TO WHAT EXTENT DO GENES
The heritability of autism is a source of controversy
about the causes of
autism. Though it is agreed that there is a genetic susceptibility
to autism, disagreements arise
over the whether the condition is genetically determined and therefore
inevitable, or is triggered by factors in the environment. The controversy
is made more difficult by the broad spectrum of phenotypes labeled
"autism", ranging from near total disability to mild social
Identical twin studies put autism's heritability
in a range between 0.36 and 0.957, with concordance for a broader
phenotype usually found at the higher end of the range. Autism
concordance in siblings and fraternal twins is anywhere between
0 and 23.5%. This is more likely 2–4% for classic autism and 10–20%
for a broader spectrum. Assuming a general-population prevalence
of 0.1%, the risk of classic autism in siblings is 20- to 40-fold
that of the general population.
Researchers usually note that autism is among
the most heritable of all neurological conditions, even among the
more than 90% of cases not associated with known genetic diseases
such as fragile X syndrome
or muscular dystrophy.
Twin studies are a helpful tool in determining
the heritability of disorders and low-prevalence human traits in
general. They involve determining concordance of characteristics
between identical (monozygotic or MZ) twins and between fraternal
(dizygotic or DZ) twins. Possible problems of twin studies are:
(1) errors in diagnosis of monozygocity, and (2) the assumption
that social environment sharing by DZ twins is equivalent to that
of MZ twins.
A condition that is environmentally caused without
genetic involvement would yield a concordance for MZ twins equal
to the concordance found for DZ twins. In contrast, a condition
that is completely genetic in origin would theoretically yield a
concordance of 100% for MZ pairs and usually much less for DZ pairs
depending on factors such as the number of genes involved and assortative
An example of a condition that appears to have
very little if any genetic influence is irritable bowel syndrome
(IBS), with a concordance of 28% vs. 27% for MZ and DZ pairs respectively.
An example of a human characteristics that is extremely heritable
is eye color, with a concordance of 98% for MZ pairs and 7–49% for
DZ pairs depending on age.
Notable twin studies have attempted to shed light
on the heritability of autism.
A small scale study in 1977 was the first of its
kind to look into the heritability of autism. It involved 10 DZ
and 11 MZ pairs in which at least one twin in each pair showed infantile
autism. It found a concordance of 36% in MZ twins compared to 0%
for DZ twins. Concordance of "cognitive abnormalities"
was 82% in MZ pairs and 10% for DZ pairs. In 12 of the 17 pairs
discordant for autism, a biological hazard was believed to be associated
with the condition.
A 1979 case report discussed a pair of identical
twins concordant for autism. The twins developed similarly until
the age of 4, when one of them spontaneously improved. The other
twin, who had suffered infrequent seizures,
remained autistic. The report noted that genetic factors were not
"all important" in the development of the twins.
In 1985, a study of twins enrolled with the UCLA
Registry for Genetic Studies found a concordance of 95.7% for autism
in 23 pairs of MZ twins, and 23.5% for 17 DZ twins.
In a 1989 study, Nordic countries were screened
for cases of autism. Eleven pairs of MZ twins and 10 of DZ twins
were examined. Concordance of autism was found to be 91% in MZ and
0% in DZ pairs. The concordances for "cognitive disorder"
were 91% and 30% respectively. In most of the pairs discordant for
autism, the autistic twin had more perinatal stress.
A British twin sample was reexamined in 1995 and
a 60% concordance was found for autism in MZ twins vs. 0% concordance
for DZ. It also found 92% concordance for a broader spectrum in
MZ vs. 10% for DZ. The study concluded that "obstetric hazards
usually appear to be consequences of genetically influenced abnormal
development, rather than independent aetiological factors."
A 1999 study looked at social cognitive skills
in general-population children and adolescents. It found "poorer
social cognition in males", and a heritability of 0.68 with
higher genetic influence in younger twins.
In 2000, a study looked at reciprocal social behavior
in general-population identical twins. It found a concordance of
73% for MZ, i.e. "highly heritable", and 37% for DZ pairs.
