A critical discussion of the genetic contributions to the aetiology of autism.

‘Genetic contributions’ refers a branch of biology that deals with heredity and how much of a disorder is determined by genes.

Autism is a lifelong developmental disorder, characterised by impaired communication, imagination and socialisation. Leo Kanner (1943) first claimed that the characteristics of the children he studied were attributable to their parent’s lack of warmth and affection. This view led to the ‘refrigerator mother’ hypothesis which was based on the notion that ‘cold’ mothering styles lead to autism. However, genetic, environmental, and neuroanatomical findings have provided new scope and refuted these early findings (Goldstein & Reynolds, 2011). There is strong evidence for the genetic contributions to the aetiology of autism and autism has been recognized as being the neuropsychiatric disorder with the greatest genetic component. Therefore, this essay will discuss the role of genetics in the aetiology of autism, while also reviewing further contributions such as the neurological basis of autism and environmental factors, which should not be disregarded.

Autism was first described by Leo Kanner (1943) after he observed similar behaviour patterns in 11 children. He noticed a common theme of extreme aloneness from the beginning of life and an anxiously obsessive desire for the preservation of consistency. This led to the coining of the term ‘autism’ which was used to refer to the narrowing of relationships with people and the outside world – a narrowing so extreme that it excluded everything and everyone except the person’s own self (Joshi, Percy & Brown, 2003). It has been stated that the condition includes characteristics such as the inability to relate to people, failure to develop speech or abnormal non-communicative use of language, good cognitive potential with excellent rote memory and normal physical status. Other manifestations of these symptoms are sometimes associated with ‘Asperger Syndrome’, ‘Atypical Autism’, or ‘Pervasive Developmental Disorder’.

According to the DSM-IV-TR, autism is characterised by impairment to three behavioural domains – social interaction, language/communication/imaginative play, and range of interests and activities (Muhle, Trentacoste & Rapin, 2004). It has been found that males are three to four times more affected than females. While all children with autism are severely impaired in their social relationships, the severity and nature of cognitive impairment vary widely; therefore individual differences should be considered. The intellectual competence of children with autism ranges from profound mental deficiency to high intelligence. Autism was first described as being psychogenic in nature, suggesting that it stems from emotional or mental stress. However, the high incidence of mental deficiency and seizures lead to the rationale for autism having a biological basis (Trottier, Srivasrava & Walker, 1999).

Substantial support for the genetic basis of autism derives from twin studies. Twin studies aim to explore the similarities and differences of identical twins and non-identical twins. A condition with high heritability (usually over 50 per cent) is believed to have a strong genetic basis; therefore twin studies are of particular importance when establishing the role of genes in autism. It is known that dizygotic twins share 50 per cent of the genome, while the genome is shared completely in monozygotic twins (Froehlich-Santino et al., 2014). Epidemiological studies initially found that the risk of autism in the siblings of an autistic child is about three per cent, which is 50 times higher than the prevalence rate for the whole population. A British twin study found 36 per cent concordance for diagnosed autism in monozygotic twins, compared with no concordance in dizygotic twins (Folstein & Rutter, 1977). However, when assessed later using a broader look at cognitive and social abnormalities, the concordance for monozygotic twins increased to 82 per cent, and ten per cent for dizygotic twins (Trottier, Srivastava & Walker, 1999). This decrease in risk of monozygotic twins and dizygotic twins and siblings suggests that two or more genes may interact to contribute to autism susceptibility (Cook et al., 1998).

Further twin studies have found that there is a 60 per cent concordance rate for classical autism in monozygotic twins versus zero in dizygotic twins (Muhle, Trentacoste & Rapin, 2004). Another valid twin study found that the concordance rates in monozygotic twins were 70 per cent for autism and nine per cent for ASD, whereas the concordance rates in dizygotic twins were five per cent and ten per cent respectively (Sebat et al., 2010). Although these studies show that genetics play a major role in autism, it should be considered that errors in diagnosis of monozygocity are common and that social environment sharing by dizygotic items is equivalent to monozygotic twins. Therefore the environment should not be ignored. Family studies of autism indicate that a sibling’s chance of having autism is between two and eight per cent – much higher than that of the general population (Turkington & Anan, 2007). Family studies have also shown that first degree relatives of individuals with autism have an increased risk of autism compared with the general population. This further confirms the role of genetics in autism – it is more common in genetically similar individuals (Bolton et al., 1994).

