medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Дек. 14, 2023
Abstract
Background
The
ganglionic
eminences
are
fetal-specific
structures
that
give
rise
to
gamma-
aminobutyric
acid
(GABA)-
and
acetylcholine-
releasing
neurons
of
the
forebrain.
Given
evidence
for
GABAergic
cholinergic
disturbances
in
schizophrenia,
as
well
an
early
neurodevelopmental
component
disorder,
we
tested
potential
involvement
developing
cells
mediating
genetic
risk
condition.
Study
Design
We
combined
data
from
a
recent
large-scale
genome-wide
association
study
schizophrenia
with
single
cell
RNA
sequencing
human
test
enrichment
variation
genes
high
expression
specificity
particular
populations
within
these
structures.
additionally
performed
nuclei
Assay
Transposase-Accessible
Chromatin
Sequencing
(snATAC-Seq)
map
regulatory
genomic
regions
operating
individual
eminences,
using
common
variant
liability
functionally
annotate
non-coding
variants
associated
disorder.
Results
Schizophrenia
was
enriched
neuron
predicted
form
dopamine
D1
D2
receptor
expressing
medium
spiny
striatum,
cortical
somatostatin-positive
interneurons,
calretinin-positive
neurons.
Consistent
findings,
also
concentrated
sequence
mapped
neuronal
eminences.
Conclusions
Our
provides
role
prenatal
development
later
susceptibility
schizophrenia.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 27, 2024
Abstract
Pathophysiology
of
many
neuropsychiatric
disorders,
including
schizophrenia
(SCZD),
is
linked
to
habenula
(Hb)
function.
While
pharmacotherapies
and
deep
brain
stimulation
targeting
the
Hb
are
emerging
as
promising
therapeutic
treatments,
little
known
about
cell
type-specific
transcriptomic
organization
human
or
how
it
altered
in
SCZD.
Here
we
define
molecular
neuroanatomy
identify
changes
individuals
with
SCZD
compared
neurotypical
controls.
Utilizing
Hb-enriched
postmortem
tissue,
performed
single
nucleus
RNA-sequencing
(snRNA-seq;
n=7
donors)
identified
17
molecularly
defined
types
across
16,437
nuclei,
3
medial
7
lateral
populations,
several
which
were
conserved
between
rodents
humans.
Single
molecule
fluorescent
situ
hybridization
(smFISH;
n=3
validated
snRNA-seq
mapped
their
spatial
locations.
Bulk
type
deconvolution
tissue
from
35
33
controls
yielded
45
SCZD-associated
differentially
expressed
genes
(DEGs,
FDR
<
0.05),
32
(71%)
unique
tissue.
eQTL
analysis
717
independent
SNP-gene
pairs
(FDR
where
either
SNP
a
risk
variant
(16
pairs)
gene
DEG
(7
pairs).
colocalization
16
colocalized
genes.
These
results
topographically
organized
distinct
signatures
demonstrate
genetic
associated
SCZD,
thereby
providing
novel
insights
into
role
disorders.
One
Sentence
Summary
Transcriptomic
identification
illness
state.
Schizophrenia Bulletin,
Год журнала:
2024,
Номер
50(5), С. 1171 - 1184
Опубликована: Июнь 13, 2024
Abstract
Background
The
ganglionic
eminences
(GE)
are
fetal-specific
structures
that
give
rise
to
gamma-aminobutyric
acid
(GABA)-
and
acetylcholine-releasing
neurons
of
the
forebrain.
Given
evidence
for
GABAergic,
cholinergic,
neurodevelopmental
disturbances
in
schizophrenia,
we
tested
potential
involvement
GE
neuron
development
mediating
genetic
risk
condition.
Study
Design
We
combined
data
from
a
recent
large-scale
genome-wide
association
study
schizophrenia
with
single-cell
RNA
sequencing
human
test
enrichment
variation
genes
high
expression
specificity
developing
cell
populations.
additionally
performed
single
nuclei
Assay
Transposase-Accessible
Chromatin
Sequencing
(snATAC-Seq)
map
regulatory
genomic
regions
operating
individual
populations
GE,
using
these
common
variant
liability
functionally
annotate
non-coding
variants-associated
disorder.
