LETTER

Twin Studies in Autism: What Might They Say About Geneticand Environmental Influences

George M. Anderson

Published online: 18 May 2012

� Springer Science+Business Media, LLC 2012

Abstract Genetic and epigenetic differences exist within

monozygote twin-pairs and might be especially important

in the expression of autism. Assuming phenotypic differ-

ences between monozygotic twins are due to environ-

mental influences may lead to mistaken conclusions

regarding the relative genetic and environmental contri-

bution to autism risk.

Keywords Autism � Risk � Twin � Monozygotic �Heritability � Genetic � Environmental

The authors of a paper recently published in the Archives

of General Psychiatry concluded that autism has moderate

genetic heritability (37 %) and a substantial shared twin

environmental (55 %) component (Hallmayer et al. 2011).

This conclusion was based on concordance rates observed

for autism in monozygotic (MZ) and dizygotic (DZ) twins.

The proband-wise autism concordance rate seen for MZ

twins of 0.58 was lower, and the rate for DZ twins of 0.21

was higher, than has been previously reported. The results

have prompted a reconsideration of the relative contribu-

tion of genetic and environmental factors to autism and

autism spectrum disorder (ASD) risk. The author of an

accompanying Commentary asked ‘‘Where did all the

heritability go’’ and suggested that ‘‘…research on shared

environmental mechanisms has received renewed impe-

tus.’’ (Szatmari 2011).

While previous heritability estimates of up to 90 %

could prove to be too high, it should be recognized that MZ

twins can differ genetically in ways that might be espe-

cially relevant in autism. First, MZ twins have been

reported to have within-pair differences in copy-number-

variation (CNV) profiles and other de novo mutations, and

these within-pair genetic differences appear to contribute to

phenotypic differences (Bruder et al. 2008). It is pertinent

that CNVs have been reported to play a role in autism

etiology in an estimated 5–10 % of cases (State and Levitt

2011). Second, twinning is not expected to be perfectly

symmetrical with respect to pre-programmed epigenetic

changes that begin immediately upon fertilization. Such a

stochastically-based epigenetic asymmetry would tend to

be greater in later-stage twinning (Steinmetz et al. 1995).

Readily apparent differences in MZ twins due the timing of

twinning are seen in placentation status (mono or dichori-

onic) and amniotic cavity (mono or diamniotic) (Sadler

2006). In female MZ twins, the random pattern of epige-

netic deactivation on the X chromosome will also con-

tribute to genetically based differences. The genetic and

epigenetic mechanisms that might contribute to MZ dif-

ferences in linguistic ability have been thoroughly

reviewed and seem quite relevant (Stromswold 2006). The

point here is that early epigenetic (and genetic) differences

in MZ twins can occur without any environmental influ-

ence, but such differences would lower estimates of genetic

heritability (Haque et al. 2009). Conversely, the shared

gestational environment of DZ twins might contribute to an

increased epigenetic and phenotypic similarity that has

little or nothing to do with exogenous factors (Titlestad

et al. 2002).

Thus, it can be suggested that at least some of the ASD

risk attributed by the authors to an environmental compo-

nent might actually be due to genetic factors. Relatively

subtle genetic differences between MZ twins might be

particularly influential in the ASD context. It has been

G. M. Anderson (&)

Child Study Center, Yale University School of Medicine,

230 S. Frontage Road, New Haven, CT 06519, USA

e-mail: george.anderson@yale.edu

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J Autism Dev Disord (2012) 42:1526–1527

DOI 10.1007/s10803-012-1552-6

suggested that interactions between autism domain traits

and among the traits’ underlying factors are crucial

regarding phenotypic expression in this realm. These

interactions can be speculated to be additive, multiplicative

(synergistic), and emergenic in nature (Anderson, 2008;

Lykken 2006). The expression of apparently non-familial

(potentially emergenic) phenomena in ASD, including

intellectual disability (ID) and seizures, might be especially

sensitive to an individual’s specific configuration or con-

stellation of genetic factors. In this regard, it would be

informative if Hallmayer and colleagues could provide

individual and group data concerning the occurrence of ID

and seizures for the twins studied. Whole genome

sequencing and epigenomic characterization of concordant

and discordant twin pairs in this set and others would also

be of obvious benefit (Bell and Spector 2011; Zwijnenburg

et al. 2010).

The investigation of a large and well-assessed sample of

twin pairs by Hallmayer et al. (2011) has given the field

invaluable information. However, it is important that the

results are interpreted in a way that takes account of the

complexities and does not over-state conclusions regarding

the relative genetic and environmental contributions to

ASD risk.

References

Anderson, G. M. (2008). The potential role for emergence in autism.

Autism Research, 1(1), 18–30.

Bell, J. T., & Spector, T. D. (2011). A twin approach to unraveling

epigenetics. Trends in Genetics, 27(3), 116–125.

Bruder, C. E., Piotrowski, A., Gijsbers, A. A., Andersson, R.,

Erickson, S., Diaz de Stahl, T., et al. (2008). Phenotypically

concordant and discordant monozygotic twins display different

DNA copy-number-variation profiles. American Journal ofHuman Genetics, 82(3), 763–771.

Hallmayer, J., Cleveland, S., Torres, A., Phillips, J., Cohen, B.,

Torigoe, T., et al. (2011). Genetic heritability and shared

environmental factors among twin pairs with autism. Archivesof General Psychiatry, 68(11), 1095–1102.

Haque F. N., Gottesman I. I., Wong A. H. (2009). Not really identical:

Epigenetic differences in monozygotic twins and implications

for twin studies in psychiatry. American Journal of MedicalGenetic C Seminars in Medical Genetics, 15;151C(2):136–141.

Lykken, D. T. (2006). The mechanism of emergenesis. Genes, Brain& Behavior, 5(4), 306–310.

Sadler, T. W. (2006). Langman’s medical embryology (10th ed.).

Philadelphia, PA: Lippincott Williams & Wilkins.

State, M. W., & Levitt, P. (2011). The conundrums of understanding

genetic risks for autism spectrum disorders. Nature Neurosci-ence, 14(12), 1499–1506.

Steinmetz, H., Herzog, A., Schlaug, G., Huang, Y., & Jancke, L.

(1995). Brain (A) symmetry in monozygotic twins. CerebralCortex, 5(4), 296–300.

Stromswold, K. (2006). Why aren’t identical twins linguistically

identical? Cognition, 101(2), 333–384.

Szatmari, P. (2011). Is autism, at least in part, a disorder of fetal

programming? Archives of General Psychiatry, 68(11),

1091–1092.

Titlestad, I. L., Kyvik, K. O., Kristensen, T., & Lillevang, S. (2002).

HLA haplotypes in dizygotic twin pairs: are dizygotic twins

more similar than sibs? Twin Research, 5(4), 287–288.

Zwijnenburg, P. J., Meijers-Heijboer, H., & Boomsma, D. I. (2010).

Identical but not the same: the value of discordant monozygotic

twins in genetic research. American Journal of Medical Genet-ics, B Neuropsychiatric Genetics, 153B(6), 1134–1149.

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