Research Points to Shared Environmental Factors for Autism and ASD

While the decades-long search for genetic causes of autism and autism spectrum disorder (ASD) continues, recent studies looking at twins with autism and at possible causes of the disorders indicate that environmental (non-genetic) factors may play an even larger role than genetics.

In the California Autism Twin Study (CATS)-reportedly the largest population-based twin study of autism to date using contemporary standards for diagnosis-researchers and scientists from 6 academic/research institutions found that shared environmental factors explain about 55% of the liability to autism and 58% of the liability to ASD. This compares with a genetics heritability of 37% for autism and 38% for ASD).¹

For the study, twins in which at least 1 twin had a diagnosis of autism or ASD were identified from records of the California Department of Developmental Services (CDDS). Excluded were those with probands of neurogenetic conditions that might account for autism, such as fragile X syndrome or neurofibromatosis.

“What makes our study so different is that we directly assessed the twins,” said Joachim Hallmayer, MD, Associate Professor of Psychiatry and Behavioral Science at Stanford University and principal investigator/director of the study.

Rather than relying on the CDDS reports for diagnosis, the study investigators performed their own evaluations using structured diagnostic as-sessments (Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule), along with parental interviews.

The study also determined twin status through genetic testing-something that was not available when the first twin studies on autism were conducted many years ago.

Funded by grants from the NIMH and Autism Speaks, the study, according to Hallmayer, was undertaken in part because important data were missing about the true autism concordance rate in dizygotic twins.

Three twin studies published between 1977 and 1995, which provided the main body of knowledge on heritability of autism, showed a concordance rate of 72% for a total of 36 monozygotic pairs and a concordance rate of 0% for 30 dizygotic pairs.

“There was grave doubt that the zero rate of concordance in dizygotic twins was correct,” Hallmayer said.

“Our study,” the investigators reported, “provides evidence that the rate of concordance in dizygotic twins may have been seriously un­derestimated in previous studies and the influence of genetic factors on the susceptibility to develop autism overestimated.”

Another aim of the study, Hallmayer told Psychiatric Times, was to further examine the severity of inherited autism. “For example, what happens if one twin is nonverbal, is the other twin nonverbal as well? We need a much more refined analysis of the phenotype and how it is inherited.”

The study included data from 54 monozygotic twins (45 male, 9 female) and 138 dizygotic twins (45 male, 13 female, and 80 sex discordant). Considered demographic factors included twin types, sex, birth weights, and gestational ages, as well as parental ages, education, and ethnicity. The monozygotic twins were slightly older and had shorter gestation periods. The mothers of the dizygotic twins were older than the mothers of the monozygotic twins, “consistent with the known increase in dizygotic twinning with maternal age, and more likely to be white and non-Hispanic,” the investigators reported.

To expand on the recent twins study, Hallmayer said, the next step should include siblings, so as to collect information on the entire family.

“We need to see how the sibling rate for autism or ASD rate compares with the dizygotic rate,” he said.

“The risk of siblings being affected by ASD is higher than we previously thought,” Hallmayer said. “We may be talking about some other forms of autism that we have overlooked before.”

The recently published Baby Siblings Research Consortium study, which used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD, found that 18.7% of the infants developed ASD.²

Discussing the relevance of the twins and sibling studies for psychiatrists, Hallmayer said the twins study demonstrated that autism is as etiologically complex as schizophrenia, bipolar disorder, and major depression. Regarding the sibling research, he recommended that psychiatrists refer parents of a child with autism or ASD who are contemplating another pregnancy to very good genetics counselors “so they know what the risks are.”

Shared environment

Evidence is accumulating that overt symptoms of autism emerge around the end of the first year of life. Because prenatal and early postnatal environments are shared between twins, the twin study investigators hypothesized that shared environmental factors might include parental age, low birth weight, multiple births, and maternal infections during pregnancy.

On the basis of the twins and baby siblings studies, Hallmayer speculated that the shared environmental factors, such as autoimmune factors in the mother, might be ones that affect the development of the child in the womb.

One of Hallmayer’s coauthors on the twin pairs with autism study was Lisa Croen, PhD, Senior Research Scientist with Kaiser Permanente Northern California and Director of the Kaiser Permanente Autism Research Program. Recently, she was first author on a study that examined whether exposure to antidepressants in early pregnancy may increase the risk of ASD.³

The population-based study involved 298 children with ASD and their mothers and 1507 randomly selected control children and their mothers drawn from the Kaiser Permanente Medical Care Program in Northern California.

“We found an approximately 2-fold increased risk of ASD associated with treatment with SSRIs of the mother during the year before delivery and an approximately 3-fold increased risk associated with treatment during the first trimester, independent of indication,” the investigators reported. “Additionally, we observed no increase in ASD risk associated with a history of mental disorders after controlling for SSRI use during pregnancy.”

