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The quest for autism’s causes, and what it reveals about all of us

This story was originally published by Knowable Magazine.

As alarm grew over autism prevalence at the turn of this
century, there was much public talk of a growing “epidemic.” That
language has since softened, and it is now clear that many autistic
people were there all along, their condition unrecognized until
relatively recently.

But what is the cause? The emerging narrative today is that
there is no single cause — rather, multiple factors, roughly sorted
into the categories of genetics and environment, work together in
complex ways. Because of this complexity and the hundreds of gene
variants
that have been implicated, developing human brains may follow many
possible paths to arrive at a place on the autism spectrum.

And this may help explain something true about autism: It varies greatly from one person to the
next
.

As clinicians view it, autism involves communication deficits
and formulaic, repetitive behaviors that present obstacles to
establishing conventional relationships. The soft borders of that
definition — where does communication difficulty cross over into
communication deficit? — suggest blurred margins between people who
are diagnosed with autism and those who approach, but never quite
cross, the line into diagnostic territory.

Those who do have diagnoses display behaviors on a continuum of
intensity. Their use of spoken language ranges from not speaking at
all to being hyperverbal. They can have a unique interest in the
finer details of window blinds or an intense but more socially
tolerated fascination with dinosaurs. As with many human behaviors,
each feature exists on a spectrum, and these spectra blend in a
person to create what clinicians call autism.

By pinpointing risk-associated genes and uncovering their roles,
studying the roots of autism also is providing new insights into
the development of all human brains, autistic or not. Here is a
taste of what we now know, and what we don’t, about autism’s causes
— and what that search is teaching us about everybody’s
neurology.

They know it when they see it

Despite the many and varied threads that may interweave to cause
autism, the condition is largely identifiable. What clinicians are
really saying when they diagnose autism, says James McPartland, a
clinical psychologist at the Yale Child Study Center, is that they
see a recognizable, if broadly defined, constellation of behaviors.
“So really, there is something true about autism, and everyone who
meets the diagnosis of autism shows these kinds of behaviors.”

US rates of autism diagnoses have increased over the years, as shown in a graph. Numbers are averages of prevalence among 8-year-old children from several reporting sites of the CDC's Autism and Developmental Disabilities Monitoring Network. Not all sites reported in each year shown, and the ranges can be broad (for example, in 2000 the average was 6.7 per 1,000 children, but the range from different reporting sites was 4.5 to 9.9). At least part of the increase is due to heightened awareness and shifting diagnostic criteria.
US rates of autism diagnoses have increased
over the years, as shown in this graph. Numbers are averages of
prevalence among 8-year-old children from several reporting sites
of the CDC’s Autism and Developmental Disabilities Monitoring
Network. Not all sites reported in each year shown, and the ranges
can be broad (for example, in 2000 the average was 6.7 per 1,000
children, but the range from different reporting sites was 4.5 to
9.9).  At least part of the increase is due to heightened awareness
and shifting diagnostic criteria.

At the same time, the subtle differences in how each autistic
person manifests the telltale features make it highly individual,
says Pauline Chaste, a child psychiatrist at Inserm U 894, the
Centre de Psychiatrie et Neurosciences, in Paris. “We describe a
specific behavior that exists — that kind of social impairment and
rigidity. You can have more or less of it, but it definitely
exists.”

The more or less of autism could trace, in part, to the types of
gene variants that contribute to it in a given person. Some of
these variants have a big effect by themselves, while others make
tiny contributions
, and any autistic person could have their
own unique mix of both. One thing seems clear: Though there may be
something true about autism, as McPartland puts it, the existence
of “one true autism gene” or even one gene for each autism feature
is unlikely.

Instead, there will be patterns of gene combinations and the
results they produce, says epidemiologist Elise Robinson of the
Harvard T.H. Chan School of Public Health and an associate member
of the Broad Institute. People who have both autism and
intellectual disability, for example, tend to have more big-effect
gene mutations than people with autism alone.

Facial communication

Looking for these contributing gene variants isn’t simply an
exercise in scientific curiosity or in finding potential targets
for drug treatments. Because most of these genes direct how human
brains develop and nerve cells communicate, learning about how they
lead to autism can also reveal a lot about how everyone’s brain
works.

