Heritability of autism

The heritability of autism is debated by psychologyresearchers, parents of children diagnosed with autism, and members of the autistic community. Many researchers suspect that autism results from genetically mediated vulnerabilities to environmental triggers. And while there is disagreement about the magnitude, nature, and mechanisms for such environmental factors, researchers have found at least seven major genes prevalant among many individuals diagnosed as autistic.

There is some disagreement as to what the exact heritability of autism is. Identical twin studies put it anywhere between 36% and 95.7%, with concordance for a broader phenotypeusually found at the higher end of the range. Many conflicting claims about the heritability of autism can be found on the web, for example, that it is about 80% [1], 87% [2], 60% [3], 90% [4], 80%-100% [5], 91%-93% [6], 60%-92% [7], 60%-80% [8]and even as low as 10% [9].

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.

Genetic predisposition

Researchers have noted that autism is among the most heritable of all neurological conditions. There is significant evidence that "idiopathic" autism is a heritable disorder [10].

Twin studies

Twin studiesare a helpful tool in determining the heritability of disorders and low-prevalence human traits in general. They involve determining concordance of characteristics between identical (monozygoticor MZ) twins and between fraternal (dizygoticor 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 mating.

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 [11]. 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 [12].

Notable twin studies that have attempted to shed light on the heritability of autism are the following:

• Folstein-Rutter (1977)

This small scale study 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.

• Wessels-Pompe-van Meerdervoort (1979) [13]

This was a case report of 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.

• Ritvo-Freeman-Mason-Brothers-Mo-Ritvo (1985) [14]

This 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.

• Steffenburg-Gillberg-Hellgren-Andersson-Gillberg-Jakobsson-Bohman (1989) [15]

In this study, Nordiccountries 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.

• Bailey-Le-Couteur-Gottesman-Bolton-Simonoff-Yuzda-Rutter (1995) [16]

The study reexamined a British twin sample and found 60% concordance 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."

Researchers have noted that this study contained many methodological improvements, a possible reason why it is frequently cited.

• Scourfield-Martin-Lewis-McGuffin (1999) [17]

This 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.

• Constantino-Todd (2000) [18]

This 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.

• Kates-Burnette-Eliez-Strunge-Kaplan-Landa-Reiss-Pearlson (2004) [19]

This 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 phenotype.

• Kolevzon-Smith-Schmeidler-Buxbaum-Silverman (2004) [20]

This study examined whether the characteristic symptoms of autism (impaired social interaction, communication deficits, and repetitive behaviors) show decreased variance of symptoms among monozygotictwins 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."

Sibling studies

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 pressumably 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.

• Bolton-Macdonald-Pickles-Rios-Goode-Crowson-Bailey-Rutter (1994) [21]

This was 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.

• Hughes-Plumet-Leboyer (1999) [22]

This was 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."

• Lauritsen-Pedersen-Mortensen (2005) [23]

This 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 syndromeor PDDwas 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."

Other family studies

• Piven-Wzorek-Landa-Lainhart-Bolton-Chase-Folstein (1994) [24]

This study looked at the personalities of parents of autistic children, using parents of children with Down's syndromeas controls. Using standardized tests it was found that parents of autistic children were "more aloof, untactful and unresponsive."

• Piven-Palmer-Jacobi-Childress-Arndt (1997) [25]

This study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism.

• Baron-Cohen-Bolton-Wheelwright-Scahill-Short-Mead-Smith (1998) [26]

This study confirms the suspicion that autism occurs more often in families of physicists, engineers and scientists.

Other studies have yielded similar results [27][28]. Findings of this nature have led to the coinage of the term "geek syndrome" [29].

• Happe-Briskman-Frith (2001) [30]

This study examined brothers and parents of autistic boys. It looked into the phenotypein 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.

• Abramson-Ravan-Wright-Wieduwilt-Wolpert-Donnelly-Pericak-Vance-Cuccaro (2005) [31]

This study showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents.

