Insufficient Evidence for “Autism-Specific” Genes
The American Journal of Human Genetics,
Год журнала:
2020,
Номер
106(5), С. 587 - 595
Опубликована: Апрель 30, 2020
Despite
evidence
that
deleterious
variants
in
the
same
genes
are
implicated
across
multiple
neurodevelopmental
and
neuropsychiatric
disorders,
there
has
been
considerable
interest
identifying
that,
when
mutated,
confer
risk
is
largely
specific
for
autism
spectrum
disorder
(ASD).
Here,
we
review
findings
limitations
of
recent
efforts
to
identify
relatively
"autism-specific"
genes,
which
focus
on
rare
large
effect
size
thought
account
observed
phenotypes.
We
present
a
divergent
interpretation
published
evidence;
discuss
practical
theoretical
issues
related
studying
relationships
between
rare,
large-effect
phenotypes;
describe
potential
future
directions
this
research.
argue
currently
insufficient
establish
meaningful
ASD
specificity
any
based
rare-variant
data.
Autism
(ASD)
clinically
etiologically
heterogeneous,
unifying
pathophysiology
not
yet
identified
either
as
whole
or
its
core
behavioral
components.
Heritability
estimates
high
(0.65–0.91)
family
twin
studies,1Sandin
S.
Lichtenstein
P.
Kuja-Halkola
R.
Larsson
H.
Hultman
C.M.
Reichenberg
A.
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familial
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PubMed
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M.
Rijsdijk
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D.
Yip
B.H.K.
Windham
G.C.
Sourander
Francis
Yoffe
Glasson
E.
Mahjani
Suominen
Leonard
et
al.Association
genetic
environmental
factors
with
5-country
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2019;
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(209)
Scholar
elucidation
complex
architecture
revealing
contributions
from
both
common
variants.
Chromosomal
microarray
next-generation
sequencing
studies
have
many
de
novo
inherited
contribute
substantially
etiology
ASD.
It
also
become
clear
pathogenic
individuals
variety
different
defined
brain
including
ASD,
intellectual
disability
(ID),
epilepsy,
schizophrenia,
other
conditions.4Moreno-De-Luca
Myers
S.M.
Challman
T.D.
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Evans
D.W.
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D.H.
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H.A.
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T.N.
Eichler
E.E.
Molecular
subtyping
improved
treatment
disease.Genome
Med.
8:
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M.C.
Owen
M.J.
implications
shared
genetics
psychiatric
disorders.Nat.
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P.F.
Geschwind
Defining
genetic,
genomic,
cellular,
diagnostic
architectures
disorders.Cell.
177:
162-183Abstract
(183)
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W.
Corominas
Lin
G.N.
De
mutations
exome
From
discovery
application.Front.
Genet.
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258https://doi.org/10.3389/fgene.2019.00258Crossref
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Burton
C.L.
Engchuan
Young
E.J.
Higginbotham
MacDonald
J.R.
Trost
Chan
A.J.S.
Walker
Lamoureux
al.A
data
resource
genomic
copy
number
variation
disorders.NPJ
Genom.
4:
26https://doi.org/10.1038/s41525-019-0098-3Crossref
(76)
known
collective
contribution
greatest
disorders
(NDDs)
such
ID,
but
they
important
etiologic
conditions
onset
childhood
(e.g.,
attention-deficit/hyperactivity
[ADHD])
adolescence
schizophrenia)
and,
lesser
degree,
later-onset
mood
disorders.
literature
reflects
comment
"autism
genes,"
phenotype
participants.
NDD
phenotypes,
along
current
lack
sufficient
specificity,
well
possibility
sources
variation,
variant-related
polygenic
risk,
may
ASD-specific
risk.
To
date,
no
only
ID
NDDs.
However,
several
attempted
(ASD-predominant
ASD-biased)
by
comparing
distribution
likely
gene-disruptive
cohorts
ascertained
and/or
developmental
delay
(ID/DD).10Stessman
Xiong
Coe
B.P.