For example, a key autism trait is atypical social behaviors,
such as, sometimes, not focusing on “social” facial features like
the eyes. Although the tendency to look into another person’s eyes
seems like something we might learn simply from being around other
people, autism research has revealed that genes underlie the
instinct.

In a 2017 study, the authors first showed that identical
twins are similar in how they look at a video with social content,
such as faces. When viewing the same video, the identical twin
pairs shifted their eyes with the same timing and focused on the
same things far more than did two non-identical siblings or
unrelated children. The fact that almost all twin pairs shared this
tendency suggests solid genetic underpinnings for the behavior.

Having established a strong genetic contribution to this trait,
the investigators, from Emory University and the Marcus Autism
Center in Georgia and Washington University in St. Louis, then
showed that the tendency to look at the eye and mouth areas of a
human face is decreased in autistic children. They concluded that
while not all of the inclination to look at certain parts of a face
is genetic, much of it is.

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Twin studies like this are powerful tools for evaluating how
much genes dictate a feature, and such investigations reveal that
the genetic contribution to autism is substantial. Autism also
tends to cluster in non-twin family members: One in five infants
who has an older sibling with autism also
develops it.

Genetic determinants

Overall, genetics accounts for about 70 to 80 percent of factors
contributing to autism, says neurologist Daniel Geschwind, director
of UCLA’s autism research and treatment center. By comparison, a
condition like depression has an underlying genetic contribution of
about 50 percent, he says. Alessandro Gozzi, neuroscientist and
group leader at the Istituto Italiano di Tecnologia, weights the
power of genes even more, placing the shared diagnosis rate between
twins as high as 95 percent, depending on how strict the diagnostic
boundaries are. But regardless of the precise value, he says that
the “wide consensus” among autism researchers is that genetics is a
powerful determinant of autism.

Going the next step — finding the specific genes involved — is a
monumental task. It’s also one that yields dividends for
understanding brain function more broadly.

The candidate gene variants are today very numerous, but a few
stand out for their potential to exert a large effect. Chaste cites
fragile X syndrome and Rett syndrome as examples — both are genetic
conditions (termed syndromes because they are defined by a cluster
of traits) that are tied to variants of a single gene or chromosome
region and are closely associated with autism.

Children with fragile X syndrome carry X chromosomes with an abnormality at the tip of one of the chromosome arms, as shown in an illustration. This affects a gene called FMR1, which carries instructions for a protein important for brain activity, such that little or no protein is made. Fragile X is associated with a range of developmental disabilities, often including autism.
Children with fragile X syndrome carry X
chromosomes with an abnormality at the tip of one of the chromosome
arms, as shown in this illustration (normal X on the left, abnormal
X on the right). This affects a gene called FMR1, which
carries instructions for a protein important for brain activity,
such that little or none of the protein is made. Fragile X is
associated with a range of developmental disabilities, often
including autism.

CREDIT: MONICA SCHROEDER / SCIENCE SOURCE

The gene linked to fragile X syndrome lies on the X chromosome.
Its name, FMR1, is easily forgettable, but the effects
of its variants are not. Studies on the causes of fragile X reveal
that the protein this gene encodes, FMRP, acts as a cellular
shuttle for RNA molecules that are crucial for nerve-cell
communication and plasticity of connections in the brain. In people
with fragile X, cells don’t produce the protein, or make very
little of it. The FMR1 variants underlying fragile X are
the most common known genetic cause of intellectual
disability and are implicated in 1 to 6 percent of autism cases.

Like FMR1, the genetic changes involved in Rett
syndrome also affect brain development. A gene called methyl CpG
binding protein 2, or MECP2, oversees the activity of many
brain-related genes, turning them off or on. Because of this
pivotal role for MECP2
, mutations that affect its
function can lead to broad effects. Some of the resulting features
look so much like autism that Rett syndrome was categorized as an autism spectrum
disorder
until 2013.

Other genetic syndromes also include autism as a feature. Some
are caused by variants in a gene called SHANK3 which, like most genes implicated in
autism, is involved in brain development and function. The protein
that it encodes helps to coax nerve extensions to form and take
shape so that a nerve cell can communicate with others. The SHANK3
protein also provides a physical scaffold for those cells to link
up. In populations of people with mutations that prevent SHANK3
protein production or who are missing the segment of chromosome 22
that contains the gene, most will have autism or Phelan-McDermid syndrome, which often includes
autism.

