Editorial: Advancements and prospects of genome-wide association studies
Frontiers in Genetics,
Год журнала:
2025,
Номер
16
Опубликована: Фев. 19, 2025
Since
the
very
first
Genome-Wide
association
study
was
published
in
2005
followed
by
pivotal
manuscript
Wellcome
Trust
Case
Control
Consortium
(WTCCC)
2007
(Klein
et
al.,
2005;Wellcome
Control,
2007),
several
thousands
of
studies
(GWAS)
have
been
conducted
(>45
000)
and
yielded
a
myriad
loci
associated
with
diverse
human
phenotypic
traits
or
diseases
(>5000)
(Sollis
2023).
These
not
only
shed
light
on
involvement
common
variants
but
also
discovered
important
insights
into
biology
(Uffelmann,
2021)
The
field
GWAS
has
seen
tremendous
advances
both
technologically
methodologically.
For
example,
facilitated
single
nucleotide
polymorphisms
(SNPs)-arrays
containing
couple
thousand
hundred
to
2
million
SNPs
(Visscher
2017).
ability
impute
untyped
increased
marker
density,
improved
statistical
power
GWAS,
enabled
large-scale
metaanalyses
across
populations,
aided
fine-mapping
regions
interest
genetic
(Cahoon
2024;Zhihui
Zhang,
2022).
Additionally,
sequencing
technologies
drop
cost,
latest
follow-up
sequence-based
allowed
for
assessment
low-frequency
rare
(Acar
2023;McMahon
2021;Pan
Despite
all
Genomics,
global
populations
are
evenly
represented
GWAS.
mainly
limited
European
descent
could
exacerbate
existing
health
disparities
implementation
precision
medicine
(Doumatey
push
genomic
equity
representation
biomedical
research
led
initiatives
such
as
the1000
Genomes,
Human
Heredity&
Health
(H3Africa),
Trans-omics
Precision
Medicine
(TOPMed),
All
Us
recent
years
(Auton
2015;Investigators,
2024;Peprah
2017;Taliun
2021).
Some
these
imputation
references,
1000
genomes
TOPMed
(Kowalski
2019).
Others,
H3Africa,
helped
develop
population-specific
genotype
arrays,
thus
improving
discovery
populations.
In
this
topic,
Brandenburg,
JT
al.
used
custom
array
enriched
African
variants,
H3A
genotyping
array,
largest
urinary
albumin-to-creatinine
ratio
(UACR),
biomarker
kidney
disease,
Sub
Saharan
Africans
living
different
continent
non-resident
individuals
ancestry
(UK
BioBank)
American
cohorts
(CKD-Gen
Ancestry).
authors
identified
two
novel
UACR
(BMP6,
HBB),
they
replicated
three
out
60
known
UACR-associated
previously
multiancestry
studies.
performed
polygenic
score
(PGS)
comparison
analyses
evaluate
transferability
PGS
derived
from
non-African
multi-ancestry
https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1372042/full).A
comprehensive
review
Bruner,
S.W.
al,
topic
underscored
need
account
population-biased
findings
various
ancestral
which
should,
turn,
address
replication
challenges
especially
highlighted
advancements
methods
techniques
available
resources
conduct
functional
annotations
mechanistic
"variant-to-function
They
described
(e.g.
epigenetic
annotations,
pathway
network
analyses,
quantitative
trait
loci)
validations
(reporter
assays,
genome
editing,
animal
models)
approaches
characterize
effector
genes.
https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1375481/full.
were
included
topic.
Abbas,
M
ancestries,
leveraged
expression
locus
(eQTL)
understand
mechanisms
connecting
phenotypes
(ref.
Abbas
Brandenburg
al.)
using
strategies.
al
subsequently
carried
annotation
lead
(SNP)
relevant
tissue
profile
(glomerular
tubulointerstitial
tissues)
cis-eQTL
analysis.
contrast,
differential
analysis
identify
mRNAs
that
differentially
expressed
between
Low-Density
Lipoproteins,
LDL
groups
(low
tertile
vs
upper
tertile),
then
extracted
SNP
cis
region
each
mRNA
perform
an
eQTL
eQTLs
significantly
overlapped
catalogue
database.
further
decipher
relationships
transcriptomics,
genomics,
phenotype.
