Communications Biology,
Год журнала:
2025,
Номер
8(1)
Опубликована: Апрель 5, 2025
Non-obstructive
azoospermia,
a
severe
form
of
male
infertility
caused
by
spermatogenic
failure
(SPGF),
has
largely
unknown
genetic
basis
across
ancestries.
To
our
knowledge,
this
is
the
first
trans-ethnic
meta-analysis
genome-wide
association
studies
on
SPGF,
involving
2255
men
with
idiopathic
SPGF
and
3608
controls
from
European
Asian
populations.
Using
logistic
regression
inverse
variance
methods,
we
identify
two
significant
associations
Sertoli
cell-only
(SCO)
syndrome,
most
extreme
phenotype.
The
G
allele
rs34915133,
in
major
histocompatibility
complex
class
II
region,
significantly
increases
SCO
risk
(P
=
5.25E-10,
OR
1.57),
supporting
potential
immune-related
cause.
Additionally,
rs10842262
variant
SOX5
gene
region
also
marker
5.29E-09,
0.72),
highlighting
key
role
reproductive
function.
Our
findings
reveal
shared
factors
ancestries
provide
insights
into
molecular
mechanisms
underlying
SCO.
Abstract
Background
The
Critical
Assessment
of
Genome
Interpretation
(CAGI)
aims
to
advance
the
state-of-the-art
for
computational
prediction
genetic
variant
impact,
particularly
where
relevant
disease.
five
complete
editions
CAGI
community
experiment
comprised
50
challenges,
in
which
participants
made
blind
predictions
phenotypes
from
data,
and
these
were
evaluated
by
independent
assessors.
Results
Performance
was
strong
clinical
pathogenic
variants,
including
some
difficult-to-diagnose
cases,
extends
interpretation
cancer-related
variants.
Missense
methods
able
estimate
biochemical
effects
with
increasing
accuracy.
regulatory
variants
complex
trait
disease
risk
less
definitive
indicates
performance
potentially
suitable
auxiliary
use
clinic.
Conclusions
show
that
while
current
are
imperfect,
they
have
major
utility
research
applications.
Emerging
increasingly
large,
robust
datasets
training
assessment
promise
further
progress
ahead.
Abstract
Background
Humans
and
viruses
have
co-evolved
for
millennia
resulting
in
a
complex
host
genetic
architecture.
Understanding
the
mechanisms
of
immune
response
to
viral
infection
provides
insight
into
disease
etiology
therapeutic
opportunities.
Methods
We
conducted
comprehensive
study
including
genome-wide
transcriptome-wide
association
analyses
identify
loci
associated
with
immunoglobulin
G
antibody
28
antigens
16
using
serological
data
from
7924
European
ancestry
participants
UK
Biobank
cohort.
Results
Signals
human
leukocyte
antigen
(HLA)
class
II
region
dominated
landscape
response,
40
independent
14
classical
alleles,
7
which
exhibited
pleiotropic
effects
across
families.
identified
specific
amino
acid
(AA)
residues
that
are
seroreactivity,
strongest
associations
presented
range
AA
positions
within
DRβ1
at
11,
13,
71,
74
Epstein-Barr
virus
(EBV),
Varicella
zoster
(VZV),
herpesvirus
7,
(HHV7),
Merkel
cell
polyomavirus
(MCV).
Genome-wide
discovered
novel
outside
HLA
(
P
<
5.0
×
10
−8
),
FUT2
(19q13.33)
BK
(BKV),
STING1
(5q31.2)
MCV,
CXCR5
(11q23.3)
TBKBP1
(17q21.32)
HHV7.
Transcriptome-wide
114
genes
infection,
12
region,
ECSCR
:
=
−15
(MCV),
NTN5
1.1
−9
P2RY13
EBV
nuclear
antigen.
also
demonstrated
pleiotropy
between
diseases,
autoimmune
disorders
cancer
neurodegenerative
psychiatric
conditions.
Conclusions
Our
confirms
importance
elucidates
determinants
beyond
contribute
host-virus
interaction.
Nature Communications,
Год журнала:
2022,
Номер
13(1)
Опубликована: Июль 27, 2022
Abstract
Sjögren’s
disease
is
a
complex
autoimmune
with
twelve
established
susceptibility
loci.