Wang
T.
Hoekzema
K.
Fenckova
Kvarnung
Gerdts
J.
Trinh
Cosemans
N.
al.Targeted
identifies
91
neurodevelopmental-disorder
developmental-disability
biases.Nat.
2017;
49:
515-526Crossref
(310)
11Satterstrom
F.K.
Kosmicki
J.A.
Breen
M.S.
Rubeis
An
J.-Y.
Peng
Collins
Grove
Klei
L.
al.).
Large-scale
study
implicates
functional
changes
neurobiology
autism.Cell.
2020;
https://doi.org/10.1016/j.cell.2019.12.036Abstract
(723)
12Coe
Stessman
H.A.F.
Sulovari
Geisheker
M.R.
Bakken
T.E.
Lake
A.M.
Dougherty
J.D.
Lein
E.S.
Hormozdiari
Bernier
R.A.
Neurodevelopmental
disease
mutation
morbidity.Nat.
51:
106-116Crossref
(147)
For
example,
Satterstrom
al.11Satterstrom
asserted
among
102
some
ASD-predominant,
others
associated
more
global
impairment,
severe
(ASD
ID/DD),
comparison
frequency
disruptive
(n
=
11,986)
those
ID/DD
5,264).
In
study,
authors
"ASD-predominant
genes"
ratio
compared
was
greater
than
1.0.
Conversely,
were
classified
"ASD
(referred
here
ID/DD")
ASD-ascertained
participants
ID/DD-ascertained
less
manner,
50
ASD-predominant
49
ID/DD.
Three
additional
assigned
group
basis
case-control
data,
bringing
total
53
genes.11Satterstrom
al.12Coe
ASD-
did
find
253
candidate
excess
through
use
two
statistical
models.
fact,
72%
predicted
be
significant
models
showed
cohorts.
This
included
fewer
5,624)
colleagues,11Satterstrom
similar
5,303).
evaluated
these
overlapped
almost
completely;
each
used
samples
five
previously
studies,
four
accounting
99%
samples.11Satterstrom
13Rauch
Wieczorek
Graf
Wieland
Endele
Schwarzmayr
Albrecht
Bartholdi
Beygo
Di
Donato
al.Range
non-syndromic
sporadic
disability:
an
study.Lancet.
2012;
380:
1674-1682Abstract
(764)
14de
Ligt
Willemsen
M.H.
van
Bon
B.W.
Kleefstra
Yntema
H.G.
Kroes
Vulto-van
Silfhout
A.T.
Koolen
D.A.
Vries
Gilissen
C.
al.Diagnostic
persons
disability.N.
Engl.
367:
1921-1929Crossref
(1130)
15Lelieveld
S.H.
Reijnders
Pfundt
Kamsteeg
B.B.
Löhner
al.Meta-analysis
2,104
trios
provides
support
10
disability.Nat.
Neurosci.
19:
1194-1196Crossref
(269)
16Deciphering
Disorders
Study.Prevalence
disorders.Nature.
542:
433-438Crossref
(765)
Although
issue
whether
loss-of-function
certain
explored
mainly
relation
question
applies
NDDs
well.
Recently,
burden
protein-truncating
evolutionarily
constrained
shown
ADHD.17Satterstrom
Walters
R.K.
Singh
Wigdor
E.M.
Lescai
Demontis
Stevens
Bybjerg-Grauholm
al.iPSYCH-Broad
ConsortiumAutism
attention
deficit
hyperactivity
variants.Nat.
1961-1965Crossref
(81)
One
analysis
limited
one
diagnosis
ADHD,
both;
comorbid
diagnoses)
confined
set
212
variant
Even
ASD-derived
gene
set,
rates
ADHD
significantly
different.17Satterstrom
pragmatic
terms
availability,
problem
cohort-ascertainment-based
approach
bias
introduced
unequal
opportunity
participant
receive
(i.e.,
ID)
due
uniform
phenotyping
studies.