Results
Schizophrenia
was
enriched
predicted
form
dopamine
D1
D2
receptor-expressing
GABAergic
medium
spiny
striatum,
cortical
somatostatin-positive
interneurons,
calretinin-positive
neurons,
cholinergic
neurons.
Consistent
findings,
concentrated
sequence
mapped
neuronal
GE.
Conclusions
Our
implicates
prenatal
specific
later
susceptibility
provides
elements
cells
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 3, 2024
The
interaction
between
genetic
variants
and
environmental
stressors
is
key
to
understanding
the
mechanisms
underlying
neurological
diseases.
In
this
study,
we
used
human
brain
organoids
explore
how
varying
oxygen
levels
expose
context-dependent
gene
regulatory
effects.
By
subjecting
a
genetically
diverse
panel
of
21
hypoxic
hyperoxic
conditions,
identified
thousands
changes
that
are
undetectable
under
baseline
with
1,745
trait-associated
genes
showing
effects
only
in
response
stress.
To
capture
more
nuanced
transcriptional
patterns,
employed
topic
modeling,
which
revealed
context-specific
regulation
linked
dynamic
cellular
processes
responses,
offering
deeper
modulated
brain.
These
findings
underscore
importance
genotype-environment
interactions
studies
disorders
provide
new
insights
into
hidden
influenced
by
factors
While
context-type-specific
regulation
of
genes
is
largely
determined
by
cis-regulatory
regions,
attempts
to
identify
cell
type-specific
eQTLs
are
complicated
the
nested
nature
types.
We
present
hierarchical
eQTL
(H-eQTL),
a
network-based
model
for
annotation
bulk-derived
levels
type
tree
using
single-cell
chromatin
accessibility
data
and
no
clustering
cells
into
discrete
Using
our
model,
we
annotate
from
developing
brain
with
high
specificity
hierarchy,
which
allows
sensitive
detection
multiple
distinct
non-coding
elements
regulating
their
expression
in
different
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Ноя. 29, 2024
Abstract
RNA
sequencing
has
the
potential
to
reveal
many
modalities
of
transcriptional
regulation,
such
as
various
splicing
phenotypes,
but
studies
on
gene
regulation
are
often
limited
expression
due
complexity
extracting
and
analyzing
multiple
phenotypes.
Here,
we
present
Pantry,
a
framework
efficiently
generate
diverse
phenotypes
from
data
perform
downstream
integrative
analyses
with
genetic
data.
Pantry
generates
six
(gene
expression,
isoform
ratios,
splice
junction
usage,
alternative
TSS/polyA
stability)
integrates
them
via
QTL
mapping,
TWAS,
colocalization
testing.
We
apply
Geuvadis
GTEx
data,
finding
that
4768
genes
no
identified
eQTL
in
have
at
least
one
other
modality,
resulting
66%
increase
over
mapping.
further
found
exhibit
modality-specific
functional
properties
reinforced
by
joint
analysis
different
modalities.
also
show
generalizing
TWAS
approximately
doubles
discovery
unique
gene-trait
associations,
enhances
identification
regulatory
mechanisms
underlying
GWAS
signal
42%
previously
associated
pairs.
Human Molecular Genetics,
Год журнала:
2023,
Номер
32(20), С. 2941 - 2949
Опубликована: Июль 14, 2023
MicroRNA
(miRNA)
are
small
non-coding
RNA
involved
in
post-transcriptional
gene
regulation.
Given
their
known
involvement
early
neurodevelopment
processes,
we
here
sought
to
identify
common
genetic
variants
associated
with
altered
miRNA
expression
the
prenatal
human
brain.
We
performed
sequencing
on
brain
tissue
from
112
genome-wide
genotyped
fetuses
second
trimester
of
gestation,
identifying
high-confidence
(false
discovery
rate
<
0.05)
quantitative
trait
loci
for
30
mature
miRNA.
Integrating
our
findings
association
study
data
brain-related
disorders,
implicate
increased
miR-1908-5p
as
a
risk
mechanism
bipolar
disorder
and
find
that
predicted
mRNA
targets
expressed
fetal
enriched
variant
condition.
Extending
these
analyses
other
traits,
variation
is
additionally
depressive
symptoms,
irritability,
right
cerebellum
exterior
volume
sleep
duration
general
population.
Our
provide
support
view
can
influence
susceptibility
neuropsychiatric
illness
suggest
an
neurodevelopmental
disorder.