A 2004 study looked at 16 MZ twins and found a
concordance of 43.75% for "strictly defined autism". Neuroanatomical
differences (discordant cerebellar white and grey matter volumes)
between discordant twins were found. The abstract notes that in
previous studies 75% of the non-autistic twins displayed the broader
Another 2004 study examined whether the characteristic
symptoms of autism (impaired social interaction, communication deficits,
behaviors) show decreased variance of symptoms among monozygotic
twins compared to siblings in a sample of 16 families. The study
demonstrated significant aggregation of symptoms in twins. It also
concluded that "the levels of clinical features seen in autism
may be a result of mainly independent genetic traits."
An English twin study in 2006 found high heritability
for autistic traits in a large group of 3,400 pairs of twins.
One critic of the pre-2006 twin studies said that
they were too small and their results can be plausibly explained
on non-genetic grounds.
The importance of sibling studies lies in contrasting
their results to those of fraternal (DZ) twin studies, plus their
sample sizes can be much larger. Environment sharing by siblings
is presumably different enough to that of DZ twins to shed some
light on the magnitude of environmental influence. This should even
be true to some extent regarding the prenatal environment. Unfortunately
DZ twin study findings have yielded a very large range of variance
and are error prone because of the apparent low concordance and
the fact that they typically look at a small number of DZ pairs.
For example, in studies involving 10 DZ pairs, a concordance below
10% would be impossible to determine precisely.
A study of 99 autistic probands which found a
2.9% concordance for autism in siblings, and between 12.4% and 20.4%
concordance for a "lesser variant" of autism.
A study of 31 siblings of autistic children, 32
siblings of children with developmental delay, and 32 controls.
It found that the siblings of autistic children, as a group, "showed
superior spatial and verbal span, but a greater than expected number
performed poorly on the set-shifting, planning, and verbal fluency
A 2005 Danish study looked at "data from
the Danish Psychiatric Central Register and the Danish Civil Registration
System to study some risk factors of autism, including place of
birth, parental place of birth, parental age, family history of
psychiatric disorders, and paternal identity." It found an
overall prevalence rate of roughly 0.08%. Prevalence of autism in
siblings of autistic children was found to be 1.76%. Prevalence
of autism among siblings of children with Asperger's syndrome or
PDD was found to be 1.04%. The risk was twice as high if the mother
had been diagnosed with a psychiatric disorder. The study also found
that "the risk of autism was associated with increasing degree
of urbanisation of the child's place of birth and with increasing
paternal, but not maternal, age."
A study in 2007 looked at a database containing pedigrees of 86
families with two or more autistic children and found that 42 of
the third-born male children showed autistic symptoms, suggesting
that parents had a 50% chance of passing on a mutation to their
offspring. The mathematical models suggest that about 50% of autistic
cases are caused by spontaneous mutations. The simplest model was
to divide parents into two risk classes depending on whether the
parent carries a pre-existing mutation that causes autism; it suggested
that about a quarter of autistic children have inherited a copy
number variation from their parents.
Other family studies
A 1994 looked at the personalities of parents
of autistic children, using parents of children with Down's syndrome
as controls. Using standardized tests it was found that parents
of autistic children were "more aloof, untactful and unresponsive."
A 1997 study found higher rates of social and communication deficits
and stereotyped behaviors in families with multiple-incidence autism.
Autism was found to occur more often in families of physicists,
engineers and scientists. Other studies have yielded similar
results. Findings of this nature have led to the coinage
of the term "geek syndrome".
A 2001 study of brothers and parents of autistic boys looked into
the phenotype in terms of one current cognitive theory of autism.
The study raised the possibility that the broader autism phenotype
may include a "cognitive style" (weak central coherence)
that can confer information-processing advantages.
A study in 2005 showed a positive correlation between repetitive
behaviors in autistic individuals and obsessive-compulsive behaviors
in parents. Another 2005 study focused on sub-threashold autistic
traits in the general population. It found that correlation for
social impairment or competence between parents and their children
and between spouses is about 0.4.
A 2005 report examined the family psychiatric
history of 58 subjects with Asperger's syndrome (AS) diagnosed according
to DSM-IV criteria. Three (5%) had first-degree relatives with Aspergers syndrome.
Nine (19%) had a family history of schizophrenia. Thirty five (60%)
had a family history of depression. Out of 64 siblings, 4 (6.25%)
were diagnosed with Aspergers syndrome.
It has been suggested that the twinning process
itself is a risk factor in the development of autism, presumably
due to perinatal factors. However, three large-scale epidemiological
studies have refuted this idea.
