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GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease.
[krabbe disease]
DNA
copy
number
variants
(
CNVs
)
have
been
reported
in
many
human
diseases
including
autism
and
schizophrenia
.
Primary
Open
Angle
Glaucoma
(
POAG
)
is
a
complex
adult-onset
disorder
characterized
by
progressive
optic
neuropathy
and
vision
loss
.
Previous
studies
have
identified
rare
CNVs
in
POAG
;
however
,
their
low
frequencies
prevented
formal
association
testing
.
We
present
here
the
association
between
POAG
risk
and
a
heterozygous
deletion
in
the
galactosylceramidase
gene
(
GALC
)
.
This
CNV
was
initially
identified
in
a
dataset
containing
71
Caucasian
POAG
cases
and
478
ethnically
matched
controls
obtained
from
dbGAP
(
study
accession
phs
000126
.
v
1
.
p
1
.
)
(
p
=
0
.
017
,
fisher
's
exact
test
)
.
It
was
validated
with
array
comparative
genomic
hybridization
(
arrayCGH
)
and
realtime
PCR
,
and
replicated
in
an
independent
POAG
dataset
containing
959
cases
and
1852
controls
(
p
=
0
.
021
,
OR
(
odds
ratio
)
=
3
.
5
,
95
%
CI
-
1
.
1
-
12
.
0
)
.
Evidence
for
association
was
strengthened
when
the
discovery
and
replication
datasets
were
combined
(
p
=
0
.
002
;
OR
=
5
.
0
,
95
%
CI
1
.
6
-
16
.
4
)
.
Several
deletions
with
different
endpoints
were
identified
by
array
CGH
of
POAG
patients
.
Homozygous
deletions
that
eliminate
GALC
enzymatic
activity
cause
Krabbe
disease
,
a
recessive
Mendelian
disorder
of
childhood
displaying
bilateral
optic
neuropathy
and
vision
loss
.
Our
findings
suggest
that
heterozygous
deletions
that
reduce
GALC
activity
are
a
novel
mechanism
increasing
risk
of
POAG
.
This
is
the
first
report
of
a
statistically-significant
association
of
a
CNV
with
POAG
risk
,
contributing
to
a
growing
body
of
evidence
that
CNVs
play
an
important
role
in
complex
,
inherited
disorders
.
Our
findings
suggest
an
attractive
biomarker
and
potential
therapeutic
target
for
patients
with
this
form
of
POAG
.