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The characterizing features of autism spectrum disorder (ASD) are continuously distributed in nature; however, prior twin studies have not systematically incorporated this knowledge into estimations of concordance and discordance. We conducted a quantitative analysis of twin-twin similarity for autistic trait severity in three existing data sets involving 366 pairs of uniformly-phenotyped monozygotic (MZ) twins with and without ASD. Probandwise concordance for ASD was 96%; however, MZ trait correlations differed markedly for pairs with ASD trait burden below versus above the threshold for clinical diagnosis, with R 2 s on the order of 0.6 versus 0.1, respectively. Categorical MZ twin discordance for ASD diagnosis is rare and more appropriately operationalized by standardized quantification of twin-twin differences. Here we provide new evidence that although ASD itself is highly heritable, variation-in-severity of symptomatology above the diagnostic threshold is substantially influenced, in contrast, by non-shared environmental factors which may identify novel targets of early ASD amelioration.

The preponderance of causal influence on total population attributable risk for autism is polygenic in nature, but it is not known how such liability engenders the development of the syndrome. In 348 epidemiologically ascertained toddler twins, we explored associations between autistic traits and three robust, highly heritable predictors of familial autism recurrence: variation in attention, motor coordination, and parental autistic trait burden. We observed that these predictors-despite collectively accounting for over one third of variance in clinical recurrence-are genetically independent in early childhood, and jointly account for a comparable share of inherited influence on early reciprocal social behavior in the general population. Thus, combinations of what are otherwise discrete, inherited behavioral liabilities-some not specific to autism-appear to jointly mediate common genetic risk for autism. Linking genetic variants and neural signatures to these independent traits prior to the onset of the development of autism will enhance understanding of mechanisms of causation in familial autistic syndromes. Moreover, ongoing biomarker discovery efforts will benefit from controlling for the effects of these common liabilities, which aggregate in individuals with autism but are also continuously distributed in "controls". Finally, early inherited liabilities that participate in the early ontogeny of autistic syndromes represent parsimonious intervention targets for polygenic forms of the condition, and represent candidate trans-diagnostic endophenotypes of potential relevance to a diversity of neuropsychiatric syndromes.

Objective: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder frequently co-occur. Several studies show increased risk of substance use disorders in ADHD, yet there is limited information related to how ADHD symptoms, autistic traits, and their combined effects are associated with nicotine, alcohol, and cannabis use and use disorders in the general population., Method: Cross-sectional interview and self-report questionnaire data from 3,080 young adult Australian twins (mean age 31.9 years) were used to assess ADHD symptoms, autistic traits, substance use, and substance use disorders. Substance use disorders-based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria-were assessed in the full sample as well as in those who reported substance use. Logistic regression analyses were used for comparing the associations between ADHD symptoms, autistic traits, substance use, and substance misuse after conduct disorder, sex, age, and zygosity were controlled for., Results: Greater ADHD symptoms and autistic traits scores were associated with elevated levels of regular smoking; cannabis use; and nicotine, alcohol, and cannabis use disorders, even after conduct disorder was adjusted for. In contrast, for alcohol use, those with high autistic traits scores were less likely to report drinking to intoxication. However, upon initiation, and similar to the findings for nicotine and cannabis, they were at elevated risk for developing alcohol dependence., Conclusions: Increased liability to ADHD and elevated autistic traits scores were associated with substance use and misuse, with the exception of alcohol use. Given the social underpinnings of drinking, persons with autistic traits may be less likely to engage in it; however, upon engagement in drinking, their vulnerability to alcohol dependence is elevated.

Objective: To investigate the relation between parent reports of motor problems and clinically significant autistic symptoms in children with and without attention-deficit/hyperactivity disorder (ADHD)., Method: Subjects were male (n = 521) and female (n = 330) twins from an epidemiological study of ADHD, ages 7 to 19 years at assessment using the Child Behavior Checklist and semistructured psychiatric diagnostic interviews. Parent-rated Social Responsiveness Scale questionnaires were returned for 62% of 1,647 individuals who participated in interviews. After exclusion of subjects with incomplete data or evidence of mental retardation, 851 subjects (52%) were available for the present study analysis. Each subject was classified by DSM-IV ADHD subtype and assigned to one of seven population-defined ADHD subtypes based on latent class analysis of DSM-IV ADHD symptoms. Within each ADHD subtype, we examined the relation between Child Behavior Checklist motor problem endorsement and elevated autistic symptoms on the Social Responsiveness Scale., Results: Motor problems and high levels of autistic traits were most common in individuals with combined-type ADHD. Within each of the clinically relevant DSM-IV and latent class ADHD subtypes, individuals with the combination of motor problems and ADHD were more likely to have high levels of autistic traits than those with ADHD alone., Conclusions: Children with the combination of ADHD and parent-reported motor coordination deficits have elevated levels of autistic symptoms. Targeted treatment and prevention interventions may be warranted. The exclusion criteria for DSM-IV ADHD should be revised to reflect these population-based findings.