Yet another syndrome arises from the loss or duplication of a
chunk of chromosome 16. Researchers linked this
chromosomal change to autism in studies comparing the DNA of people
with and without the condition, singling out sequence alterations found only in
autistic participants.

Despite their clear ties to autism, these syndromes are rare.
“Collectively, they are found in about 5 percent of the total
population of patients with autism,” Gozzi says. That leaves a
great deal to explain.

Inheritance on a spectrum

So where do the other autistic people come from, genetically
speaking? Robinson says that their genetics don’t neatly fall into
two types of buckets, of either a few genes with big effects or
many genes with small effects. “It’s been well established at this
point that it’s not either–or,” she says.

In fact, says Gozzi, varying combinations of big-effect
mutations and lots of different, smaller-effect ones could explain
the wide spectrum of differences observed among autistic people.
The evidence supports such a range, he says: everything from a few
heavy-hitting variations in some people, to an additive dose from
many variants in others, and with overlap between the two patterns
in still others.

Scientists have identified many genetic variants that are linked to a raised risk of autism. Often, these variants affect the function of genes involved in the development and activity of brain cells. This graphic shows four such genes, each of which carries instructions for a protein that has an important function in neurons. The four examples are proteins called SHANK3, MECP2, FMRP and PTEN. Studies like this of autism’s causes are teaching scientists more about brain biology.
Scientists have identified many genetic
variants that are linked to a raised risk of autism. Often, these
variants affect the function of genes involved in the development
and activity of brain cells. Here are four such genes, each of
which carries instructions for a protein (called MECP2, PTEN, FMRP
and SHANK3) that has an important function in neurons. Studies like
this, of autism’s genetic causes, are teaching scientists more
about brain biology.

Geschwind adds yet another layer of complexity: the role of the
cellular environment that all the other gene variants in a person
create, known as the background effect. For example, someone could
have a mutation conferring high risk that is either enhanced or
diminished by the background input from other genes not directly
related to autism, to create a gradation of autism intensity.

Environmental influences

When researchers speak of environmental inputs to traits,
diseases and disorders, they are referring to everything from
pollutants in the air to subtle perturbations inside cells to cues
from other cells. Finding such causative candidates for autism
generally involves epidemiological studies that look for
correlations between autism rates in a population and an
environmental factor of interest.

These connections aren’t easy to locate. In the case of genes,
if a study involves enough people, even rare genetic differences
that make small contributions to autism can often be plucked from
the pile. Not so for environmental influences if their effects are
significant but small, says Robinson. Within those epidemiological
studies, you have to be able to detect that slight signal and
assess its power against the larger, background noise of lots of
other variations in the cell, body or outside environment that you
might not even be aware of and might not be relevant. “We don’t
live in a simple, single-exposure world,” says Kristen Lyall, an
epidemiologist at Drexel University in Philadelphia.

And even when a connection is made, its basis is still just
math. That is certainly the first step in evaluating a link between
an environmental factor and a condition such as autism: As one
thing goes up, does the other follow? But two things that track
together don’t necessarily share a biological association. (One of
the silliest examples to illustrate how misleading correlation can
be is how tightly the number of people killed by venomous spiders
each year tracks with the number of letters in the winning word of the same
year’s Scripps National Spelling Bee.)

In the case of genetic studies, gene changes with tiny effects
can still be considered plausible if their usual role relates to
brain function in some way. Environmental factors aren’t as well
catalogued, measured and tracked. But the better epidemiological
studies do look for correlations with credible and pre-identified
factors of interest (so, not Scripps Spelling Bee words).

For feasibility’s sake, work on environmental factors in autism
has tended to focus on inputs that have broad effects on brain
development. Robinson points to extreme preterm birth, which is related to many
kinds of neurodevelopmental disorders — autism among them.

Eventually, studies can add up to connect dots and arrive at a
plausible story of cause and effect. For example, along with
preterm birth, air pollution also has been linked to autism
risk. Another recent study found that when oil and power plants
close down, preterm births in the region drop. It’s therefore a
reasonable hypothesis that very preterm birth operates as an
intermediate between air pollution exposure and autism.

