Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism

18 Jul

The results of the long-awaited California Autism Twin Study (CATS) have been published. The article, Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism appears in the Archives of General Psychiatry and is open-access (i.e. free). The study set out “To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment.”

The basic idea of a twin study is fairly straighforward: “identical” (or monozygotic, MZ) twins share 100% of their DNA, “fraternal” (dizygotic, or DZ) twins share about 50% of their DNA. If a condition is purely genetic, identical twins will both have the condition or not have the condition. The percentage of twins with a condition is called concordance. High concordance implies a highly genetic condition.

Early twin studies showed a high concordance. These studies were relatively small. The first study, Infantile autism: a genetic study of 21 twin pairs, was published in 1977 and included, as you might guess, only 21 twin pairs. Of these, 10 DZ and 11 MZ twins. There were three twin studies which made up the main body of knowledge suggesting a strong heritability of autism, including a total of 56 pairs.

The California Twin study sought to take a much closer look. First by including a much greater number of twin pairs, and second by including modern diagnostic methods. They used the California Department of Developmental Services as a resource to identify twin pairs with at least one autistic. The CDDS database has advantages and disadvantages. First, the database is large and covers fairly diverse state. This is important when you consider that (a) only about 1% of the population is autistic and (2) only about 3.2% of the population are twins. That means about 1 in 3000 are twins+autistic.

The disadvantages of the CDDS as a resource include the fact that not everyone with an ASD qualifies for services or is correctly classified. Of those who qualify, inclusion in the CDDS is voluntary. Technically, the CDDS serves only those with autistic disorder or those in the “fifth category” which includes “…disabling conditions found to be closely related to mental retardation or requiring treatment similar to that required for individuals with mental retardation.” This would limit the ability to identify ASD concordance. For example, twins who both have Asperger syndrome.

One major strength of the study was the use of clinical assessments plus parent interviews for diagnosis. They did not rely upon the CDDS reports for diagnoses. Also, the study determined twin status (MZ or DZ) through genetic testing, something which wasn’t available when the first twin studies were performed.

Here is the abstract for the study:

Context Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins.

Objective To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment.

Design, Setting, and Participants Twin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004 were identified through the California Department of Developmental Services.

Main Outcome Measures Structured diagnostic assessments (Autism Diagnostic Interview–Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD).

Results For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD).

Conclusion Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.

The concordance values are 77% for male MZ twins and 50% for female MZ twins. These values are high. But the heritability estimates are influenced not just by the MZ twin concordance, but by the difference between MZ and DZ concordance. Consider if 100% of “identical” twins had a condition. This doesn’t necessarily mean that the condition is fully caused by hertiablity if, say, 100% of the “fraternal” twins also had the condition. In the California Twin study, DZ concordance values were relatively high (31% for males and 36% for females).

Based on these values, the authors calculate that shared environment accounts for 55% of the risk of autism and 37% for genetic heritability. There are big “error bars” (or confidence intervals) for the concordance and heritablity values. It is worth noting that the concordance values here are similar to those reported recently by Bearman’s team at Columbia (40-50% pairwise concordance for MZ twins. This study also used the CDDS as a resource, but did not use clinical assessments) and Goldsmith’s group at the University of Wisconsin (43% pairwise concordance). These studies also concluded that genetic heritability was lower than previously thought.

The authors concluded their paper:

Our study 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. Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes. The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research paradigms. Increasingly, evidence is accumulating that overt symptoms of autism emerge around the end of the first year of life. Because the prenatal environment and early postnatal environment are shared between twin individuals, we hypothesize that at least some of the environmental factors impacting susceptibility to autism exert their effect during this critical period of life. Nongenetic risk factors that may index environmental influences include parental age, low birth weight, multiple births, and maternal infections during pregnancy. Future studies that seek to elucidate such factors and their role in enhancing or suppressing genetic susceptibility are likely to enhance our understanding of autism.

The authors can be heard on KQED in San Francisco discussing the paper.

In a companion commentary on Archives of General Psychiatry, Is Autism, at Least in Part, a Disorder of Fetal Programming?, Peter Szatmari comments on the shift in perception based on the new heritability estimates: “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.”

“Inflated” seems a bit of a loaded word. There are big error bars on the current study, there were even bigger ones in the old studies. What I found very interesting was this peak at an upcoming paper by the Baby Siblings Research Consortium:

The high DZ concordance rate is consistent with estimates reported from the Baby Siblings Research Consortium. 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.

(reference: Ozonoff S, Young G, Carter AS, Messinger D, Yirmiya N, Zwaigenbaum L, Bryson SE, Carver L, Constantino J, Dobkins K, Hutman T, Iverson J, Landa R, Rogers S, Sigman M, Stone W. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium Study. Pediatrics. In press.)

They commentary poses some good questions about potential bias in the California Autism Twin Study:

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.

It’s taken 34 years since the first autism twin study until the much larger California Autism Twin Study. This has been a time consuming and expensive undertaking. I doubt there will be a chance in the near future for a larger study to address the issues laid out above. This doesn’t preclude some other studies to clarify some questions, but the California Autism Twin Study will likely stand for some time before being challenged or confirmed.

12 Responses to “Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism”

  1. passionlessDrone July 18, 2011 at 14:47 #

    In a companion commentary on Archives of General Psychiatry, Is Autism, at Least in Part, a Disorder of Fetal Programming?,


    – pD

  2. RAJ July 19, 2011 at 12:21 #

    The California twin study reported a moderate genetic heritability estimate of 37%. This has been interpreted as suggesting that the genetic heritability for autism has been overestimated by previous twin studies. In fact, the moderate genetic heritability of 37% may itself be an overestimate. The rapidly advancing technology and rapidly lowering costs of genome scans has advanced so rapidly that is now routine that gene scans of probands and first degree relatives (parents and siblings) is becoming routine. All the excitement is now about the discovery that copy number variations (CNV) are associated with autism risk and that a high rate of CNV’s are de novo (not inherited). The definition of a de novo mutation is a reproductive error that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) derived from one of the parents or an error of cell division occurring during early fetal development and that the mutation is not present in the parent(s). De novo mutations are rare, random events that can strike within any family at any time.

