Journal of Intellectual Disability Research 231 pp – Blackwell Science, LtdOxford, UKJIRJournal of Intellectual Disability Research-Blackwell Publishing Ltd, 4231238Original ArticleAetiology of autismM. Rutter invited review Aetiology of autism: findings and questions* M. Rutter SGDP Centre, Institute of Psychiatry, Denmark Hill, London, UK Abstract Keywords autism spectrum disorders, epidemiology, genetic influences, incidence, measles- Background Although there is good evidence that mumps-rubella vaccine autism is a multifactorial disorder, an adequate understanding of the genetic and non-genetic causes has yet to be achieved. Introduction Methods Empirical research findings and concep- tual reviews are reviewed with respect to evidence on Before turning to what is known on the aetiology of possible causal influences. autism, it is necessary to note that, over the last few Results Much the strongest evidence concerns the decades, there have been important changes in the importance of susceptibility genes, but such genes diagnostic concept. During the s, it was gener- have yet to be identified. Specific somatic conditions ally assumed that autism was a rare, seriously hand- (such as tuberous sclerosis and the fragile X anomaly) icapping disorder, usually associated with intellectual account for a small proportion of cases. Over recent disability (ID), constituting a condition that was decades there has been a major rise in the rate of qualitatively distinct from variations in social and diagnosed autism. The main explanation for this rise communicative competence within the normal range. is to be found in better ascertainment and a broad- Both epidemiological and genetic research findings ening of the diagnostic concept. Nevertheless, some have forced a change in concept as a result of the degree of true rise cannot be firmly excluded. How- evidence that autistic-like abnormalities can and do ever, the epidemiological evidence on the main occur in individuals of normal intelligence (see Rut- hypothesized environmental explanation, namely the ter ). There appears to be a broad spectrum of measles-mumps-rubella vaccine, is consistently disorders that are closely similar in quality but milder negative. in some respects and often occurring in individuals Conclusion Progress on the elucidation of the causes of normal intelligence. Even further outside the core of autism will be crucially dependent on the combi- is a group of much milder, but apparently similar, nation of epidemiology with more basic science lab- conditions that have come to be termed the ‘broader oratory studies. phenotype’. They are found in some one in five first- degree relatives of individuals with autism. But outside even this broad spectrum there are Correspondence: Michael Rutter, PO , SGDP Centre, Institute other disorders that may sometimes be confused with of Psychiatry, De Crespigny Park, Denmark Hill, London SE AF, autism. First, there is the well-defined condition UK. Tel. (e-mail: [email protected]). *Based on a paper given at the IASSID Conference in Montpellier, called Rett syndrome after the physician who first France, June . described it (Rett ; Hagberg et al. ); it has © Blackwell Publishing Ltd Journal of Intellectual Disability Research 232 M. Rutter • Aetiology of autism been shown to be a result, in almost all cases, of a population, it is very high. Putting together the twin mutant gene on the X chromosome. Its downward and family findings, the figures indicate that it is likely clinical course and neurological features mark it out that there are somewhere between and suscep- as different from autism but many of those who suffer tibility genes for autism that act synergistically. The from this condition go through a phase that involves reason why most siblings do not have ASD, despite social impairments superficially similar to autism. In the high heritability, is that they have only some of addition, there are several less well-defined quasi- the relevant genes. autistic patterns, similar to autism in many respects, but different in some features. These include the pat- terns seen in some congenitally blind children (Hob- Susceptibility genes for autism son et al. ) and some children reared in seriously A major growth area in psychiatric genetics as applied depriving institutions (Rutter et al. ); in some to ASD concerns the search, using linkage and young adults who had a serious developmental disor- association strategies, to identify susceptibility der of receptive language when young (Clegg et al. genes (Rutter ). There are very promising, par- ; Howlin et al. ), and in some children with tially replicated, findings with respect to loci on a semantic pragmatic language disorder (Bishop et al. chromosomes and , as well as leads on other ; Bishop ). In the remainder of this paper I chromosome locations. It may be anticipated, with will confine attention to what is known about the some confidence, that the actual susceptibility genes aetiology of autism and the more closely associated will be determined during the next decade, if not autism spectrum disorders (ASD), and for the most rather earlier than that. Linkage strategies study the part will not deal with either the broader phenotype degree to which affected members in the same family or these varied more atypical patterns. show coinheritance of the same genetic loci on par- ticular chromosomes. Association strategies, by con- trast, determine whether individuals with ASD differ Susceptibility genes for autism from controls in their pattern of allelic variations of spectrum disorders specific genes. That is, each person inherits one out of several possible allelic copies of each gene. Some Much the best-established risk factor for ASD is copies will carry risk whereas others will not. Note genetic liability (Rutter ). In idiopathic cases that the susceptibility genes may well turn out to be without a known medical cause, twin studies have common genes that, on their own, do not directly shown a concordance rate in monozygotic (identical) cause disease – rather than rare pathogenic muta- twin pairs of about % as compared with a rate of tions. Although it may be expected that the identifi- % in dizygotic (fraternal) pairs. Taken together with cation of susceptibility genes will be enormously the population base rate for autism, this implies that helpful in shaping the biological research that will the heritability or underlying genetic liability is about determine the neural basis of autism, it is much less % – the highest figure among all multifactorial likely that the genes themselves will be of much prac- child psychiatric disorders. However, the twin data tical utility in terms of either screening or diagnosis. also show that the genetic liability extends well beyond the traditional core diagnosis of autism to include a wider spectrum of autistic-like disorders Single gene conditions including the broader phenotype. In other words, in twin pairs discordant for core autism, the monozy- The only single gene condition with an established gotic concordance for the broader phenotype far association with ASD is tuberous sclerosis (Smalley exceeds the dizygotic concordance. ). The best estimates suggest that this is found Family studies tell a similar story. The rate of ASD in about % to % of cases of ASD (Harrison & in the siblings of individuals with autism is about % Bolton ). Although the association with ASD is – a rate many times higher than the rate of about well established, its meaning in terms of the causal .% in the general population. The rate of % seems mechanisms that are involved is less well understood. low in absolute terms but, relative to the general It is probably important that the association with © Blackwell Publishing Ltd, Journal of Intellectual Disability Research , – Journal of Intellectual Disability Research 233 M. Rutter • Aetiology of autism ASD is particularly marked only when tuberous scle- Medical conditions and autism rosis is associated with severe ID, severe epilepsy and There have been various debates in the literature the location of tubers in the temporal lobe (Bolton concerning the frequency with which ASD are asso- et al. ). In other words, the implication is that ciated with definite diagnosable medical conditions the causal pathway may involve the type and location that are likely to have been implicated in the causal of the pathophysiology of brain disturbance deriving processes (Rutter et al. ; Gillberg & Coleman from tuberous sclerosis, rather than from anything ). One of the major difficulties in coming to a directly associated with the genes on chromosome specific figure concerns the major extent to which and chromosome that give rise to tuberous findings are likely to be influenced by both the nature sclerosis. of the samples investigated and the thoroughness of the medical investigations undertaken. However, a reasonable estimate would be that something in the Chromosome anomalies order of % of individuals with ASD has some potentially relevant identifiable somatic disease or Most of the evidence on connections between chro- disorder. This means that an appropriately thorough mosome anomalies and ASD come from isolated medical assessment is essential in all cases. The gen- case reports (Gillberg ). These are of little use eral consensus would be that this should include care- in testing causal hypotheses and greater reliance ful medical examination, including the use of Wood’s needs to be placed on systematic studies of either