This
genome-wide
association
study
(GWAS)
identifies
ten
novel
significant
(GWS)
regions
in
cases
of
European
ancestry:
CD247
,
NAB1
PTTG1-MIR146A
PRDM1-ATG5
TNFAIP3
XKR6
MAPT-
CRHR1
RPTOR-CHMP6-BAIAP6
TYK2
SYNGR1
.
Polygenic
risk
scores
yield
predictability
(AUROC
=
0.71)
and
relative
12.08.
Interrogation
bioinformatics
databases
refine
the
associations,
define
local
regulatory
networks
GWS
SNPs
from
95%
credible
set,
expand
implicated
gene
list
to
>40.
Many
are
eQTLs
for
genes
within
topologically
associated
domains
immune
cells
and/or
main
target
tissue,
salivary
glands.
Frontiers in Bioscience-Scholar,
Год журнала:
2024,
Номер
16(1)
Опубликована: Март 1, 2024
Genome-wide
association
studies
(GWAS)
have
mapped
over
90%
of
disease-
and
quantitative-trait-associated
variants
within
the
non-coding
genome.
Non-coding
regulatory
DNA
(e.g.,
promoters
enhancers)
RNA
5′
3′
UTRs
splice
sites)
are
essential
in
regulating
temporal
tissue-specific
gene
expressions.
can
potentially
impact
phenotype
an
organism
by
altering
molecular
recognition
cis-regulatory
elements,
leading
to
dysregulation.
However,
determining
causality
between
variants,
regulation,
human
disease
has
remained
challenging.
Experimental
computational
methods
been
developed
understand
mechanism
involved
variant
interference
at
transcriptional
post-transcriptional
levels.
This
review
discusses
recent
approaches
evaluating
disease-associated
single-nucleotide
(SNVs)
determines
their
on
transcription
factor
(TF)
binding,
expression,
chromatin
conformation,
translation.
Human Mutation,
Год журнала:
2019,
Номер
40(9), С. 1197 - 1201
Опубликована: Июль 23, 2019
Interpretation
of
genomic
variation
plays
an
essential
role
in
the
analysis
cancer
and
monogenic
disease,
increasingly
also
complex
trait
with
applications
ranging
from
basic
research
to
clinical
decisions.
Many
computational
impact
prediction
methods
have
been
developed,
yet
field
lacks
a
clear
consensus
on
their
appropriate
use
interpretation.
The
Critical
Assessment
Genome
(CAGI,
/'kā-jē/)
is
community
experiment
objectively
assess
for
predicting
phenotypic
impacts
variation.
CAGI
participants
are
provided
genetic
variants
make
blind
predictions
resulting
phenotype.
Independent
assessors
evaluate
by
comparing
experimental
data.
has
completed
five
editions
goals
establishing
state
art
genome
interpretation
encouraging
new
methodological
developments.
This
special
issue
(https://onlinelibrary.wiley.com/toc/10981004/2019/40/9)
comprises
reports
CAGI,
focusing
fifth
edition
that
culminated
conference
took
place
5
7
July
2018.
CAGI5
was
comprised
14
challenges
engaged
hundreds
dozen
countries.
had
notable
increase
splicing
expression
regulatory
variant
challenges,
while
continuing
genomics,
as
well
disease
datasets
missense
diseases
Pompe
schizophrenia.
Full
information
about
at
https://genomeinterpretation.org.
Cell Genomics,
Год журнала:
2023,
Номер
3(10), С. 100404 - 100404
Опубликована: Сен. 15, 2023
Genome-wide
association
studies
(GWASs)
have
successfully
identified
145
genomic
regions
that
contribute
to
schizophrenia
risk,
but
linkage
disequilibrium
makes
it
challenging
discern
causal
variants.
We
performed
a
massively
parallel
reporter
assay
(MPRA)
on
5,173
fine-mapped
GWAS
variants
in
primary
human
neural
progenitors
and
439
with
allelic
regulatory
effects
(MPRA-positive
variants).
Transcription
factor
binding
had
modest
predictive
power,
while
fine-map
posterior
probability,
enhancer
overlap,
evolutionary
conservation
failed
predict
MPRA-positive
Furthermore,
64%
of
did
not
exhibit
expressive
quantitative
trait
loci
signature,
suggesting
MPRA
could
identify
yet
unexplored
potentials.
To
the
combinatorial
effect
gene
regulation,
we
propose
an
accessibility-by-contact
model
combines
MPRA-measured
activity
neuronal
chromatin
architecture.