Noteworthy,
African-specific
TTC38
Americans.
upregulated
elevated
LDL.
https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1345541/full.Animal
models
proposed
variant-to-function
method
discovery.
can
take
many
effectively
underpinnings
humans.
one
studies,
Fowler
S
heterogeneous
stock
(HS)
intraocular
pressure
(IOP).
indicated
few
advantages
conducting
rats
like
IOP:
1)
control
environmental
variables
affect
IOP
humans,
2)
humans
share
similar
anatomical
developmental
characteristics
eyes
aqueous
outflow
pathway),
ideal
model
pathophysiology
ophthalmologic
disorders,
3)
tissues
phenotyping
gene
be
easily
collected.
combination
~1800
HS
5
candidate
genes,
(Ctsc2
Plekhf2-never
reported
studies);
concluded
use
resulted
new
provide
molecular
basis
IOP.
https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.1029058/full
linked
trait/disease,
cannot
always
establish
causality.
Thus,
epidemiology-based
Mendelian
randomization
(MR)
causality
instrumental
variables,
risk
factors
lifestyle
(Benn
&
Nordestgaard,
2018).
Lin,
X
strategy
causal
relationship
reproductive
age
at
menopause,
menarche,
live
birth)
bone
density.
Their
suggest
early
menopause
late
childbirth
may
Язык: Английский
Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Апрель 11, 2025
Язык: Английский
MultiSuSiE improves multi-ancestry fine-mapping in All of Us whole-genome sequencing data
medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Май 14, 2024
Abstract
Leveraging
data
from
multiple
ancestries
can
greatly
improve
fine-mapping
power
due
to
differences
in
linkage
disequilibrium
and
allele
frequencies.
We
propose
MultiSuSiE,
an
extension
of
the
sum
single
effects
model
(SuSiE)
that
allows
causal
effect
sizes
vary
across
based
on
a
multivariate
normal
prior
informed
by
empirical
data.
evaluated
MultiSuSiE
via
simulations
analyses
14
quantitative
traits
leveraging
whole-genome
sequencing
47k
African-ancestry
94k
European-ancestry
individuals
All
Us.
In
simulations,
applied
Afr47k+Eur47k
was
well-calibrated
attained
higher
than
SuSiE
Eur94k;
interestingly,
variant
PIPs
Afr47k
compared
Eur47k
were
entirely
explained
extent
LD
quantified
4th
moments.
Compared
very
recently
proposed
multi-ancestry
methods,
and/or
much
lower
computational
costs,
making
analysis
large-scale
Us
feasible.
real
trait
analyses,
Afr47k+Eur94k
identified
579
fine-mapped
variants
with
PIP
>
0.5,
44%
more
0.5
Eur94k.
validated
results
for
functional
enrichment
variants.
highlight
several
examples
where
implicates
well-studied
or
biologically
plausible
not
implicated
other
methods.
Язык: Английский
The impact on clinical success from the 23andMe cohort
medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 18, 2024
Abstract
90%
of
therapeutic
programs
that
enter
clinical
trials
ultimately
fail.
Human
genetic
variation
provides
a
set
“natural
experiments”
can
inform
successful
strategies
for
discovery.
Previous
work
has
estimated
drug
targets
with
human
genetics
supported
mechanisms
have
2-3x
increased
likelihood
succeeding
in
the
clinic
compared
to
those
without.
23andMe,
Inc.
is
direct-to-consumer
company
created
dataset
approximately
an
order
magnitude
larger
sample
size
than
current
publically
available
cohorts.
As
2024,
23andMe
15
million
individuals
genotype
and
phenotype
data,
which
∼80%
consent
participation
research.
In
this
work,
we
explore
how
both
scale
data
improved
methods
link
associations
putative
causal
genes
impact
prediction
success.
Comparing
total
number
target-indication
pairs
reached
at
least
phase
I
are
also
by
evidence,
support
from
60%
greater
all
GWAS
datasets
public
domain.
Including
evidence
doubles
genetics.
Furthermore,
show
derived
entirely
self-reported
phenotypes
enriched
success,
just
as
clinically
phenotypes.
contrast
conclusions
recent
publication
Minikel
et
al.
,
found
minor
allele
frequencies
effect
sizes
influence
relative
success
estimates
program
approvals,
rare
large
(3-4x)
be
approved
common
variant
small
effects.
Finally,
gene
mapping
identify
likely
underlying
result
up
4-5x
enrichment
trial
With
power
dataset,
expansive
opportunities
may
pursued
clinic,
emphasizing
importance
cohort
confidence
deriving
value.
