Heritability of autism: Encyclopedia II - Heritability of autism - Genetic predisposition

Heritability of autism - 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].

Heritability of autism - Twin studies

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 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, 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.

• 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 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."

Heritability of autism - 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 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."

Heritability of autism - 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 syndrome as 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 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.

• 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-IV criteria. 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.

Heritability of autism - 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.

Heritability of autism - 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 syndrome and tuberous sclerosis are well-known causes of autism-like symptoms.

Heritability of autism - 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 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.

A Mendelian model tries 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.

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 alleles would 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-locus hypothesis 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.

In reality alleles are not passed down at random and genetic expression is not clear-cut. Sometimes alleles have incomplete dominance or codominance. Some traits are linked on the same chromosome.

A number of epigenetic models of autism have been proposed (e.g. [42]) as have several genetic imprinting models (e.g. [43]).

Heritability of 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 inconclussive, 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 [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

GABA is the primary inhibitory neurotransmitter of 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 savant skills [49].

• Engrailed 2 (EN2)

Engrailed 2 is believed to be associated with cerebellar development. 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 syndrome with this locus [52][53]. The most prominent markers are in the vicinity of D3S3715 and D3S3037 [54].

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

• 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 [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].

• PRKCB1

Philippi et al (2005) [68] 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 [69][70].

• UBE3A

The UBE3A gene has been associated with Angelman syndrome. Samaco et al (2005) [71] 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 loci which either should be looked at or have been shown to be promising. Several genome-wide scans have been performed identifying markers across many chromosomes [72][73][74]. A few examples of loci that have been studied are the 17q21 region [75], the 3p24-26 locus [76], PTEN [77], 15q11-q13 [78], 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)

Adapted from the Wikipedia article "Genetic predisposition", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki