Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample

Abstract

Importance: Most evidence to date highlights the importance of genetic influences on the liability to autism and related traits. However, most of these findings are derived from clinically ascertained samples, possibly missing individuals with subtler manifestations, and obtained estimates may not be representative of the population.

Objectives: To establish the relative contributions of genetic and environmental factors in liability to autism spectrum disorder (ASD) and a broader autism phenotype in a large population-based twin sample and to ascertain the genetic/environmental relationship between dimensional trait measures and categorical diagnostic constructs of ASD.

Design, setting, and participants: We used data from the population-based cohort Twins Early Development Study, which included all twin pairs born in England and Wales from January 1, 1994, through December 31, 1996. We performed joint continuous-ordinal liability threshold model fitting using the full information maximum likelihood method to estimate genetic and environmental parameters of covariance. Twin pairs underwent the following assessments: the Childhood Autism Spectrum Test (CAST) (6423 pairs; mean age, 7.9 years), the Development and Well-being Assessment (DAWBA) (359 pairs; mean age, 10.3 years), the Autism Diagnostic Observation Schedule (ADOS) (203 pairs; mean age, 13.2 years), the Autism Diagnostic Interview-Revised (ADI-R) (205 pairs; mean age, 13.2 years), and a best-estimate diagnosis (207 pairs).

Main outcomes and measures: Participants underwent screening using a population-based measure of autistic traits (CAST assessment), structured diagnostic assessments (DAWBA, ADI-R, and ADOS), and a best-estimate diagnosis.

Results: On all ASD measures, correlations among monozygotic twins (range, 0.77-0.99) were significantly higher than those for dizygotic twins (range, 0.22-0.65), giving heritability estimates of 56% to 95%. The covariance of CAST and ASD diagnostic status (DAWBA, ADOS and best-estimate diagnosis) was largely explained by additive genetic factors (76%-95%). For the ADI-R only, shared environmental influences were significant (30% [95% CI, 8%-47%]) but smaller than genetic influences (56% [95% CI, 37%-82%]).

Conclusions and relevance: The liability to ASD and a more broadly defined high-level autism trait phenotype in this large population-based twin sample derives primarily from additive genetic and, to a lesser extent, nonshared environmental effects. The largely consistent results across different diagnostic tools suggest that the results are generalizable across multiple measures and assessment methods. Genetic factors underpinning individual differences in autismlike traits show considerable overlap with genetic influences on diagnosed ASD.

Figure 1. Social Relationship Study (SRS) Sample Selection Stages and the Overall Number of Participants Included in the Analysis

ADI-R indicates Autism Diagnostic Interview–Revised; ADOS, Autism Diagnostic Observation Schedule; ASD, autism spectrum disorder; DAWBA, Development and Well-being Assessment; DZ, dizygotic; MZ, monozygotic; OS, opposite-sex; SS, same-sex; and TEDS, Twins Early Development Study. ^aSome twins met both criteria, so numbers total more than 412.

Figure 2. Diagram of the Correlated Factors Solution of the Joint Continuous-Ordinal Model of Effects on the Childhood Autism Spectrum Test (CAST) Results and Best-Estimate Diagnosis (BeD)

The model represents the standardized effects of additive genetic (A₁ and A₂) and nonshared environmental factors (E₁ and E₂) on each trait separately and the A and E correlations between the 2 variables (r_A and r_E). We found no shared environmental influences at play for the CAST score; therefore, no covariance due to correlated shared environmental factors is possible with the autism spectrum disorder (ASD) measures. We modeled the shared environmental effects for the ASD measures, which were nonsignificant for most as shown for the BeD (striped line).