bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: June 17, 2024
Abstract
Natural
selection
on
complex
traits
is
difficult
to
study
in
part
due
the
ascertainment
inherent
genome-wide
association
studies
(GWAS).
The
power
detect
a
trait-associated
variant
GWAS
function
of
frequency
and
effect
size
—
but
for
under
selection,
determines
strength
against
it,
constraining
its
frequency.
To
account
ascertainment,
we
propose
studying
joint
distribution
allele
frequencies
across
populations,
conditional
cohort.
Before
considering
these
spectra,
first
characterized
impact
non-equilibrium
demography
dynamics
forwards
backwards
time.
We
then
used
results
understand
spectra
realistic
human
demography.
Finally,
investigated
empirical
variants
associated
with
106
traits,
finding
compelling
evidence
either
stabilizing
or
purifying
selection.
Our
provide
insight
into
polygenic
score
portability
other
properties
ascertained
GWAS,
highlighting
utility
spectra.
Molecular Psychiatry,
Journal Year:
2023,
Volume and Issue:
28(9), P. 3638 - 3647
Published: Sept. 1, 2023
Abstract
There
has
been
substantial
progress
in
understanding
the
genetics
of
schizophrenia
over
past
15
years.
This
revealed
a
highly
polygenic
condition
with
majority
currently
explained
heritability
coming
from
common
alleles
small
effect
but
additional
contributions
rare
copy
number
and
coding
variants.
Many
specific
genes
loci
have
implicated
that
provide
firm
basis
upon
which
mechanistic
research
can
proceed.
These
point
to
disturbances
neuronal,
particularly
synaptic,
functions
are
not
confined
brain
regions
circuits.
Genetic
findings
also
nature
schizophrenia’s
close
relationship
other
conditions,
bipolar
disorder
childhood
neurodevelopmental
disorders,
provided
an
explanation
for
how
risk
persist
population
face
reduced
fecundity.
Current
genomic
approaches
only
potentially
explain
around
40%
heritability,
proportion
this
is
attributable
robustly
identified
loci.
The
extreme
polygenicity
poses
challenges
biological
mechanisms.
high
degree
pleiotropy
points
need
more
transdiagnostic
shortcomings
current
diagnostic
criteria
as
means
delineating
biologically
distinct
strata.
It
inferring
causality
observational
experimental
studies
both
humans
model
systems.
Finally,
Eurocentric
bias
needs
be
rectified
maximise
benefits
ensure
these
felt
across
diverse
communities.
Further
advances
likely
come
through
application
new
emerging
technologies,
such
whole-genome
long-read
sequencing,
large
samples.
Substantive
will
require
parallel
functional
genomics
proteomics
applied
developmental
stages.
For
efforts
succeed
identifying
disease
mechanisms
defining
novel
strata
they
combined
sufficiently
granular
phenotypic
data.
Science Advances,
Journal Year:
2023,
Volume and Issue:
9(41)
Published: Oct. 12, 2023
The
cellular
complexity
of
the
human
brain
is
established
via
dynamic
changes
in
gene
expression
throughout
development
that
mediated,
part,
by
spatiotemporal
activity
cis-regulatory
elements
(CREs).
We
simultaneously
profiled
and
chromatin
accessibility
45,549
cortical
nuclei
across
six
broad
developmental
time
points
from
fetus
to
adult.
identified
cell
type-specific
domains
which
highly
correlated
with
expression.
Differentiation
pseudotime
trajectory
analysis
indicates
at
CREs
precedes
transcription
structure
play
a
critical
role
neuronal
lineage
commitment.
In
addition,
we
mapped
temporally
specific
genetic
loci
implicated
neuropsychiatric
traits,
including
schizophrenia
bipolar
disorder.
Together,
our
results
describe
complex
regulation
composition
stages
determination
shed
light
on
impact
alterations
disease.
Science,
Journal Year:
2023,
Volume and Issue:
380(6644), P. 485 - 490
Published: May 4, 2023
Autoimmune
diseases
display
a
high
degree
of
comorbidity
within
individuals
and
families,
suggesting
shared
risk
factors.