Background: Autistic disorder (AD) is a disabling oligogenic condition characterized by severe social impairment. Subthreshold autistic social impairments are known to aggregate in the family members of autistic probands; therefore, we conducted this study to examine the intergenerational transmission of such traits in the general population., Methods: The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was completed on 285 pairs of twins (by maternal report) and on their parents (by spouse report)., Results: Correlation for social impairment or competence between parents and their children and between spouses was on the order of .4. In families in which both parents scored in the upper quartile for social impairment on the SRS, mean SRS score of offspring was significantly elevated (effect size 1.5). Estimated assortative mating explained approximately 30% of the variation in parent SRS scores., Conclusions: Children from families in which both parents manifest subthreshold autistic traits exhibit a substantial shift in the distribution of their scores for impairment in reciprocal social behavior, toward the pathological end. As has been previously demonstrated in children, heritable subthreshold autistic impairments are measurable in adults and appear continuously distributed in the general population.

Previous studies have suggested that among affected sib pairs with autism there is an increase in the frequency of twins over what would be expected in comparison to the prevalence of twins in the general population. In this study we sought to determine whether sub-threshold autistic traits were more pronounced in twins than in non-twins. The Social Responsiveness Scale (SRS) was administered in an epidemiologic twin sample (n=802) and in a separate population-based sample of non-twins ascertained from a local school district (n=255). For males (but not females), the mean SRS score was significantly higher among twins than among non-twins. As has been suggested for autism, twin status may incur increased liability to subthreshold autistic symptomatology, particularly in males.

Background: Recent research has indicated that autism is not a discrete disorder and that family members of autistic probands have an increased likelihood of exhibiting autistic symptoms with a wide range of severity, often below the threshold for a diagnosis of an autism spectrum disorder., Objective: To examine the distribution and genetic structure of autistic traits in the general population using a newly established quantitative measure of autistic traits, the Social Responsiveness Scale (formerly known as the Social Reciprocity Scale)., Methods: The sample consisted of 788 pairs of twins aged 7 to 15 years, randomly selected from the pool of participants in a large epidemiologic study (the Missouri Twin Study). One parent of each pair of twins completed the Social Responsiveness Scale on each child. The data were subjected to structural equation modeling., Results: Autistic traits as measured by the Social Responsiveness Scale were continuously distributed and moderately to highly heritable. Levels of severity of autistic traits at or above the previously published mean for patients with pervasive developmental disorder not otherwise specified were found in 1.4% of boys and 0.3% of girls. Structural equation modeling revealed no evidence for the existence of sex-specific genetic influences, and suggested specific mechanisms by which females may be relatively protected from vulnerability to autistic traits., Conclusions: These data indicate that the social deficits characteristic of autism spectrum disorders are common. Given the continuous distribution of these traits, it may be arbitrary where cutoffs are made between research designations of being "affected" vs "unaffected" with a pervasive developmental disorder. The genes influencing autistic traits appear to be the same for boys and girls. Lower prevalence (and severity) of autistic traits in girls may be the result of increased sensitivity to early environmental influences that operate to promote social competency.

Objective: The study examined the genetic structure of deficits in reciprocal social behavior in an epidemiologic sample of male twins., Method: Parents of 232 pairs of 7-15-year-old male twins completed the Social Reciprocity Scale to provide data on their children's reciprocal social behavior. Scale scores were analyzed by using structural equation modeling., Results: Intraclass (twin-twin) correlations for scores on the Social Reciprocity Scale were 0.73 for monozygotic twins (N=98 pairs) and 0.37 for dizygotic twins (N=134 pairs). The best fitting model of causal influences on reciprocal social behavior incorporated additive genetic influences and unique environmental influences., Conclusions: For school-age boys in the general population, reciprocal social behavior is highly heritable, with a genetic structure similar to that reported for autism in clinical samples. Continuous measures of reciprocal social behavior may be useful for characterizing the broader autism phenotype and may enhance the statistical power of genetic studies of autism.