• Constantino-Todd (2005) [32]

This 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.

• Ghaziuddin (2005) [33]

This report examined the family psychiatric history of 58 subjects with Asperger's syndrome(AS) diagnosed according to DSM-IVcriteria. Three (5%) had first-degree relatives with AS. 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 AS.

Twin risk

Some studies have suggested that the twinning process itself is a risk factor in the development of autism, pressumably due to perinatal factors [34]. At least one study shows no correlation between twinning and autism, however [35]. Higher risk among twins due to environmental factors would have significant implications on twin studies.

Phenocopies

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[36], profound institutional privation [37][38], and a number of conditions related to mental retardation [39].

Fragile-X syndrome, Rett syndromeand tuberous sclerosisare well-known causes of autism-like symptoms.

Proposed models

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 mental retardation a characteristic of the genotypeor 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 genotypemodel 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.

Mendelian models

A Mendelian modeltries to explain observations using a single gene variation or allele. That is, a model of this type proposes that there is an "autism gene" which is passed down from one of the parents. Pressumably the gene is recessive most of the time in the father or the mother of an autistic child. There are a number of problems with this kind of model:

• It indicates that a sibling of an autistic individual should have 50% risk of having the autistic genotype, which is incosistent with fraternal twin and sibling study results.
• It indicates that at least a grandparent of an autistic child should have the autistic genotype, which hasn't been found to be the case in practice.
• It proposes that the 3 main characteristic features of autism are all caused by a single allele.

Multigene models

Reduced risk to relative probands and identical/fraternal twin ratios indicate that a multigene model is more likely to account for the autistic genotype. That is, at least 2 alleleswould be involved, and most likely 3 to 5. 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 collected by Pickles et al (1995) [40]supports the multiple-locushypothesis and also that a 3-loci model is the best fit. Risch et al (1999) [41]found results most compatible with a large number of loci (>= 15).

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 a diagnosis 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 population.

Introgression model

If the autistic alleles were introgressed from another species, this would explain why they are linked to highly successful traits. It would also explain the multigenetic nature of autism, the environmental vulnerabilities and the linkage with other psychiatric disorders.

Other models

In reality allelesare not passed down at random and genetic expression is not clear-cut. Sometimes alleles have incomplete dominanceor codominance. Some traits are linkedon the same chromosome.

A number of epigeneticmodels of autism have been proposed (e.g. [42]) as have several genetic imprintingmodels (e.g. [43]).

Candidate gene loci

A number of alleleshave been shown to have strong linkage to the autism phenotype. In many cases the findings are inconclussive, with some studies showing no linkage. Alleles linked so far strongly support the assertion that there is a large number of genotypesthat 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 depressionbut only as a result of social adversity, although other studies have found no link [44].

Highly significant linkage in families with only affected males has been shown [45][46]. Researchers have also suggested that the gene contributes to hyperserotonemia[47].

• GABA receptor subunit genes

GABAis the primary inhibitory neurotransmitterof the human brain. Ma et al (2005) [48]has 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 savantskills [49].

• Engrailed 2 (EN2)

Engrailed 2 is believed to be associated with cerebellardevelopment. Benayed et al (2005) [50] estimates that this gene contributes to as many as 40% of ASD cases, about twice the prevalence of the general population. But at least one study has found no association [51].

• 3q25-27 region

A number of studies have shown a significant linkage of autism and Asperger's syndromewith this locus [52][53]. The most prominent markers are in the vicinity of D3S3715 and D3S3037 [54].

• 7q21-q36 region, REELIN (RELN)

In adults, Reelinglycoproteinis 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 [55][56]. A couple of studies were unable to duplicate linkage findings, however [57][58].

• SLC25A12

This gene, located in chromosome2q31, encodes the mitochondrialaspartate/glutamatecarrier (AGC1). It has been found to have a significant linkage to autism in some studies [59][60] but linkage was not replicated in others [61].