An interactive map created by the team at www.spectrumnews.org displays autism prevalence studies conducted at different times and places around the world. Each dot refers to a study. Clicking on the dots reveals granular information such as the country, sample size, years studied, autism prevalence, age of children, diagnostic criteria and sex ratio.

View this interactive map created by the team at Spectrum News.
The map displays autism prevalence studies conducted at different
times and places around the world. Each dot refers to a study.
Clicking on the dots reveals granular information such as the
country, sample size, years studied, autism prevalence, age of
children, diagnostic criteria and sex ratio.

CREDIT: SPECTRUMNEWS.ORG

Lyall believes that prenatal exposures to environmental
pollutants that can behave like hormones are particularly strong
candidates for involvement in autism risk. These chemicals,
collectively known as endocrine-disrupting compounds, include pesticides and even heavy metals, and
they are pretty much everywhere — in air, land, water, food and
us.

Some research suggests, for example, that exposure to the endocrine disruptor mercury in air
pollution raises autism odds
. The studies are few and the data
haven’t overwhelmingly showed increases in risk, Lyall
acknowledges, “but I think that it’s an interesting and important
area for future research given the lack of regulation around these
chemicals, their ubiquity in the environment and their known
adverse effects on broader neurodevelopment.”

Researchers have also homed in on plausible biological bases for
a couple of other potential environmental effects. Gozzi points to
animal studies, mostly in mice, that bolster human work linking
autism in a child with prenatal
exposure to a mother’s ramped-up immune responses
as a result
of infections. Again, Gozzi stresses that the findings are far from
definitive, and most studies involving humans have focused on
infections severe enough to require hospitalization.

Another unearthed link is to paternal age at conception: Studies find that autism
risk increases with the age of the father, usually starting in the
thirties or forties, although the age range and magnitude of the
increase vary among different studies. The cells that give rise to
sperm tend to accumulate new mutations over the years, so the
sperm contain sequence changes that pass to offspring but aren’t
present in the father’s own body cells. Some of these changes
involve regions or genes already implicated in autism risk. Sperm
also show changes in the chemical tagging of DNA that
controls the activity of genes.

Scanning electron microscopy image of human sperm cells. One of the more plausible environmental links to autism is age of the father. Over a man’s lifetime, genetic changes accrue in the cells that give rise to sperm. Among them are alterations in genes that can raise the risk of autism.
One of the more plausible environmental links
to autism is age of the father. Over a man’s lifetime, genetic
changes accrue in the cells that give rise to sperm, shown here in
a scanning electron microscopy image. Among them are alterations in
genes that can raise the risk of autism.

CREDIT: DENNIS KUNKEL MICROSCOPY / SCIENCE
SOURCE

Establishing environmental cause unequivocally is almost
impossible, because of ethical constraints. It’s one thing to
examine blood or tissue samples for genetic variants that track
with autism diagnoses. It’s another thing entirely to manipulate
factors to see if they induce autism or not. No one’s going to
deliberately infect a pregnant woman or have a group of men
specifically delay fatherhood just to test how these factors
influence autism odds.

Researchers instead are stuck finding correlations between these
factors and then looking at available measures, such as changes in
gene activity, accrual of mutations over the lifespan and studies
of autism-like behavior in animal models. And as they look at these
associations, they often make discoveries that are relevant beyond
autism — ones that have now been extended to studies of schizophrenia, aging and even human
evolution
. The link between autism and having an older father,
for example, has led to studies examining how changes in sperm over
time affect brain development in later generations.

While most environmental candidates remain just that —
candidates — Lyall says emphatically that one factor is out of the
running: vaccines. “That’s pretty conclusively been
shown to have no association with autism,” she says, noting the
numerous large epidemiological studies that have reached that
conclusion.

The settled vaccine question is a small point of clarity in an
otherwise blurred landscape of autism cause-and-effect research.
Every new finding seems to open up yet more pathways, some leading
toward autism, and some toward broader revelations about the brain
and how hormones, the immune system, the air we breathe and more
add up to make their mark on neural development. The network of
genetic and environmental factors that converge and diverge to
produce autism may reflect not only the multiplicity of ways of
being autistic — but also, more broadly, of being human.

This story was originally published by Knowable Magazine. Knowable Magazine is an independent journalistic endeavor from Annual Reviews.

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