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Peter Szatmari, MD

Arch Gen Psychiatry. 2011;68(11):1091-1092. doi:10.1001/archgenpsychiatry.2011.99

The year 1977 marked an important milestone in the history of autism. In this year, the first twin study in autism was published by Folstein and Rutter¹; it demonstrated a striking difference in concordance rates between monozygous (MZ) and dyzgyous (DZ) twins. The studies that followed reported even higher MZ concordance rates, up to 90%, for a broader phenotype resembling what is currently labeled as autism spectrum disorder (ASD)^2-4 and DZ concordance rates at or close to 0%. This resulted in heritability estimates greater than 90%, suggesting that almost all of the variance in phenotypic expression could be attributed to inherited genetic factors.

There was an important need to revisit those early heritability estimates given that there have been significant improvements in the diagnosis of ASD and that the prevalence rates on which the original models were based are now much greater. In addition, the fact that the concordance for DZ twins was so close to 0% has always been a puzzling finding largely ascribed to the imprecision of the estimates. Family studies of nontwin siblings have suggested that the recurrence risk is closer to 5%, or even 10%, once stoppage rules are taken into account.⁵ Even so, based on these twin studies, ASD was often described as the most heritable of psychiatric disorders. It must be admitted, though, that the field has been frustrated by the difficulty in identifying the specific inherited genetic mechanisms for the etiology of ASD. Even the recent genome-wide association studies have not given us any smoking guns, and the top hits have been difficult to replicate.

The autism field can now join the chorus and ask, "Where did all the heritability go?" We now appear to have an answer, at least in part: those original estimates were inflated. The California Twin Study has shown that both the DZ concordance rates are higher and the MZ rates are lower than previously believed. The results provided by Hallmayer et al⁶ must be taken very seriously. The study has many strengths, including a large sample size, close attention to ascertainment, the use of gold-standard diagnostic instruments, and sophisticated statistical modeling to parcel out genetic and environmental influences. The high DZ concordance rate is consistent with estimates reported from the Baby Siblings Research Consortium.⁷ In these studies, infant siblings of children with ASD are followed up from birth to age 36 months so that risk can be calculated in a prospective fashion. The latest report from the Baby Siblings Research Consortium suggests that the risk is upwards of 20%, which is slightly less than the DZ rate provided by Hallmayer and colleagues (31%-36% for ASD). The confidence intervals of the estimates overlap to be sure, but this may also suggest potential ascertainment bias for concordant as opposed to nonconcordant DZ twin pairs or that twinning itself is a risk factor for ASD.

Given that the prevalence of the disorder has increased and that DZ concordance rates needed to increase from those reported in the previous twin studies, the remaining puzzling finding is an MZ concordance rate at the low end of those reported.^2-4 One must ask whether there was any bias artificially reducing concordance in the study by Hallmayer and colleagues. One possibility is missing data, which are substantial. Another possibility is differential misclassification. It is not inconceivable that parents are more likely to rate MZ twins with a disability as more dissimilar than DZ twins. There may be an unconscious effort on their part to see one twin as less affected than the other. Such reporting effects, known as sibling deidentification, have been reported for twin studies of temperament.⁸ It would be extremely interesting to see whether concordance rates differ by instrument, ie, the Autism Diagnostic Interview–Revised, which is based on parental report, vs the Autism Diagnostic Observation Schedule, which is based on an independent observer. If the sensitivity of the measurement tool is less in MZ twins than in DZ twins, a smaller difference in observed concordance rates would be expected compared with true concordance rates based on no measurement error.

A third threat to the validity of the findings is that twinning itself might be a risk factor for ASD, so that the heritability estimates generated would not be generalizable to the population of nontwin children with ASD. There may be some factor associated with twinning such as maternal age, coming from a monochoreonic placenta, prematurity, or in vitro fertilization that could place twins at risk for ASD. There is in fact some evidence that twins have a higher rate of autism than nontwins,⁹ but further work needs to be undertaken to provide better evidence.

These results should not stop the ongoing search for genetic variants that cause ASD. The results of Hallmayer and colleagues clearly confirm the importance of genes to the etiology of ASD. However, these new findings should caution us against the tendency to rapidly embrace the latest technology. As a field, we are perhaps prone to move one foot forward without ensuring that all other feet are moving at the same rate. Perhaps the field was too ready to abandon the tools of standard genetic epidemiology (family, twin, and linkage studies). We should realize, though, that heritability is a poor indication of the ease with which inherited genetic variants can be discovered.¹⁰ After all, the importance of discovering those variants is not so much to cumulatively explain the variance in autism but rather to point to potential biochemical pathways that could be interrupted.

The recent switch from an almost exclusive focus on inherited genes controlling neurotransmitters to rare de novo copy number variants that might affect genes regulating synaptic and axonal development has been an extremely important advance. However, it is true that the field will have to reassess the extent to which these rare de novo variants can explain a large proportion of cases because such models would predict much higher MZ and much lower DZ concordance rates than are reported by Hallmayer and colleagues.

The exciting news is that research on shared environmental mechanisms for the etiology of ASD has received renewed impetus. Perhaps ASD can be considered, at least in part, a disorder of fetal programming.¹¹ There is in fact evidence that certain risk factors that affect the maternal fetal environment may place the fetus at increased risk for ASD. Clearly a renewed effort needs to be undertaken through the use of well-designed community-based epidemiologic studies. Many potential risk factors have been and need to be investigated, including parental age, maternal genotype, maternal-fetal immunoreactivity, in vitro fertilization, maternal ingestion of drugs, toxic chemicals in the environment during pregnancy, and maternal illnesses during pregnancy such as maternal diabetes or infections.

The fetal programming hypothesis of ASD could uncover environmental risk factors that affect the fetal environment and interact with genetic variants. Some of these factors may be modifiable and could possibly reduce the risk of ASD in the long term. Whatever happens in the future, the finding by Hallmayer and colleagues is an extraordinarily important one and has the potential to shift autism research into a new field of study in much the same way that the original twin study by Folstein and Rutter accomplished back in 1977.

AUTHOR INFORMATION
Correspondence: Dr P. Szatmari, Offord Centre for Child Studies, McMaster University, Hamilton Health Sciences, Hamilton, ON L8N 3Z5, Canada (szatmar{at}mcmaster.ca).

Published Online: July 5, 2011. doi:10.1001/archgenpsychiatry.2011.99

Financial Disclosure: None reported.

Author Affiliation: Offord Centre for Child Studies, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.

REFERENCES
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Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism
Joachim Hallmayer, Sue Cleveland, Andrea Torres, Jennifer Phillips, Brianne Cohen, Tiffany Torigoe, Janet Miller, Angie Fedele, Jack Collins, Karen Smith, Linda Lotspeich, Lisa A. Croen, Sally Ozonoff, Clara Lajonchere, Judith K. Grether, and Neil Risch
Arch Gen Psychiatry. 2011;68(11):1095-1102.
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