“This is the first study to ever establish this association, and it has to be treated with a great deal of caution,” Croen said. “It has to be replicated before we can say there is a causal connection. And we know there is a risk to the mother of not being treated for depression if she’s depressed, so the risk to the baby really has to be balanced with the potential risks of not treating the mom for depression. . . . We are not advocating that women stop taking their medication during pregnancy. It is really a decision that has to be made between the patient and the provider as to what’s best.”

Replication

Some efforts are under way that will facilitate replication and extension of the antidepressant study, according to Croen.

One is the Study to Explore Early Development (SEED), a national, multisite, case-control, large, epidemiological study funded by the CDC. Croen is one of the site investigators.

“We have very comprehensive information on all sorts of things in that study, including medication use and illnesses during pregnancy and a very large sample size (more than 3500 children and their parents). So that’s one opportunity to try and replicate these findings,” she said.

Recruitment for phase 1 of the SEED study is complete, Croen said, and investigators are beginning to analyze the data. The CDC has funded a second phase of the study that will involve recruitment and data collection for a new cohort of children.

Croen also is a principal investigator on the Early Autism Risk Longitudinal Investigation (EARLI)-a prospective cohort study in which women with 1 or more children already affected by ASD are being followed.

“We are following subsequent pregnancies of those women through the pregnancy and early years of their new baby’s life,” Croen said, adding that enrollment is about 30% complete. “In that study, we have very comprehensive data collection during pregnancies, including illnesses and medication use, and then we will have the outcome of the babies.”

In both studies, Croen said investigators are obtaining biological samples, so they “have the ability to look at genetic factors in combination with nongenetic factors, such as medication use or illness.”

When the data are ready, Croen said, both studies will have an op­portunity to examine the question of SSRI use and autism. She is also planning a study within the Kaiser system to examine the issue in more depth with an enhanced sample size.

Another medication class Croen and colleagues studied recently was β₂-adrenergic receptor agonists (B2AR agonists) and the risk of ASD.⁴

Some reports indicate “that these types of medications with these properties have an effect on neurodevelopment and yield the kinds of abnormalities in brain and behavior that are represented by autism,” Croen said.

In a recently reported study, Croen and colleagues found that exposure to B2AR agonists other than terbutaline (Brethine, Bricanyl) was not associated with an increased risk of ASDs. But terbutaline exposure for more than 2 days (usually between 10 and 12 days) during the third trimester was associated with more than a 4-fold increased risk of ASDs, independent of indication.

“A very small percentage of women had that amount of exposure, so the statistical significance of that association was very marginal,” Croen said.

Aware of a possible association between infertility, fertility treatments, and autism, Croen said she and others are preparing a paper that examines specific medications women take when undergoing fertility treatments and the risk of autism.

Evidence has linked various types of maternal immune activation and dysregulation to behavioral disorders, including ASD.

Croen and colleagues⁵ published a paper on maternal autoimmune diseases, asthma, and allergies. “We found a significant association between maternal asthma and allergy during pregnancy and autism in their kids,” she said. “Also, one of the autoimmune diseases-psoriasis-was significantly associated with a modestly increased risk for autism.”

Croen is also the principal investigator of the Early Markers for Autism (EMA) study, designed to evaluate biological markers of susceptibility and exposure in archived maternal mid-pregnancy and neonatal blood specimens from the same mother-baby pairs.

In the past few years, researchers have used those blood samples to research possible immunological connections for ASD.^6,7

Much of the future of research into autism and ASD, Croen said, depends on funding through public-private partnerships and donations from financial “angels” and referrals from the medical community.

“For success of these studies,” she said, “it is important that psychiatrists and other physicians encourage patients and families to participate.”

References:

References

1.

Hallmayer J, Cleveland S, Torres A, et al. Genetic heritability and shared environmental factors among twin pairs with autism.

Arch Gen Psychiatry

. 2011;68:1095-1102.

2.

Ozonoff S, Young GS, Carter A, et al. Recurrence risk for autism spectrum disorders: a baby siblings research consortium study.

Pediatrics.

2011 Aug 15; [Epub ahead of print].

3.

Croen LA, Grether JK, Yoshida CK, et al. Anti­depressant use during pregnancy and childhood autism spectrum disorders.

Arch Gen Psychiatry

. 2011;68:1104-1112.

4.

Croen LA, Connors SL, Matevia M, et al. Prenatal exposure to β2-adrenergic receptor agonists and risk of autism spectrum disorders.

J Neurodev Disord.

2011;3:307-315.

5.

Croen LA, Grether JK, Yoshida CK, et al. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study.

Arch Pediatr Adolesc Med.

2005;159:151-157.

6.

Croen LA, Goines P, Braunschweig D, et al. Brain-derived neurotrophic factor and autism: maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) Study.

Autism Res

. 2008;1:130-137.

7.

Goines PE, Croen LA, Braunschweig D, et al. Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: a case-control study.

Mol Autism

. 2011;2:13.