Heritability of autism
The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation. Autism has a strong genetic basis. Although the genetics of autism are complex, the disorder is explained more by multigene effects than by rare mutations with large effects.
Autism may be influenced by genetics, with studies consistently demonstrating a higher prevalence among siblings and in families with a history of autism. This led researchers to investigate the extent to which genetics contribute to the development of autism. Numerous studies, including twin studies and family studies, have estimated the heritability of autism to be around 80 to 90%, indicating that genetic factors play a substantial role in its etiology. Heritability estimates do not imply that autism is solely determined by genetics, as environmental factors also contribute to the development of the disorder.
Studies of twins from 1977 to 1995 estimated the heritability of autism to be more than 90%; in other words, that 90% of the differences between autistic and non-autistic individuals are due to genetic effects. When only one identical twin is autistic, the other often has learning or social disabilities. For adult siblings, the likelihood of having one or more features of the broad autism phenotype might be as high as 30%, much higher than the likelihood in controls.
File:ASDPlot.png|thumb|277x277px|A variety of genetic associations with autism spectrum disorder have been reported. This Manhattan plot shows the statistical significance of each variant in a scan across the entire genome. The plot is similar to those in published articles.
Though genetic linkage analysis have been inconclusive, many association analyses have discovered genetic variants associated with autism. For each autistic individual, mutations in many genes are typically implicated. Mutations in different sets of genes may be involved in different autistic individuals. There may be significant interactions among mutations in several genes, or between the environment and mutated genes. By identifying genetic markers inherited with autism in family studies, numerous candidate genes have been located, most of which encode proteins involved in neural development and function. However, for most of the candidate genes, the actual mutations that increase the likelihood for autism have not been identified. Typically, autism cannot be traced to a Mendelian mutation or to single chromosome abnormalities such as fragile X syndrome or 22q13 deletion syndrome.
10–15% of autism cases may result from single gene disorders or copy number variations —spontaneous alterations in the genetic material during meiosis that delete or duplicate genetic material. These sometimes result in syndromic autism, as opposed to the more common idiopathic autism. Sporadic cases have been examined to identify candidate genetic loci involved in autism. A substantial fraction of autism may be highly heritable but not inherited: that is, the mutation that causes the autism is not present in the parental genome.
Although the fraction of autism traceable to a genetic cause may grow to 30–40% as the resolution of array comparative genomic hybridization improves, several results in this area have been described incautiously, possibly misleading the public into thinking that a large proportion of autism is caused by CNVs and is detectable via array CGH, or that detecting CNVs is tantamount to a genetic diagnosis. The Autism Genome Project database contains genetic linkage and CNV data that connect autism to genetic loci and suggest that every human chromosome may be involved. It may be that using autism-related sub-phenotypes instead of the diagnosis of autism per se may be more useful in identifying susceptible loci.
Twin studies
Twin studies provide a unique opportunity to explore the genetic and environmental influences on autism spectrum disorder. By studying identical twins, who share identical DNA, and fraternal twins, who share about half of their DNA, researchers can estimate the heritability of autism by comparing the rates of when one twin is diagnosed with autism while the other is not in identical vs. fraternal twins. Twin studies are a helpful tool in determining the heritability of disorders and human traits in general. They involve determining concordance of characteristics between identical twins and between fraternal twins. Possible problems of twin studies are: errors in diagnosis of monozygocity, and 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 mating.
An example of a condition that appears to have very little if any genetic influence is irritable bowel syndrome, with a concordance of 28% vs. 27% for MZ and DZ pairs respectively. An
example of a human characteristic that is extremely heritable is eye color, with a concordance of 98% for MZ pairs and 7–49% for DZ pairs depending on age.
Identical twin studies put autism's heritability in a range between 36% and 95.7%, 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.
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 twins and 11 MZ twins 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 had infrequent seizures, remained autistic. The report noted that genetic factors were not "all-important" in the development of 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 the general-population of 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 between discordant twins were found. The abstract notes that in previous studies 75% of the non-autistic twins displayed the broader phenotype.
Another 2004 study examined whether the characteristic symptoms of autism 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.
In a 2015 meta-analysis of previously conducted twin studies, the authors found that genetics play a substantial role in the development of autism, contributing between 64% to 91% to the chances of developing autism.
In a 2024 study of twins conducted by Martini et al., findings suggests that genetic factors have a greater influence on the stability of autistic traits compared to environmental factors.
Sibling studies
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 tasks."
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 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.