Evidence has mounted indicating that clinical
pictures that look like autism (phenocopies) may not be due to the
same genetic liability. Examples are congenital blindness, profound
institutional privation, and a number of conditions related
Fragile-X syndrome, Rett
Syndrome and tuberous
sclerosis are well-known causes of autism-like symptoms.
Twin and family studies show that autism is a
highly heritable condition, but they have left many questions for
researchers, most notably
Why is fraternal twin concordance so low considering
that identical twin concordance is high?
Why are parents of autistic children typically non-autistic?
Which factors could be involved in the failure to find a 100% concordance
in identical twins?
Is profound intellectual disability a characteristic of the genotype
or something totally independent?
Some researchers have speculated that what we currently refer to
as "autism" may be a catch-all description for many yet
unknown conditions with different genetic and/or environmental etiologies.
This would appear to make the effort to find a genotype model a
lot more difficult, and perhaps even pointless. Nevertheless, a
number of genetic models have been proposed to try to explain the
results of twin and sibling studies.
The original Mendelian model tried to explain
observations using distinct genes existing in clearly dominant or
recessive alleles. That would imply a recessive "autism gene"
inherited from each of the parents. This kind of model is clearly
It indicates that a sibling of an autistic individual should have
25% risk of having the autistic genotype, which is inconsistent
with fraternal twin and sibling study results.
It would require several characteristic features of autism to be
caused by a single allele at a single locus.
Further considerations for the 'autism gene model' of also show
(a) only a small number of cases can be clearly
linked to a possible genetic cause and these are often allele deletions;
(b) the majority of patients with autism do not marry and do not
have offspring which should result in a decreased incidence of the
presumed gene in the general population.
(c) the incidence of autism in the population has been increasing
instead, making the likelihood of a single genetic cause extremely
Mendel's later work and work based on it introduced polygenic inheritance,
but taking into account linkage of genes required understanding
where they were located - elucidating the role of the chromosomes.
Reduced risk to relatives of probands and identical/fraternal
twin ratios indicate that a multigene model is more likely to account
for the autistic genotype. That is, at least two alleles would be
involved, and most likely three to five. Researchers have suggested
models of 15 and even up to 100 genes.
The fraternal twin results found by Ritvo et al (1985) and the
broader phenotype results of Bolton et al (1994) suggest that
a 2-gene model is plausible. Kolevzon et al (2004) proposed that
the 3 characteristic symptoms of autism may be the result of 3 different
alleles. Data supports the multiple-locus hypothesis
and also that a 3-loci model is the best fit. Risch et al (1999)
found results most compatible with a large number of loci (>=
Given the significant prevalence of autism, perhaps
0.1% for classic autism and at least 0.6% for a broader spectrum,
a multigene model has important implications. Since intelligence
appears to be independent of the recognized characteristic symptoms
of autism (and the diagnostic criteria) it is likely that many individuals
are very autistic yet highly functional, allowing them to escape
altogether. So the prevalence of the autistic genotype may be considerably
higher than thought. And if multiple alleles are part of the genotype,
then each allele must have relatively high prevalence in the general
Two family types
In this model most families fall into two types:
in the majority, sons have a low risk of autism, but in a small
minority their risk is near 50%. In the low-risk families, sporadic
autism is mainly caused by spontaneous mutation with poor penetrance
in daughters and high penetrance in sons. The high-risk families
come from (mostly female) children who carry a new causative mutation
but are unaffected and transmit the dominant mutation to grandchildren.
A number of epigenetic models of autism have been
proposed as have several genetic imprinting models. These
are suggested by the occurrence of autism in individuals with fragile
X syndrome, which arises from epigenetic mutations, and with Rett
Syndrome, which involves epigenetic regulatory factors. An epigenetic
model would help explain why standard genetic screening strategies
have so much difficulty with autism.
Candidate gene loci
A number of alleles have been shown to have strong
linkage to the autism phenotype. In many cases the findings are
inconclusive, with some studies showing no linkage. Alleles linked
so far strongly support the assertion that there is a large number
of genotypes that are manifested as the autism phenotype. At least
some of the alleles associated with autism are fairly prevalent
in the general population, which indicates they are not rare pathogenic
mutations. This also presents some challenges in identifying all
the rare allele combinations involved in the etiology of autism.
17q11.2 region, SERT (SLC6A4) locus – This gene locus has been
associated with rigid-compulsive behaviors. Notably, it has also
been associated with depression but only as a result of social adversity,
although other studies have found no link. Significant linkage
in families with only affected males has been shown. Researchers
have also suggested that the gene contributes to hyperserotonemia.
GABA receptor subunit genes – GABA is the primary inhibitory neurotransmitter
of the human brain. Ma et al (2005) concluded that GABRA4 is involved
in the etiology of autism, and that it potentially increases autism
risk through interaction with GABRB1. The GABRB3 gene has been
associated with savant skills. The GABRB3 gene deficient mouse
has been proposed as a model of Autism Spectrum Disorder.
Engrailed 2 (EN2) – Engrailed 2 is believed to be associated with
cerebellar development. Benayed et al (2005) estimate that this
gene contributes to as many as 40% of Autism Spectrum Disorder cases, about twice the
prevalence of the general population. But at least one study
has found no association.
3q25-27 region – A number of studies have shown a significant linkage
of autism and Asperger's syndrome with this locus. The most
prominent markers are in the vicinity of D3S3715 and D3S3037.
7q21-q36 region, REELIN (RELN) – In adults, Reelin glycoprotein
is believed to be involved in memory formation, neurotransmission,
and synaptic plasticity. A number of studies have shown an association
between the REELIN gene and autism, but a couple of studies
were unable to duplicate linkage findings.
SLC25A12 – This gene, located in chromosome 2q31, encodes the mitochondrial
aspartate/glutamate carrier (AGC1). It has been found to have a
significant linkage to autism in some studies, but linkage
was not replicated in others, and a 2007 study found no compelling
evidence of an association of any mitochondrial haplogroup in autism.
HOXA1 and HOXB1 – A link has been found between HOX genes and the
development of the embryonic brain stem. In particular, two genes,
HOXA1 and HOXB1, in transgenic 'knockout' mice, engineered so that
these genes were absent from the genomes of the mice in question,
exhibited very specific brain stem developmental differences from
the norm, which were directly comparable to the brain stem differences
discovered in a human brain stem originating from a diagnosed autistic
Conciatori et al (2004) found an association of HOXA1 with increased
head circumference. A number of studies have found no association
with autism. The possibility remains that single allelic
variants of the HOXA1 gene are insufficient alone to trigger the
developmental events in the embryo now associated with autism spectrum conditions. Tischfield et al published a paper which suggests
that because HOXA1 is implicated in a wide range of developmental
mechanisms, a model involving multiple allelic variants of HOXA1
in particular may provide useful insights into the heritability
mechanisms involved. Additionally, Ingram et al alighted upon
additional possibilities in this arena. Transgenic mouse studies
indicate that there is redundancy spread across HOX genes that complicate
the issue, and that complex interactions between these genes could
play a role in determining whether or not a person inheriting the
requisite combinations manifests an autistic spectum condition—transgenic
mice with mutations in both HOXA1 and HOXB1 exhibit far more profound
developmental anomalies than those in which only one of the genes
differs from the conserved 'norm'.
In Rodier's original work, teratogens are considered to play a
part in addition, and that the possibility remains open for a range
of teratogens to interact with the mechanisms controlled by these
genes unfavourably (this has already been demonstrated using valproic
acid, a known teratogen, in the mouse model).
PRKCB1 – Philippi et al (2005) found a strong association between
this gene and autism. This is a recent finding that needs to be
FOXP2 – The FOXP2 gene is of interest because it is known to be
associated with developmental language and speech deficits. An association
to autism appears to be elusive, nonetheless.
UBE3A – The UBE3A gene has been associated with Angelman syndrome.
Samaco et al (2005) suggest reduced expression of UBE3A in autism,
as is the case in Rett syndrome. In any case, it appears that
the role of UBE3A is limited.
Shank3/ProSAP2, 22q13 and Neuroligins – The gene called SHANK3
(also designated ProSAP2) regulates the structural organization
of neurotranmsitter receptors in post-synaptic dendritic spines
making it a key element in chemical binding crucial to nerve cell
communication. SHANK3 is also a binding partner of chromosome
22q13 (i.e. a specific section of Chromosome 22) and neuroligin
proteins; deletions and mutations of SHANK3, 22q13 (i.e. a specific
section of Chromosome 22) and genes encoding neuroligins have been
found in some people with Autism Spectrum Disorders.