Язык: Английский
SEAD reference panel with 22,134 haplotypes boosts rare variant imputation and genome-wide association analysis in Asian populations
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Дек. 30, 2024
Limited
whole
genome
sequencing
(WGS)
studies
in
Asian
populations
result
a
lack
of
representative
reference
panels,
thus
hindering
the
discovery
ancestry-specific
variants.
Here,
we
present
South
and
East
Database
(SEAD)
panel
(
https://imputationserver.westlake.edu.cn/
),
which
integrates
WGS
data
for
11,067
individuals
from
various
sources
across
17
countries.
The
SEAD
panel,
comprising
22,134
haplotypes
88,294,957
variants,
demonstrates
improved
imputation
accuracy
compared
to
1000
Genomes
Project,
TOPMed,
ChinaMAP
with
higher
proportion
well-imputed
rare
For
populations,
shows
concordance
comparable
ChinaMAP,
but
outperforming
TOPMed.
Additionally,
apply
conduct
genome-wide
association
study
total
hip
(Hip)
femoral
neck
(FN)
bone
mineral
density
(BMD)
traits
5369
genotyped
Chinese
samples.
single-variant
test
suggests
that
variants
near
SNTG1
are
associated
Hip
BMD
(rs60103302,
MAF
=
0.0092,
P
1.67
×
10-7),
variant-set
analysis
further
supports
(Pslide_window
9.08
10-9,
Pgene_centric
5.27
10-8).
This
was
not
reported
previously
can
only
be
detected
by
using
panels.
Preliminary
vitro
experiments
one
identified
provide
evidence
it
upregulates
expression,
could
turn
inhibit
proliferation
differentiation
preosteoblasts.
Язык: Английский
Genetic admixture predictors of fetal alcohol spectrum disorders (FASD) in a South African population
Gene,
Год журнала:
2024,
Номер
931, С. 148854 - 148854
Опубликована: Авг. 13, 2024
Язык: Английский
SNP Genotype Imputation in Forensics—A Performance Study
Genes,
Год журнала:
2024,
Номер
15(11), С. 1386 - 1386
Опубликована: Окт. 28, 2024
Emerging
forensic
genetic
applications,
such
as
investigative
genealogy
(FIGG),
advanced
DNA
phenotyping,
and
distant
kinship
inference,
increasingly
require
dense
SNP
genotype
datasets.
However,
forensic-grade
often
contains
missing
genotypes
due
to
its
quality
quantity
limitations,
potentially
hindering
these
applications.
Genotype
imputation,
a
method
that
predicts
genotypes,
is
widely
used
in
population
medical
genetics,
but
utility
genetics
has
not
been
thoroughly
explored.
This
study
aims
assess
the
performance
of
imputation
contexts
determine
conditions
under
which
it
can
be
effectively
applied.
Язык: Английский
SEAD: an augmented reference panel with 22,134 haplotypes boosts the rare variants imputation and GWAS analysis in Asian population
medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Дек. 27, 2023
Abstract
Here,
we
present
the
S
outh
and
E
ast
A
sian
reference
D
atabase
(
SEAD
)
panel
https://imputationserver.westlake.edu.cn/
),
which
comprises
whole
genome
sequencing
data
from
11,067
individuals
across
17
countries
in
Asia.
The
panel,
excludes
singleton
variants,
consists
of
22,134
haplotypes
88,294,957
variants.
demonstrated
higher
accuracy
compared
to
1kGP,
TOPMed
ChinaMAP
South
Asian
population.
And
as
proportion
ancestry
increased,
low-frequency
rare
well-imputed
variants
imputed
using
progressively
whereas
those
with
significantly
decreased.
Additionally,
when
imputing
East
population,
showed
comparable
concordance
imputation
while
was
inferior.
Finally,
applied
augmented
conduct
a
discovery
replication
genome-wide
association
study
(GWAS)
for
hip
femoral
neck
(FN)
bone
mineral
density
(BMD)
traits
within
5,369
Westlake
BioBank
Chinese
(WBBC)
genotyped
samples.
single-variant
test
suggests
that
near
SNTG1
gene
are
associated
BMD
(rs60103302,
MAF=0.0092,
P
=1.67×10
−7
).
variant-set
analysis
also
this
slide_window
=9.08×10
−9
,
gene_centric
=5.27×10
−8
achieved
suggestive
level
FN
BMD.
This
not
reported
previously
can
only
be
detected
by
panel.
preliminary
experiment
in-vitro
identified
variant
could
upregulate
expression,
turn
inhibits
proliferation
differentiation
preosteoblast.
Язык: Английский