A single gene or group of genes has not been specifically linked to autism and therefore, as it has been suggested, autism is polygenic with over 15 interacting genes involved (Risch et al., 1999). Autism is more complex than a simple one-gene disorder and has several overlapping genetic mechanisms (Bartlett, Gharana, Millonig & Brzustowicz, 2005). Cytogenetic studies, which investigate the structure and function of cells (especially chromosomes) have shed light on large chromosomal areas with additional identification of specific genes requiring further examination. It has been suggested that abnormalities in region 15q11-13 account for one to two per cent of the cases of autism. Human chromosome 15a11-13 is a complex locus containing genes and a cluster of three GABA receptor subunit (GABR) genes: GABRB3, GABRA5 and GABRG3. It has been suggested that deletion or duplication of 15q11-13 genes occurs in human neuro-developmental disorders including autism (Hogart et al., 2007). To further investigate this assumption, a study looked at whether patients with 15q11-13 duplication indicated an autistic disorder/susceptibility locus in the region. This study found linkage disequilibrium between GABRB3 155CA-2 and autistic disorder. This further supports the genetic contribution to the aetiology of autism as it shows an association of genes at two or more loci that descend from single ancestral chromosomes (Cook et al., 1998). However, this is only a small part of the puzzle, as there are many other genetic components involved.

Supplementary cytogenetic research has explored the role of the UBE3A gene by focusing on deficiencies in this gene. It has been found that the UBE3A gene involved in targeting proteins for degradation within cells and the GABRB3 that directs the production of enzyme ubiquitin protein ligase E3A (which help to regulate neuronal activity) are involved in autism (Goldstein & Reynolds, 2011). In order to test the 15q11-13 duplication underlying autism behavioural traits, a study tripled the dose of ubiquitin protein ligase UBE3A in mice and found symptoms such as defective social interaction, impaired communication and increased repetitive stereotypical behaviour. This further supports the notion that UBE3A gene dosage may contribute to the autism traits in the presence of 15q11-13 duplications (Smith et al., 2011). However, the findings of research using animals and applied to human behaviour may not be generalizable.

Linkage studies have been used to identify particular genes that are passed from parent to child, and therefore contribute to the underpinnings of the genetic contributions of autism. The regions 17q11-21, 7q and 2q24-31 have been found to be of linkage (Golstein & Reynolds, 2011). Genetic linkage studies have found that susceptibility genes may reside in chromosomes 2q and 7q (Buxbaum et al., 2001). To determine whether the region on chromosome 7q21-32 was significant, it was tested in a two stage genome search for susceptibility loci on 87 affected pairs plus 12 non-affected relative pairs. The study found that regions on six chromosomes were identified; however, a region on chromosome 7q was the most significant (International Molecular Genetic Study of Autism Consortium, 1998). Another study provided further evidence for the presence of the autistic disorder locus on chromosome 7q, as well as providing new evidence that this locus may be paternally expressed (Ashley- Kotch, 1999).

Moreover, autism candidate genes have also been identified by looking at genetic syndromes which co-occur with ASD. Influential work has found two disorders that share the same symptoms as autism (Fragile X Syndrome and Rett disorder) are typically caused by genes in the X chromosome, suggesting that this may also play a role in autism. Humans typically have 46 chromosomes in every cell (23 maternal and 23 paternal). After fertilization, the two individual sets form 23 pairs of chromosomes. The chromosomes in the 23rd pair are known as the sex determining chromosomes. It is well known that typically, males have one X and one Y chromosome, and females have two X chromosomes. The fact that prevalence of autism is higher in males supports the notion that the disorder involves genes on the X chromosome; the second X chromosome in females may allow the second X chromosome to function normally, while males would not be able to do so (Turkington & Anan, 2007). However, the male-to-male transmission and chromosomal abnormalities from maternal transmission, making it unlikely that autism is a prominently X-lined disorder, should be considered (Goldstein & Reynolds, 2011).

