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The Genetic and Environmental Contributions to AutismLooking Beyond TwinsDiana E. Schendel, PhD; Therese K. Grønborg, MSc; Erik T. Parner, MSc, PhD

Autism spectrum disorders (ASDs) are serious neurodevelop-mental disorders characterized by difficulties in socialinteraction and communication accompanied by stereotypi-

cal, repetitive behavior andrestricted interests.1 Onceconsidered rare, ASD is nowreported to affect approxi-

mately 1% to 2% of children.2,3 The increase in ASD preva-lence in recent decades combined with little understanding ofASD etiology have fostered increases in public and private re-search funding with a substantial investment in geneticresearch.4 The historical focus on genetic factors partly arosefrom evidence from the first twin studies5-7 in which concor-dance for an ASD diagnosis was reportedly as high as 90% inmonozygotic twins and substantially higher than in dizygotictwins. A more recent and larger twin study,8 however, ob-served a smaller genetic effect and a larger environmental ef-fect on ASD liability than previous work, suggesting that earlyestimates of the genetic liability for ASD may have been in-flated by ascertainment bias.9 Along with twin concordance,another important measure of genetic contribution to dis-ease is familial recurrence. Estimates of sibling recurrence ofASD in families with a previously diagnosed child have rangedfrom 5.8% to 18.7%,10,11 which are markedly higher than theoccurrence of ASD in the general population and thereby sup-port the importance of familial contributions to the risk for ASD.

In this issue of JAMA, Sandin and colleagues12 report es-timates of both familial recurrence and heritability of ASD basedon a large, Swedish population-based birth cohort of more than2 million children born 1982 through 2006. A total of 14 516 chil-dren were diagnosed with ASD, of whom 5689 had autistic dis-order. Consistent with the expectation of a significant ge-netic contribution to ASD, the risk of ASD in family membersof persons with ASD was significantly higher than the risk inthe general population, and the risk of ASD recurrence amongfamily members decreased with decreasing genetic related-ness, from a 10-fold increased risk of recurrence in full sib-lings to a 2-fold increased risk of recurrence in cousins. Simi-larly, the heritability analysis also supported the importanceof genetic factors in ASD; the authors suggested that geneticfactors explain half of the liability for autism.

Using the largest sample size to date, the report by Sandinet al is the first attempt to provide both ASD recurrence andheritability estimates from the same population. Further-more, for the first time, the authors used family linkage backto grandparents and thereby identified siblings (monozy-gotic and dizygotic twins and nontwin full and half siblings)

and cousins in order to incorporate extended family relationsinto the recurrence and heritability estimates. In terms of re-currence, the results for full and half siblings are consistentoverall with a recent study based on a Danish population-based cohort,13 but the new Swedish study was based on alarger sample and, for the first time, considered ASD recur-rence among cousins. The heritability results also are gener-ally consistent with a large, California-based twin study8 interms of observing reduced estimates for genetic liability andincreased estimates for environmental effects compared withearlier heritability estimates. The novelty of the Sandin et alstudy is in the delivery of a single, population-based “pack-age” of results of extended familial risk based on a very largesample.

The similarity in results on relative recurrence risks (RRRs)between the present study and the previous Danish population-based study should be reassuring to parents with a child withASD who are contemplating having another child. Taking the2 studies in combination provides a consistently lower bench-mark of familial risk for ASD than suggested by several previ-ous smaller studies based on clinical populations. Also reas-suring for families is the fact that there is little support for adifference in ASD recurrence according to whether the pro-band is male or female because in both studies all sibling-sexcombinations had similar relative risks of recurrence. In ad-dition, in both studies, spanning births from the early 1980sto the mid-2000s, there was no significant trend in RRRs overtime, indicating that the upward trend in autism prevalenceover the same period in both populations has either notchanged the combination of genetic and environmental fac-tors that contribute to ASD recurrence or not changed the rela-tive magnitude of risk arising from such factors.

However, much remains to be understood regarding fa-milial risk for autism. A more complete and perhaps more ac-curate perspective on familial risk using the recurrence risk ap-proach might be achieved by considering risk for recurrenceof underlying ASD-related phenotypic features. Future stud-ies might consider risks from different combinations of diag-noses in the proband and sibling; for example, the risk of anyASD diagnosis in the sibling of a child diagnosed with autisticdisorder, or other combinations of ASD-related or comorbidneurodevelopmental diagnoses (eg, ASD-epilepsy combina-tions).

Heritability is defined as the amount of phenotypicvariation in a trait in a population that can be attributed togenetic factors as opposed to environmental factors.Although the present study reinforced the heritability find-

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ings from the California twin study8 of a smaller geneticliability and larger environmental component in ASD thanreported in earlier studies, unlike that study, it actuallyobserved that genetic and nonshared environmental influ-ences on the liability for ASD and autistic disorder wereequally important (and shared environmental factors had anegligible influence). Furthermore, the present study basedon extended families estimated an ASD heritability of 50%,whereas another population-based Swedish study basedonly on twins estimated a heritability of 80%.7

The difference in heritability estimates between the 2Swedish studies highlights some limitations of the liabilitythreshold models. Although the same underlying model wasused in both studies, and both analyses were attemptingto estimate the same quantity in a similar population, differ-ent results were produced between the twin-based andextended family–based samples. The liability thresholdmodels are simplified genetic models. The models assumethat a dichotomous outcome like ASD (yes or no) is derivedfrom an underlying normally distributed trait with some

threshold value determining presence or absence of the out-come of interest. Furthermore, the models assume that thistrait can be decomposed into a sum of different genetic andenvironmental components (with no interaction betweengenetic and environmental components) and also assumethe degree of correlation among these components depend-ing on the type of familial relation. Incorporating other typesof relatives besides twins in the models, as was done in thereport in this issue,12 increases sample size (thereby enhanc-ing precision of the estimates) and provides the opportunityto estimate phenotypic variation across families and not justin twins. The assumptions regarding the shared environ-mental component, however, might be too simplified forextended family data. Altogether, the heritability models arerelatively “crude” methods for partitioning genetic vs envi-ronmental contributions to ASD.

In conclusion, the work by Sandin et al supports appre-ciation of the importance of genetic factors in ASD and addssubstantial impetus to the growing attention to environmen-tal influences in ASD etiology.

ARTICLE INFORMATION

Author Affiliations: Section for Epidemiology,Department of Public Health, Aarhus University,Aarhus, Denmark (Schendel); Department ofEconomics and Business, National Centre forRegister-Based Research, Aarhus University,Aarhus, Denmark (Schendel); Lundbeck FoundationInitiative for Integrative Psychiatric Research,iPSYCH, Aarhus, Denmark (Schendel); Section forBiostatistics, Department of Public Health, AarhusUniversity, Aarhus, Denmark (Grønborg, Parner).

Corresponding Author: Diana E. Schendel, PhD,Section for Epidemiology, Department of PublicHealth, Aarhus University, Bartholins Allé 2, 8000Aarhus C, Denmark ([email protected]).

Conflict of Interest Disclosures: All authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest andnone were reported.

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