Over
the
past
15
years,
genome-wide
association
studies
have
established
polygenic
basis
these
common
conditions
revealed
widespread
sharing
genetic
effects,
indicative
immunopathology.
Despite
ongoing
challenges
in
determining
precise
genes
molecular
consequences
variants,
functional
experiments
integration
with
multimodal
genomic
data
are
providing
valuable
insights
into
key
immune
cells
pathways
driving
diseases,
potential
therapeutic
implications.
Moreover,
ancient
populations
shedding
light
on
contribution
pathogen-driven
selection
pressures
to
increased
prevalence
autoimmune
disease.
This
Review
summarizes
current
understanding
disease
genetics,
including
mechanisms,
evolutionary
origins.
BMC Medical Genomics,
Journal Year:
2024,
Volume and Issue:
17(1)
Published: Jan. 29, 2024
Abstract
Whole
genome
sequencing
(WGS)
is
becoming
the
preferred
method
for
molecular
genetic
diagnosis
of
rare
and
unknown
diseases
identification
actionable
cancer
drivers.
Compared
to
other
methods,
WGS
captures
most
genomic
variation
eliminates
need
sequential
testing.
Whereas,
laboratory
requirements
are
similar
conventional
genetics,
amount
data
large
requires
a
comprehensive
computational
storage
infrastructure
in
order
facilitate
processing
within
clinically
relevant
timeframe.
The
output
single
analyses
roughly
5
MIO
variants
interpretation
involves
specialized
staff
collaborating
with
clinical
specialists
provide
standard
care
reports.
Although
field
continuously
refining
standards
variant
classification,
there
still
unresolved
issues
associated
application.
review
provides
an
overview
practice
-
describing
technology
current
applications
as
well
challenges
connected
processing,
reporting.
Genome Medicine,
Journal Year:
2024,
Volume and Issue:
16(1)
Published: Feb. 19, 2024
Abstract
Polygenic
scores
(PGS)
can
be
used
for
risk
stratification
by
quantifying
individuals’
genetic
predisposition
to
disease,
and
many
potentially
clinically
useful
applications
have
been
proposed.
Here,
we
review
the
latest
potential
benefits
of
PGS
in
clinic
challenges
implementation.
could
augment
through
combined
use
with
traditional
factors
(demographics,
disease-specific
factors,
family
history,
etc.),
support
diagnostic
pathways,
predict
groups
therapeutic
benefits,
increase
efficiency
clinical
trials.
However,
there
exist
maximizing
utility
PGS,
including
FAIR
(Findable,
Accessible,
Interoperable,
Reusable)
standardized
sharing
genomic
data
needed
develop
recalculate
equitable
performance
across
populations
ancestries,
generation
robust
reproducible
calculations,
responsible
communication
interpretation
results.
We
outline
how
these
may
overcome
analytically
more
diverse
as
well
highlight
sustained
community
efforts
achieve
equitable,
impactful,
healthcare.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: Jan. 6, 2024
Abstract
The
morphology
of
cells
is
dynamic
and
mediated
by
genetic
environmental
factors.
Characterizing
how
variation
impacts
cell
can
provide
an
important
link
between
disease
association
cellular
function.
Here,
we
combine
genomic
sequencing
high-content
imaging
approaches
on
iPSCs
from
297
unique
donors
to
investigate
the
relationship
variants
map
what
term
morphological
quantitative
trait
loci
(cmQTLs).
We
identify
novel
associations
rare
protein
altering
in
WASF2
,
TSPAN15
PRLR
with
several
traits
related
shape,
nucleic
granularity,
mitochondrial
distribution.
Knockdown
these
genes
CRISPRi
confirms
their
role
morphology.
Analysis
common
yields
one
significant
nominate
over
300
suggestive
evidence
(P
<
10
−6
)
or
more
traits.
then
use
data
make
predictions
about
sample
size
requirements
for
increasing
discovery
studies.
conclude
that,
similar
molecular
phenotypes,
profiling
yield
insight
function
variants.