• HOXA1 and HOXB1

Dr. Patricia Rodier [62]has identified a link 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 patient [63].

Conciatori et al (2004) [64]has found an association of HOXA1 with increased head circumference. A number of studies have found no association with autism [65][66][67].

However, the possibility remains open that while single allelic variants of the HOXA1 gene are insufficient alone to trigger the developmental events in the embryo now associated with autistic spectrum conditions, Tischfield et al [68]published a paper which suggests that bexause 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 [69]alighted upon additional possibilities in this arena. Transgenic mouse studies including Rossel & Capecchi [70]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'.

Note that 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) [71]has found a strong association between this gene and autism. This is a recent finding that needs to be replicated.

• 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 [72][73].

• UBE3A

The UBE3A gene has been associated with Angelman syndrome. Samaco et al (2005) [74]suggests there's 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.

• Others

There is a large number of other candidate lociwhich either should be looked at or have been shown to be promising. Several genome-wide scans have been performed identifying markers across many chromosomes[75][76][77]. A few examples of loci that have been studied are the 17q21 region [78], the 3p24-26 locus [79], PTEN [80], 15q11-q13 [81], etc. Other possible candidates include:

• SLC6A2 (Social phobia)
• FMR1 (Fragile-X)
• 5-HT-1Dbeta (OCD)
• 7q11.23 (William's syndrome, language impairment)
• 4q34-35, 5q35.2-35.3, 17q25 (Tourette syndrome)
• 2q24.1-31.1 (Intelligence)
• 6p25.3-22.3 (Verbal IQ)
• 22q11.2 (Visio-Spatial IQ)

Proposed environmental triggers

Monozygotic twin studies show that genetic predisposition to autism has its limitations. For example, it would appear that about 40% of diagnosed individuals originally had a 50/50 chance of being considered high functioning. About 4% to 10% had a 50/50 chance of escaping a diagnosis altogether. This has led researchers to postulate that any number of environmental factors may influence the development of persons genetically predisposed to autism; and that by locating the environmental triggers involved it might be possible to find ways to improve the outcome of biologically autistic individuals.

But not everyone agrees regarding the magnitude and nature of environmental influence. Critics of environmental theories of autism point out the following:

• If environmental factors played a major role, significantly divergent findings between fraternal twin and sibling studies would be expected.
• Evaluation margin of error and temporary behavioral differences in twins should be taken into account.
• A minority of cases characterized as "autism" could be environmentally-caused phenocopiesof the genotype, and should not be called "autism" once identified.
• Developmental and behavioral differences have been observed in identical twins with conditions that have a well-established genetic etiology [82][83][84][85][86].
• Similar cognitive differences between identical twins in the general population have been observed. For example, heritability of a broad measure of IQis estimated to be 60%.
• Therefore, any environmental influence is not necessarily pathological and could be too complex or random to be either decyphered or realistically be put under control.

The search for environmental triggers has been mostly focused on trying to find a cause for a rapid increase in the reported prevalence of autism in recent decades. The prevalence increase would appear to implicate recent changes in human lifestyle, but there is considerable disagreement as to whether the number of cases is actually increasing.

A recent finding of an anomaly in the apparent prevalence of autism among the Amish[87] would seem to support the notion that modern lifestyle has to do with the prevalence increase. The Amish, however, are a very isolated community genetically as well, so this finding does not necessarily shed any light on heritability without further study. It should be stressed that the Amish finding is very preliminary.

Many of the environmental trigger theories are based on anecdotal accounts of regressive autismobserved after a particular occurrence, vaccination being the most popular one among parents.

Heavy metal toxicity

For more details on this topic, see Thimerosal.