Because
bias,
phenotypic
overlap
groups
unclear;
prevalence
quantified,13Rauch
Scholar,18Gilissen
Hehir-Kwa
J.Y.
Thung
D.T.
Vorst
Kwint
Janssen
I.M.
Hoischen
Schenck
al.Genome
major
causes
disability.Nature.
511:
344-347Crossref
(783)
Scholar,19Halvardson
Zhao
J.J.
Zaghlool
Wentzel
Georgii-Hemming
Månsson
Ederth
Sävmarker
Brandberg
G.
Soussi
Zander
Thuresson
A.C.
Feuk
Mutations
HECW2
epilepsy.J.
53:
697-704Crossref
(46)
minority
subset
participants.11Satterstrom
Scholar,12Coe
standardized
measures
frequently
utilized
cohorts.11Satterstrom
majority
came
Deciphering
Study,
recruitment
criteria
phenotypes
congenital
anomalies,
dysmorphic
features,
abnormal
growth
addition
diagnoses.
Differences
age
impact
individual
diagnosis.
Another
type
scientifically
arbitrary
threshold
define
ASD-predominance
(relative
exomes
versus
exomes);
cutoff
>1.0
meaning
simple
could
ASD-predominance.
narrow
distinction
dubious
clinical
significance.
if
equally
sized
yielded
13
particular
cases
12
cases,
relative
would
1.08
(13/12),
met.
non-overlapping
diagnoses
none
subjects
had
ASD),
rate
52%
(13/25),
48%
(12/25),
certainly
indication
specificity.
it
possible
scenario,
all
ID.
case,
still
even
though
25
(100%)
poses
challenge
validity
ascertainment-based
approach.
able
assess
intelligence
quotient
(IQ)
differences
Individuals
who
participate
ascertainment
because
methods
tests
administered),
very
low
IQ.
someone
IQ
40
characteristics
70,
discrepant
becausee
Diagnostic
Statistical
Manual
Mental
Disorders,
5th
Edition
(DSM-5)
specifies
"to
make
disability,
social
communication
should
below
expected
general
level."20American
Psychiatric
AssociationDiagnostic
DSM-5.Fifth
Edition.
American
Association,
2012Google
degree
interaction
impairment
what
expectation
40,
resulting
former
meeting
DSM-5
latter
colleagues11Satterstrom
demonstrated
variants,
occur
commonly
higher
(defined
>
70
82
separate
analyses);
suggests
do
solely
impair
cognition.
finding
does
eliminate
difference
mean
primary
factor
responsible
classification
not.
Among
probands
detected
available
full-scale
(which
represented
46.8%
familyb
ased
25.1%
<
70)
30.6%,
three
groups:
+
(mean
62)
74)
idiopathic
82).11Satterstrom
All
means
population
100,
cognition
mutated
74),
great
62).11Satterstrom
Similarly,
Simons
Simplex
Collection
(SSC),
(LGD)
173
high-confidence
ASD-associated
lower
(69.1)
severity
2,216;
81.9).21Jensen
Smolen
Girirajan
Gene
discoveries
biased
towards
comorbidity
disability.bioRxiv.
https://doi.org/10.1101/715755Crossref
(0)
When
subgroup
100
337)
562),
LGD
overall
ID.21Jensen
cohort,
coexisting
increased
presence
gene.
evident
sources.
Geisinger
Brain
Disorder
Genes
Database
(DBD
Database)
integrates
genome
sequencing,
array,
targeted
six
(including
examine
(pLoF)
(see
Web
Resources).22Gonzalez-Mantilla
A.J.
Martin
A
cross-disorder
method
novel
disorders.JAMA
73:
275-283Crossref
(72)
At
time
accessed,
database
5,031
553
information
923
unique
articles
March
2003
2019
met
curation
criteria.22Gonzalez-Mantilla
59
at
least
pLOF
database,
exclusively
(Figure
1).
