Angelica Ronald

Time to give up on a single explanation for autism

We argue that there will be no single (genetic or cognitive) cause for the diverse symptoms defining autism. We present recent evidence of behavioral fractionation of social impairment, communication difficulties and rigid and repetitive behaviors. Twin data suggest largely nonoverlapping genes acting on each of these traits. At the cognitive level, too, attempts at a single explanation for the symptoms of autism have failed. Implications for research and treatment are discussed.

The ‘Fractionable Autism Triad’: A Review of Evidence from Behavioural, Genetic, Cognitive and Neural Research

Autism is diagnosed on the basis of a triad of impairments in social interaction, communication, and flexible imaginative functions (with restricted and repetitive behaviors and interests; RRBIs). There has been a strong presumption that these different features of the syndrome are strongly intertwined and proceed from a common cause at the genetic, cognitive and neural levels. In this review we examine evidence for an alternative approach, considering the triad as largely ‘fractionable’. We present evidence from our own twin studies, and review relevant literature on autism and autistic-like traits in other groups. We suggest that largely independent genes may operate on social skills/impairments, communication abilities, and RRBIs, requiring a change in molecular-genetic research approaches. At the cognitive level, we suggest that satisfactory accounts exist for each of the triad domains, but no single unitary account can explain both social and nonsocial features of autism. We discuss the implications of the fractionable-triad approach for both diagnosis and future research directions.

Autism spectrum disorders and autistic traits: A decade of new twin studies

Researchers continue to pursue a better understanding of the symptoms, comorbidities, and causes of autism spectrum disorders. In this article we review more than 30 twin studies of autism spectrum disorders (ASDs) and autistic traits published in the last decade that have contributed to this endeavor. These twin studies have reported on the heritability of autism spectrum disorders and autistic traits in different populations and using different measurement and age groups. These studies have also stimulated debate and new hypotheses regarding why ASDs show substantial symptom heterogeneity, and what causes their comorbidity with intellectual disability, language delay, and other psychiatric disorders such as ADHD. These studies also reveal that the etiology of autism and autistic traits assessed in the general population is more similar than different, which contributes to the question of where the boundary lies between autism and typical development. Recent findings regarding molecular genetic and environmental causes of autism are discussed in the relation to these twin studies. Lastly, methodological assumptions of the twin design are given consideration, as well as issues of measurement. Future research directions are suggested to ensure that this decade is as productive as the last in attempting to disentangle the causes of autism spectrum disorders.

How Different Are Girls and Boys Above and Below the Diagnostic Threshold for Autism Spectrum Disorders

OBJECTIVE This study aimed to explore sex differences in autistic traits in relation to diagnosis, to elucidate factors that might differentially impact whether girls versus boys meet diagnostic criteria for autism or a related autism spectrum disorder (ASD). METHOD Data from a large population-based sample of children were examined. Girls and boys (aged 10-12 years) meeting diagnostic criteria for an ASD were compared with those failing to meet diagnostic criteria despite very high scores on a trait measure of ASD, the Childhood Autism Spectrum Test (CAST). Information about behavioral difficulties as reported by teachers, and early estimates of intellectual functioning, were compared. RESULTS Girls, but not boys, meeting diagnostic criteria for ASD showed significantly more additional problems (low intellectual level, behavioral difficulties) than peers with similarly high CAST scores who did not meet diagnostic criteria. CONCLUSIONS These data suggest that, in the absence of additional intellectual or behavioral problems, girls are less likely than boys to meet diagnostic criteria for ASD at equivalently high levels of autistic-like traits. This might reflect gender bias in diagnosis or genuinely better adaptation/compensation in girls.

Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits

Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

Examining and interpreting the female protective effect against autistic behavior

Male preponderance in autistic behavioral impairment has been explained in terms of a hypothetical protective effect of female sex, yet little research has tested this hypothesis empirically. If females are protected, they should require greater etiologic load to manifest the same degree of impairment as males. The objective of this analysis was to examine whether greater familial etiologic load was associated with quantitative autistic impairments in females compared with males. Subjects included 3,842 dizygotic twin pairs from the Twins Early Development Study (TEDS) and 6,040 dizygotic twin pairs from the Child and Adolescent Twin Study of Sweden (CATSS). In both samples, we compared sibling autistic traits between female and male probands, who were identified as children scoring in the top 90th and 95th percentiles of the population autistic trait distributions. In both TEDS and CATSS, siblings of female probands above the 90th percentile had significantly more autistic impairments than the siblings of male probands above the 90th percentile. The siblings of female probands above the 90th percentile also had greater categorical recurrence risk in both TEDS and CATSS. Results were similar in probands above the 95th percentile. This finding, replicated across two nationally-representative samples, suggests that female sex protects girls from autistic impairments and that girls may require greater familial etiologic load to manifest the phenotype. It provides empirical support for the hypothesis of a female protective effect against autistic behavior and can be used to inform and interpret future gene finding efforts in autism spectrum disorders.

Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.

Prenatal Maternal Stress Associated with ADHD and Autistic Traits in early Childhood

Research suggests that offspring of mothers who experience high levels of stress during pregnancy are more likely to have problems in neurobehavioral development. There is preliminary evidence that prenatal maternal stress (PNMS) is a risk factor for both autism and attention deficit hyperactivity disorder (ADHD), however most studies do not control for confounding factors and no study has investigated PNMS as a risk factor for behaviors characteristic of these disorders in early childhood. A population cohort of 2900 pregnant women were recruited before their 18th week of pregnancy and investigated prospectively. Maternal experience of stressful life events was assessed during pregnancy. When offspring were age 2 years, mothers completed the child behavior checklist. Multiple regression showed that maternal stressful events during pregnancy significantly predicted ADHD behaviors in offspring, after controlling for autistic traits and other confounding variables, in both males (p = 0.03) and females (p = 0.01). Similarly, stressful events during pregnancy significantly predicted autistic traits in the offspring after controlling for ADHD behaviors and confounding variables, in males only (p = 0.04). In conclusion, this study suggests that PNMS, in the form of typical stressful life events such as divorce or a residential move, show a small but significant association with both autistic traits and ADHD behaviors independently, in offspring at age 2 years, after controlling for multiple antenatal, obstetric, postnatal, and sociodemographic covariates. This finding supports future research using epigenetic, cross-fostering, and gene–environment interaction designs to identify the causal processes underlying this association.

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

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.

Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B

It has been widely postulated that the categorical diagnosis of attention deficit hyperactivity disorder (ADHD) should be seen as the extreme end of a set of traits quantitatively distributed in the general population. A consequence of this is that the genes associated with DSM‐IV ADHD should also influence these underlying traits in non‐affected individuals. The aim of this study was to examine if specific candidate loci previously shown to be associated with DSM‐IV ADHD, also act as quantitative trait loci (QTLs) for ADHD‐symptoms in the general population. We have genotyped five candidate markers in a population‐based sample of male dizygous twin‐pairs (n = 329 pairs). We found little evidence to support a role for the previously‐nominated alleles of a DRD4 VNTR, a 5HT1B SNP, or a microsatellite marker near to DRD5, in the distribution of ADHD‐symptoms scores; however, we found some evidence to suggest that the DAT1 3′UTR VNTR and weak evidence that a microsatellite in SNAP‐25 may have a role in continuous measures of ADHD‐symptoms hyperactivity above and beyond their role in clinical ADHD.