bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2022,
Volume and Issue:
unknown
Published: April 19, 2022
Abstract
Genome-wide
association
studies
(GWAS)
have
highlighted
that
almost
any
trait
is
affected
by
many
variants
of
relatively
small
effect.
On
one
hand
this
presents
a
challenge
for
inferring
the
effect
single
variant
as
signal-to-noise
ratio
high
This
compounded
when
combining
information
across
in
polygenic
scores
predicting
values.
other
hand,
large
number
contributing
provides
an
opportunity
to
learn
about
average
behavior
encoded
distribution
sizes.
Many
approaches
looked
at
aspects
problem,
but
no
method
has
unified
inference
effects
individual
with
sizes
while
requiring
only
GWAS
summary
statistics
and
properly
accounting
linkage
disequilibrium
between
variants.
Here
we
present
flexible,
unifying
framework
combines
infer
uses
improve
estimation
We
also
develop
variational
(VI)
scheme
perform
efficient
under
framework.
show
useful
constructing
(PGSs)
outperform
state-of-the-art.
Our
modeling
easily
extends
jointly
multiple
cohorts,
where
building
PGSs
using
additional
cohorts
differing
ancestries
improves
predictive
accuracy
portability.
investigate
inferred
distributions
traits
find
these
ranging
over
orders
magnitude,
contrast
assumptions
implicit
commonly-used
statistical
genetics
methods.
Nature,
Journal Year:
2022,
Volume and Issue:
610(7933), P. 704 - 712
Published: Oct. 12, 2022
Common
single-nucleotide
polymorphisms
(SNPs)
are
predicted
to
collectively
explain
40-50%
of
phenotypic
variation
in
human
height,
but
identifying
the
specific
variants
and
associated
regions
requires
huge
sample
sizes
Nature,
Journal Year:
2023,
Volume and Issue:
618(7966), P. 774 - 781
Published: May 17, 2023
Abstract
Polygenic
scores
(PGSs)
have
limited
portability
across
different
groupings
of
individuals
(for
example,
by
genetic
ancestries
and/or
social
determinants
health),
preventing
their
equitable
use
1–3
.
PGS
has
typically
been
assessed
using
a
single
aggregate
population-level
statistic
R
2
)
4
,
ignoring
inter-individual
variation
within
the
population.
Here,
large
and
diverse
Los
Angeles
biobank
5
(ATLAS,
n
=
36,778)
along
with
UK
Biobank
6
(UKBB,
487,409),
we
show
that
accuracy
decreases
individual-to-individual
continuum
7
in
all
considered
populations,
even
traditionally
labelled
‘homogeneous’
ancestries.
The
decreasing
trend
is
well
captured
continuous
measure
distance
(GD)
from
training
data:
Pearson
correlation
−0.95
between
GD
averaged
84
traits.
When
applying
models
trained
on
as
white
British
UKBB
to
European
ATLAS,
furthest
decile
14%
lower
relative
closest
decile;
notably,
Hispanic
Latino
American
similar
performance
significantly
correlated
estimates
themselves
for
82
traits,
further
emphasizing
importance
incorporating
interpretation.
Our
results
highlight
need
move
away
discrete
ancestry
clusters
towards
when
considering
PGSs.
Annual Review of Biomedical Data Science,
Journal Year:
2022,
Volume and Issue:
5(1), P. 293 - 320
Published: May 16, 2022
Polygenic
risk
scores
(PRS)
estimate
an
individual's
genetic
likelihood
of
complex
traits
and
diseases
by
aggregating
information
across
multiple
variants
identified
from
genome-wide
association
studies.
PRS
can
predict
a
broad
spectrum
have
therefore
been
widely
used
in
research
settings.
Some
work
has
investigated
their
potential
applications
as
biomarkers
preventative
medicine,
but
significant
is
still
needed
to
definitively
establish
communicate
absolute
patients
for
modifiable
factors
demographic
groups.
However,
the
biggest
limitation
currently
that
they
show
poor
generalizability
diverse
ancestries
cohorts.
Major
efforts
are
underway
through
methodological
development
data
generation
initiatives
improve
generalizability.
This
review
aims
comprehensively
discuss
current
progress
on
PRS,
affect
generalizability,
promising
areas
improving
accuracy,
portability,
implementation.
Nature Medicine,
Journal Year:
2024,
Volume and Issue:
30(2), P. 480 - 487
Published: Feb. 1, 2024
Polygenic
risk
scores
(PRSs)
have
improved
in
predictive
performance,
but
several
challenges
remain
to
be
addressed
before
PRSs
can
implemented
the
clinic,
including
reduced
performance
of
diverse
populations,
and
interpretation
communication
genetic
results
both
providers
patients.
To
address
these
challenges,
National
Human
Genome
Research
Institute-funded
Electronic
Medical
Records
Genomics
(eMERGE)
Network
has
developed
a
framework
pipeline
for
return
PRS-based
genome-informed
assessment
25,000
adults
children
as
part
clinical
study.
From
an
initial
list
23
conditions,
ten
were
selected
implementation
based
on
PRS
medical
actionability
potential
utility,
cardiometabolic
diseases
cancer.
Standardized
metrics
considered
selection
process,
with
additional
consideration
given
strength
evidence
African
Hispanic
populations.
We
then
(score
transfer
laboratory,
validation
verification
score
performance),
used
ancestry
calibrate
mean
variance,
utilizing
genetically
data
from
13,475
participants
All
Us
Program
cohort
train
test
model
parameters.
Finally,
we
created
regulatory
compliance
report
inclusion
assessment.
The
experience
eMERGE
inform
approach
needed
implement
testing
settings.
Science,
Journal Year:
2023,
Volume and Issue:
380(6643)
Published: April 27, 2023
Thousands
of
genomic
regions
have
been
associated
with
heritable
human
diseases,
but
attempts
to
elucidate
biological
mechanisms
are
impeded
by
an
inability
discern
which
positions
functionally
important.
Evolutionary
constraint
is
a
powerful
predictor
function,
agnostic
cell
type
or
disease
mechanism.
Single-base
phyloP
scores
from
240
mammals
identified
3.3%
the
genome
as
significantly
constrained
and
likely
functional.
We
compared
annotation,
association
studies,
copy-number
variation,
clinical
genetics
findings,
cancer
data.
Constrained
enriched
for
variants
that
explain
common
heritability
more
than
other
functional
annotations.
Our
results
improve
variant
annotation
also
highlight
regulatory
landscape
still
needs
be
further
explored
linked
disease.
Cell Genomics,
Journal Year:
2023,
Volume and Issue:
3(5), P. 100297 - 100297
Published: April 6, 2023
Sex
differences
in
complex
traits
are
suspected
to
be
part
due
widespread
gene-by-sex
interactions
(GxSex),
but
empirical
evidence
has
been
elusive.
Here,
we
infer
the
mixture
of
ways
which
polygenic
effects
on
physiological
covary
between
males
and
females.
We
find
that
GxSex
is
pervasive
acts
primarily
through
systematic
sex
magnitude
many
genetic
("amplification")
rather
than
identity
causal
variants.
Amplification
patterns
account
for
trait
variance.
In
some
cases,
testosterone
may
mediate
amplification.
Finally,
develop
a
population-genetic
test
linking
contemporary
natural
selection
sexually
antagonistic
variants
affecting
levels.
Our
results
suggest
amplification
common
mode
contribute
fuel
their
evolution.