Some parents and researchers have pointed out that heavy metal poisoning, particularly that involving mercury, results in symptoms similar to those of autism. They propose that one of the following could be the case:

• Mercury poisoning in children may be a phenocopyof autism.
• One of the liabilities of the autism genotypecould be markedly reduced tolerance to heavy metal toxicity.
• Mercury toxicity could simply amplify the symptoms of autism.

Some studies have implicated mercury and other metals used in dental fillingsas playing a role in the etiology of autism [88][89]. A theory that is very popular among parents is that vaccines that use thimerosalas a preservative are to blame for the prevalence increase in cases of autism.

Nevertheless, the link is inconclusive. Ip et al (2004) compared hair and blood mercury levels in autistic children with those of non-autistic controls, and found no causal relationship (although they did find a difference that is not significant statistically) [90]. Madsen et al (2003) found no reduction (and in fact, the opposite) in the prevalence of autism in Denmark after thimerosal was removed there.

Prenatal and perinatal factors

Individuals diagnosed with ASD have repeatedly been shown to have significantly higher incidence of prenatal and perinatal complications [91][92]. This link does not demonstrate a causal relationship, however. Researchers have suggested that birth complicatons are the result of genetic predisposition.

Stress

Some studies have shown that autistic children are affected by stressfulevents more than their non-autistic counterparts [93][94]. (But a subset of them seem to be less affected by psychosocial stress in particular [95]).

The occurrence of autistic withdrawal under stress was suggested in the 1970s [96]. More recently, the occurrence of "shutdowns" under social pressure has been recognized [97][98]. Catatonia, which may be the result of psychological trauma, has been noted for its similarities with autism.

A suggestive link can be drawn between stressand seizures[99] and between seizuresand regression[100].

Folic acid

The possibility that Folic acidcould be involved in the etiology of autism has been raised because increased supplementation overlaps with the reported increase in the incidence of autism in recent years [101]. Folic acid plays a role in the production and maintenance of new cells, including neurons. This hypothesis is only suggestive at this point, and does not appear in the scientific literature.

Parenting

For more details on this topic, see Refrigerator mother.

Since the 1950s up to the 1970s it was believed that autism was the result of the faulty environment provided by uncaring "refrigerator" mothers, a theory that went largely unchallenged by psychologistsat the time. This theory is discredited now, along with its main champion, Bruno Bettelheim.

The Folstein-Rutter (1977) twin study is credited with shifting the focus from psychological factors to genetics. But in retrospect, it did not prevent other environmental theories from arising.

It was also observed that many mothers of autistic children were very loving. In cases where social interaction was found to be impaired between mother and child, it has been proposed this is simply due to social deficits in the child. Today, parent-blame theories are considered offensive. Hence, this is a sensitive topic, perhaps a reason why it has not been studied in recent decades.

There has been a general drastic shift in the focus of psychiatry in recent history, from theories based on early childhood psychological trauma to genetic and other neurological causes for disorders. Additionally, comparisons of twins reared apart with those reared together have shown that the shared environment (i.e. the family) is not as influential as the non-shared environment.

This is not to say that parenting is irrelevant. Some case reports have shown that profound institutional privation can result in quasi-autistic symptoms [102]. Children genetically predisposed to autism are likely not immune to the effects of psychological privation, and in fact could be more sensitive to them. This also has some implications regarding instituionalization of autistic individuals, a practice still common today. The specific forms of institutional privation involved are unknown (though it is known that it is not nutritional privation). This information could pressumably shed some light on subtle ways to affect the outcome of autistic individuals.

See also

• Autism
• Heritability

External links

• FindArticles.com- 'Genetic Studies of Autism: From the 1970s into the Millennium', Michael Rutter, Journal of Abnormal Child Psychology, (February, 2000)
• NewScientist.com- 'Families share traits of autistic children', Helen Phillips, New Scientist (November 24, 2005)
• The California Autism Twin Study (CATS)

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It uses material from the http://en.wikipedia.org/wiki/Heritability+of+autism Wikipedia article Heritability of autism.