Mutations in the SHANK3 gene have been strongly associated with
the Autism Spectrum Disorders. If the SHANK3 gene is not adequately
passed to a child from the parent (haploinsufficiency) there will
possibly be significant neurological changes that are associated
with yet another gene, 22q13, which interacts with SHANK3. Alteration
or deletion of either will effect changes in the other.
A deletion of a single copy of a gene on chromosome 22q13 has been
correlated with global developmental delay, severely delayed speech
or social communication disorders and moderate to profound delay
of cognitive abilities. Behavior is described as "autistic-like"
and includes high tolerance to pain and habitual chewing or mouthing
(see also 22q13 deletion syndrome). This appears to be connected
to the fact that signal transmission between nerve cells is altered
with the absence of 22q13.
SHANK3 proteins also interact with neuroligins at the synapses
of the brain further complicating the widespread effects of changes
at the genetic level and beyond.
Neuroligin is a cell surface protein (homologous to acetylcholinesterase
and other esterases) that binds to synaptic membranes. Neuroligins
organize postsynaptic membranes that function to transmit nerve
cell messages (excitatory) and stop those transmissions (inhibitory);
In this way, neuroligins help to ensure signal transitions between
nerve cells. Neuroligins are also regulate the maturation of synapses
and ensure there are sufficient receptor proteins on the synaptic
Mice with a neuroligin-3 mutation exhibit poor social skills but
increased intelligence. Though not present in all individuals
with autism, these mutations hold potential to illustrate some of
the genetic components of spectrum disorders.
MET – The MET gene (MET receptor tyrosine kinase gene) linked to
brain development, regulation of the immune system, and repair of
the gastrointestinal system, has been linked to autism. This MET
gene codes for a protein that relays signals that turn on a cell’s
internal machinery. Impairing the receptor’s signaling interferes
with neuron migration and disrupts neuronal growth in the cerebral
cortex and similarly shrinks the cerebellum—abnormalities also seen
It is also known to play a key role in both normal and abnormal
development, such as cancer metastases (hence the name MET). A mutation
of the gene, rendering it less active, has been found to be common
amongst children with autism. Mutation in the MET gene demonstrably
raises risk of autism by 2.27 times.
neurexin 1 – In February 2007, researchers in the Autism Genome
Project (an international research team composed of 137 scientists
in 50 institutions) reported possible implications in aberrations
of a brain-development gene called neurexin 1 (located on chromosome
11) as a cause of some cases of autism. Linkage analysis was
performed on DNA from 1,181 families in what was the largest-scale
genome scan conducted in autism research at the time.
The objective of the study was to locate specific brain cells involved
in autism to find regions in the genome linked to autism susceptibility
genes. The focus of the research was copy number variations (CNVs),
extra or missing parts of genes. Each person does not actually have
just an exact copy of genes from each parent. Each person also has
occasional multiple copies of one or more genes or some genes are
missing altogether. The research team attempted to locate CNVs when
they scanned the DNA.
Neurexin 1 is one of the genes that may be involved in communication
between nerve cells (neurons). Neurexin 1 and other genes like it
are very important in determining how the brain is connected from
cell to cell, and in the chemical transmission of information between
nerve cells. These genes are particularly active very early in brain
development, either in utero or in the first months or couple of
years of life. In some families their autistic child had only one
copy of the neurexin 1 gene.
Besides actually locating yet another possible genetic influence
(the findings were statistically insignificant), the research also
reinforced the theory that autism involves many forms of genetic
GSTP1 – A 2007 study suggested that the GSTP1*A haplotype of the
glutathione S-transferase P1 gene (GSTP1) acts in the mother during
pregnancy and increases the likelihood of autism in the child.
Others – There is a large number of other candidate loci which
either should be looked at or have been shown to be promising. Several
genome-wide scans have been performed identifying markers across
A few examples of loci that have been studied are the 17q21 region, the 3p24-26 locus, PTEN, and 15q11-q13.
Other possible candidates include:
SLC6A2 (Social phobia)
7q11.23 (William's syndrome, language impairment)
4q34-35, 5q35.2-35.3, 17q25 (Tourette
6p25.3-22.3 (Verbal IQ)
22q11.2 (Visio-Spatial IQ)
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