK3β
β-catenin)
to
activate
transcription
target
genes.
These
genes
subsequently
control
like
cell
proliferation,
maturation,
determination
fate.
Previous
studies
suggest
that
this
can
also
be
associated
with
Attention-Deficit
Hyperactivity
Disorder
(ADHD),
neurodevelopmental
disorder
multifactorial
etiology.
This
study
aimed
clarify
if
at
what
stage
is
altered
ADHD.
Accordingly,
we
carried
out
proteomic
functional
assessments
using
Western
Blot
reporter
assays,
respectively.
were
performed
induced
pluripotent
stem
(iPSC),
neural
(NSC),
neuronal
phases.
IPSCs
generated
from
somatic
cells
retrieved
5
controls
patients
diagnosed
As
opposed
iPSCs,
ADHD
NSCs
showed
alterations
protein
expression
β-catenin,
suggesting
increased
activity
group.
Moreover,
assays
confirmed
higher
NSCs.
Our
molecular
findings
correlated
genetic
predisposition
clinical
traits
displayed
by
their
respective
donors.
In
conclusion,
these
results
crucial
cellular
disrupted
patient-specific
NSCs,
potentially
explaining
deficits
clinically
exhibited
patients.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Апрель 30, 2024
The
polygenic
architecture
of
schizophrenia
implicates
several
molecular
pathways
involved
in
synaptic
function.
However,
it
is
unclear
how
risk
funnels
through
these
to
translate
into
syndromic
illness.
Using
tensor
decomposition,
we
analyze
gene
co-expression
the
caudate
nucleus,
hippocampus,
and
dorsolateral
prefrontal
cortex
post-mortem
brain
samples
from
358
individuals.
We
identify
a
set
genes
predominantly
expressed
nucleus
associated
with
both
clinical
state
genetic
for
that
shows
dopaminergic
selectivity.
A
higher
score
parsed
by
this
predicts
greater
dopamine
synthesis
striatum
striatal
activation
during
reward
anticipation.
These
results
dopamine-linked
variation
vivo
neurochemical
hemodynamic
phenotypes
have
long
been
implicated
pathophysiology
schizophrenia.