    There is a profound flaw in classical twin study design that simplistically calculates a ‘heritability’ estimate based on the difference between concordant rates in MZ and DZ twin pairs. The classical twin study has been in effect, relatively unchanged for over one hundred years. The logical flaw in calculating ‘heritability’ estimates is that it assumes that ‘genetic’ = ‘heritable’. The heritability estimates cannot control for de novo mutations that are not inherited. Completely overlooked in the excitement over CNV’s and de novo CNV’s is that about 10% or more of autism is associated with the single-gene disorders with high rates of co-occurring autism (Fragile X, Rhett Syndrome, Downs Syndrome etc.). The strong association between the single gene disorders with high rates of co-occurring autism (and the twin studies) has led to the oft made claim that autism is the most ‘heritable’ of the developmental disorders.

    What is the ratio of inherited gene mutations and de novo mutations in the single-gene disorders associated with high rates of co-occurring autism? The answer is surprising. Among the single-gene disorders Fragile X mental retardation syndrome stands virtually alone in following a Mendelian pattern of transgenerational inheritance, but in most of the single-gene disorders associated with high rates of co-occurring autism the mutations are primarily de novo mutations and are not inherited.

    Arthur Beaudet (2008) a leading authority on Prader-Willi and Angelmans Syndrome has observed ‘In terms of potential lessons for other disorders, it should be noted that almost all of these genetic and epigenetic cases of PWS and AS are de novo as contrasted to being inherited events’.

    The NIH has established a web accessible genetic reference table that is maintained and updated usually by the leading experts in the field who research the specific genetic disorder. The articles are written in clear concise English without ‘scientific’ jargon. Here is the latest data for the majoriy of single-gene disorders associated with high rates of co-ocurring autism in the NIH’s gene reference table.

    Fragile X:

    Smith-Lemli-Opitz ynrome:

    Rhett Syndrome:

    Downs Syndrome:

    Klinefelter Syndrome:

    Angleman Syndrome:

    Prader-Willi syndrome:

    Tuberous Sclerosis:

    Williams Syndrome:

    Turner Syndrome:

    16P11.2 deletion syndrome:

    Phelan-McDermis syndrome:

    CHARGE Syndrome:

  3. Jen July 19, 2011 at 17:06 #

    Why can’t you just come out and say that the genetic explanation for autism is dead. Something in the fetus/baby’s environment is causal. Oh, but it couldn’t be vaccines for pregnant women or shots on the first day of life. No way, not that.

    • Sullivan July 19, 2011 at 17:50 #

      “Why can’t you just come out and say that the genetic explanation for autism is dead.”

      Have you read the study? More importantly, did you understand it? If so, why did you ask the above question, as it doesn’t follow from the study at all.

      “Oh, but it couldn’t be vaccines for pregnant women or shots on the first day of life. ”

      Perhaps you might want to listen to the interview with the authors of the study.

  4. daedalus2u July 22, 2011 at 00:56 #

    The problem with this study and this analysis is that the genetic and environmental components cannot be separated. Genetic and environmental effects are coupled, with non-linear coupling, and coupled at the level of “noise”, that is at the level of Brownian motion of molecules via stochastic resonance.

    It is good to finally see research looking at the in utero environment. That is where and when the known causes of autism occur (valproate, thalidomide, maternal stress).

  5. RAJ July 22, 2011 at 12:04 #

    How complex genetic and environmental interactions operate in contributing to human disease has been elegantly demonstrated by AIDS researchers. Multiple groups have identified lower copy number variations in a single gene, CCL3L1, a common genetic variant located in the region near chromosome 17q12 as associated with risk for infection after exposure to the HIV-1 virus. A meta analysis demonstrated that lower copy numbers than population norms in this genetic variation increases risk for infection. Higher copy number variations than population norms in the same genetic variation confers resistance for infection after exposure. No one is claiming that lower copy number variations in in the CCL3L1 gene is an ‘AIDS’ gene.

    The claim by behavioral geneticists that copy number variations ’cause’ autism is simplistic and ignores the fact that correlation does not imply causation.

  6. Chris August 22, 2011 at 17:07 #

    alya’s link goes to advertising link farm, and is pure spam. Please do not click on it.

    • Sullivan August 22, 2011 at 17:17 #

      Thanks Chris–

      I just sent that comment to the spam queue.

  7. stanley seigler August 29, 2011 at 20:28 #

    [RAJ say] etc, etc…

    sounds good…but over my head…butbut this may be the thread to post a gene study…which is also above my pay grade…maybe of interest to the scientist.

    the study: Language gene regulates autism candidate

    [CLIP]Researchers have identified an interaction between two molecules in a signaling pathway that is involved in language, brain development and, perhaps, autism. The new study, published 10 August in the Journal of Neuroscience, reports that a protein linked to language development, FOXP2, regulates the autism candidate gene MET1.

    if interested pls goto link for rest of story.

    apologies if this already posted to LBRB..

    stanley seigler


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    […] Genetic Heritability and Shared Environmental Factors Among Twin Pairs With AutismLeft Brain/Right BrainThe finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research paradigms. Increasingly, evidence is accumulating that overt symptoms of autism emerge around the … […]

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