Although twin studies provide support the genetic basis of autism, a recent study refuted this finding (Hallmayer et al., 2011). The study used a large sample of twins and found a concordance of 0.6 for monozygotic twins and 0.25 for dizygotic twins, which suggests that environmental factors play a role in autism. These environmental factors can include prenatal infection, perinatal insults, viral infections, heavy metals, mercury, pesticides, and childhood vaccines (Grabrucker, 2012). It has also been proposed that failure in early foetal brain development has been linked to higher risks of autism and attention has been drawn to offspring exposed to viral/bacterial infections in utero (Arnt et al., 2005). These infections include prenatal influenza, rubella, and cytomegalovirus infections. However, it needs to be considered that the outcome of the exposure to one of these prenatal virus infections depends on factors such as the immune status of the mother, susceptibility of the maternal and foetal host, the developmental stage of the foetus, and the degree of exposure of the foetus to the virus (Blattner, 1974). Recently there has been interest in postnatal risk factors for autism such as the measles-mumps-rubella (MMR). There is concern that this vaccine is responsible for the huge rise in the rate of diagnosed ASD (Rutter, 2005). This idea was prompted by a vaccine-caused gut disorder, caused by a leakage of protein products into the blood stream, which caused a regressive form of autism. These environmental factors should not be overlooked as they alone may not lead to autism, but may act as triggers for the development of the disorder.

Neural mechanisms have been identified as contributing to the aetiology of autism. It has been proposed that there may be abnormal development of the neuronal arrangement in the mini columnar structures of the brain. A study investigated the idea of increased cell packing density to explain cerebral enlargement in brains of individuals with autism compared to control subjects. This study revealed that the autism group showed a different organization with more mini columns and reduced cells within the columns in the frontal and temporal lobes (Casanova, Buxhoeveden, Switala, & Roy, 2002). Although this finding has been validated by further studies in the area, it may be difficult to establish whether the adjusted mini columnar arrangements cause autism, or whether they are an effect of autism. Also, it is known that individuals with autism have difficulty with emotion and face processing as part of the symptom profile, which the amygdala is involved in. An fMRI study was conducted that involved people judging from the expression in another person’s eyes what that person was thinking or feeling. It was found that individuals with autism did not activate the amygdala when making these judgements, whereas individuals without autism activated the amygdala. This led researchers to suggest that the amygdala is one of the neural regions that are abnormal in autism (Baron-Cohen et al., 2000). Although the role of the amygdala in autism seems plausible, other neural regions may also play a role. Further research in the area could test whether the amygdala in autism can be activated to normal levels using various cognitive tasks to establish the severity of amygdala inactivation in autistic individuals.

Furthermore, studies have shed light on the involvement of the neurotransmitter serotonin in autism (Chungani, 2002) and genetic factors affecting serotonin metabolism (Williams et al., 2003). There is evidence that serotonin may be involved due to the part it plays in neurogenesis – the formation of new neurons in the brain. Serotonin levels are normally higher in children, and begin to decline during puberty. Many individuals with autism have elevated levels of serotonin in blood platelets, suggesting that they may have a defect in the gene that produces serotonin transporters. Evidence for this comes from studies which have shown a 30 – 50 per cent increase in serotonin levels in individuals with autism (Schain & Freedman, 1961). It is known that serotonin is very important during development, and if changed, it may contribute to the behavioural characteristics of autism. However, more research needs to be conducted in order to form a strong basis for this phenomenon. It may be beneficial to undertake further research into serotonin transporter genes that may be inherited by individuals with autism (Muhle, Trentacoste & Raplin, 2004).

In conclusion, there is a strong evidence to support the contribution of genetics to the aetiology of autism. The highly influential twin studies show this as concordance rates seem to be higher for monozygotic twins who have an identical genetic makeup. From the research/evidence discussed, it is known that autism is a complex polygenetic disorder, and on-going research is providing more information on the genes involved. However, the environment seems to be more important than previously thought. Therefore, It may be beneficial to consider a gene–environment interaction whereby each is essential but neither is sufficient on its own to cause autism. Environmental influences begin in utero and may contribute to alterations in brain and trigger the disorder. Some researchers suggest that a substantial proportion of autism cases could be due to multiple genes interacting with one or more environmental factors (Hertz-Picciotto et al., 2006). Another reason for considering an interactionist approach of environment–genes, or multiple gene interactions is due to autism being a syndrome of complex genetic traits, rather than a single gene locus (London, 2000). There is no doubt about the genetic basis of autism. However the whole cluster/spectrum of autism makes it challenging to establish a single cause/gene. It may be beneficial to understand how specific genes affect the structure, chemistry, and behaviour in individuals, while also understanding the environmental triggers and brain regions that may be of importance when considering the aetiology of autism.

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