CHD8
[MIM:
610528],
SHANK3
606230],
SCN2A
182390],
only,
without
(ID
68%,
52%,
62%
CHD8,
SHANK3,
SCN2A,
respectively).
variability
therefore
subject
bias.
Detailed
another
source
evaluating
discussed
model
gene"
ASD.23Bernier
Golzio
Penn
O.
Witherspoon
Baker
al.Disruptive
subtype
early
development.Cell.
158:
263-276Abstract
(469)
89
whom
available,
(62/89,
70%)
suggested
DBD
query
(Bernier,
unpublished
data).
Specific
scores
individuals:
nonverbal
67.8
(SD
28.6)
40)
verbal
65.5
28.2)
35).
Douzgou
colleagues
reported
17
(68%)
(81%
21
about
functioning).24Douzgou
Liang
H.W.
Metcalfe
Somarathi
Tischkowitz
Mohamed
Kini
U.
McKee
Yates
Bertoli
al.Deciphering
StudyThe
presentation
caused
truncating
variants.Clin.
96:
72-84Crossref
(19)
Twenty-one
(84%)
ASD.24Douzgou
concern
mild
identified.
Guo
al.
25Guo
Wu
Long
Li
Xun
Ou
Chen
D
Язык: Английский
Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
Nature Genetics,
Год журнала:
2020,
Номер
52(10), С. 1046 - 1056
Опубликована: Сен. 28, 2020
Язык: Английский
Macroautophagy in CNS health and disease
Nature reviews. Neuroscience,
Год журнала:
2022,
Номер
23(7), С. 411 - 427
Опубликована: Май 3, 2022
Язык: Английский
The contributions of rare inherited and polygenic risk to ASD in multiplex families
Proceedings of the National Academy of Sciences,
Год журнала:
2023,
Номер
120(31)
Опубликована: Июль 28, 2023
Autism
spectrum
disorder
(ASD)
has
a
complex
genetic
architecture
involving
contributions
from
both
de
novo
and
inherited
variation.
Few
studies
have
been
designed
to
address
the
role
of
rare
variation
or
its
interaction
with
common
polygenic
risk
in
ASD.
Here,
we
performed
whole-genome
sequencing
largest
cohort
multiplex
families
date,
consisting
4,551
individuals
1,004
having
two
more
autistic
children.
Using
this
study
design,
identify
seven
previously
unrecognized
ASD
genes
supported
by
majority
variants,
finding
support
for
total
74
our
152
after
combined
analysis
other
studies.
Autistic
children
demonstrate
an
increased
burden
protein-truncating
variants
known
genes.
We
also
find
that
score
(PGS)
is
overtransmitted
nonautistic
parents
who
harbor
consistent
combinatorial
effects
offspring,
which
may
explain
reduced
penetrance
these
parents.
observe
addition
social
dysfunction,
language
delay
associated
PGS
overtransmission.
These
results
are
additive
further
suggest
core
biological
feature
Язык: Английский
Recurrent gene flow between Neanderthals and modern humans over the past 200,000 years
Science,
Год журнала:
2024,
Номер
385(6705)
Опубликована: Июль 11, 2024
Although
it
is
well
known
that
the
ancestors
of
modern
humans
and
Neanderthals
admixed,
effects
gene
flow
on
Neanderthal
genome
are
not
understood.
We
develop
methods
to
estimate
amount
human-introgressed
sequences
in
apply
whole-genome
sequence
data
from
2000
three
Neanderthals.
have
2.5
3.7%
human
ancestry,
we
leverage
revise
estimates
ancestry
humans,
show
population
sizes
were
significantly
smaller
than
previously
estimated,
identify
two
distinct
waves
into
Our
provide
insights
genetic
legacy
recurrent
between
Язык: Английский
