medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2020,
Номер
unknown
Опубликована: Сен. 13, 2020
SUMMARY
Schizophrenia
is
a
psychiatric
disorder
whose
pathophysiology
largely
unknown.
It
has
heritability
of
60-80%,
much
which
attributable
to
common
risk
alleles,
suggesting
genome-wide
association
studies
can
inform
our
understanding
aetiology
1
.
Here,
in
69,369
people
with
schizophrenia
and
236,642
controls,
we
report
variant
associations
at
270
distinct
loci.
Using
fine-mapping
functional
genomic
data,
prioritise
19
genes
based
on
protein-coding
or
UTR
variation,
130
total
as
likely
explain
these
associations.
Fine-mapped
candidates
were
enriched
for
associated
rare
disruptive
coding
variants
schizophrenia,
including
the
glutamate
receptor
subunit
GRIN2A
transcription
factor
SP4
,
also
implicated
by
such
autism
developmental
disorder.
Associations
concentrated
expressed
CNS
neurons,
both
excitatory
inhibitory,
but
not
other
tissues
cell
types,
fundamental
processes
related
neuronal
function,
particularly
synaptic
organisation,
differentiation
transmission.
We
identify
biological
pathophysiological
relevance
show
convergence
neurodevelopmental
disorders,
provide
rich
resource
priority
advance
mechanistic
studies.
Bioinformatics,
Год журнала:
2019,
Номер
35(22), С. 4851 - 4853
Опубликована: Июнь 19, 2019
Abstract
Summary
PhenoScanner
is
a
curated
database
of
publicly
available
results
from
large-scale
genetic
association
studies
in
humans.
This
online
tool
facilitates
‘phenome
scans’,
where
variants
are
cross-referenced
for
with
many
phenotypes
different
types.
Here
we
present
major
update
(‘PhenoScanner
V2’),
including
over
150
million
and
more
than
65
billion
associations
(compared
to
350
V1)
diseases
traits,
gene
expression,
metabolite
protein
levels,
epigenetic
markers.
The
query
options
have
been
extended
include
searches
by
genes,
genomic
regions
phenotypes,
as
well
variants.
All
positionally
annotated
using
the
Variant
Effect
Predictor
mapped
Experimental
Factor
Ontology
terms.
Linkage
disequilibrium
statistics
1000
Genomes
project
can
be
used
search
phenotype
proxy
Availability
implementation
V2
at
www.phenoscanner.medschl.cam.ac.uk.
Nature,
Год журнала:
2020,
Номер
591(7848), С. 92 - 98
Опубликована: Дек. 11, 2020
Host-mediated
lung
inflammation
is
present1,
and
drives
mortality2,
in
the
critical
illness
caused
by
coronavirus
disease
2019
(COVID-19).
Host
genetic
variants
associated
with
may
identify
mechanistic
targets
for
therapeutic
development3.
Here
we
report
results
of
GenOMICC
(Genetics
Of
Mortality
In
Critical
Care)
genome-wide
association
study
2,244
critically
ill
patients
COVID-19
from
208
UK
intensive
care
units.
We
have
identified
replicated
following
new
significant
associations:
on
chromosome
12q24.13
(rs10735079,
P
=
1.65
×
10-8)
a
gene
cluster
that
encodes
antiviral
restriction
enzyme
activators
(OAS1,
OAS2
OAS3);
19p13.2
(rs74956615,
2.3
near
tyrosine
kinase
2
(TYK2);
19p13.3
(rs2109069,
3.98
10-12)
within
dipeptidyl
peptidase
9
(DPP9);
21q22.1
(rs2236757,
4.99
interferon
receptor
IFNAR2.
potential
repurposing
licensed
medications:
using
Mendelian
randomization,
found
evidence
low
expression
IFNAR2,
or
high
TYK2,
are
life-threatening
disease;
transcriptome-wide
tissue
revealed
monocyte-macrophage
chemotactic
CCR2
severe
COVID-19.
Our
robust
signals
relating
to
key
host
defence
mechanisms
mediators
inflammatory
organ
damage
Both
be
amenable
targeted
treatment
existing
drugs.
However,
large-scale
randomized
clinical
trials
will
essential
before
any
change
practice.
Nature Reviews Methods Primers,
Год журнала:
2021,
Номер
1(1)
Опубликована: Авг. 26, 2021
Genome-wide
association
studies
(GWAS)
test
hundreds
of
thousands
genetic
variants
across
many
genomes
to
find
those
statistically
associated
with
a
specific
trait
or
disease.
This
methodology
has
generated
myriad
robust
associations
for
range
traits
and
diseases,
the
number
is
expected
grow
steadily
as
GWAS
sample
sizes
increase.
results
have
applications,
such
gaining
insight
into
phenotype's
underlying
biology,
estimating
its
heritability,
calculating
correlations,
making
clinical
risk
predictions,
informing
drug
development
programmes
inferring
potential
causal
relationships
between
factors
health
outcomes.
In
this
Primer,
we
provide
reader
an
introduction
GWAS,
explaining
their
statistical
basis
how
they
are
conducted,
describe
state-of-the
art
approaches
discuss
limitations
challenges,
concluding
overview
current
future
applications
results.
Uffelmann
et
al.
key
considerations
best
practices
conducting
genome-wide
(GWAS),
techniques
deriving
functional
inferences
from
in
understanding
disease
architecture.
The
Primer
also
provides
information
on
data
sharing
discusses
important
ethical
when
considering
populations
data.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2020,
Номер
unknown
Опубликована: Авг. 10, 2020
Abstract
Data
generated
by
genome-wide
association
studies
(GWAS)
are
growing
fast
with
the
linkage
of
biobank
samples
to
health
records,
and
expanding
capture
high-dimensional
molecular
phenotypes.
However
utility
these
efforts
can
only
be
fully
realised
if
their
complete
results
collected
from
heterogeneous
sources
formats,
harmonised
made
programmatically
accessible.
Here
we
present
OpenGWAS
database,
an
open
source,
access,
scalable
high-performance
cloud-based
data
infrastructure
that
imports
publishes
GWAS
summary
datasets
metadata
for
scientific
community.
Our
import
pipeline
harmonises
against
dbSNP
human
genome
reference
sequence,
generates
reports
standardises
format
metadata.
Users
access
via
a
website,
application
programming
interface,
R
Python
packages,
also
as
downloadable
files
rapidly
queried
in
high
performance
computing
environments.
currently
contains
126
billion
genetic
associations
14,582
representing
range
different
phenotypes
disease
outcomes
across
populations.
We
developed
packages
serve
conduits
between
available
analytical
tools,
enabling
Mendelian
randomization,
colocalisation
analysis,
fine
mapping,
correlation
locus
visualisation.
is
freely
accessible
at
https://gwas.mrcieu.ac.uk
,
has
been
designed
facilitate
integration
third
party
tools.
