Neuropsychiatric “Comorbidity” as Causal Influence in Autism

Behavioral comorbidity is the rule rather than the exception in autism spectrum disorder (ASD), and the co-occurrence of autistic traits with subclinical manifestations of other psychiatric syndromes (eg, anxiety, developmental coordination disorder) extends to the general population, where there is strong evidence for overlap in the respective genetic causes. An ASD “comorbidity” can have several fundamentally distinct causal origins: it can arise due to shared genetic risk between ASD and non-ASD phenotypes (eg, ASD and microcephaly in the context of the MECP2 mutation), as a “secondary symptom” of ASD when engendered by the same causal influence (eg, epilepsy in channelopathies associated with ASD), due to chance co-occurrence of ASD with a causally independent liability (eg, ASD and diabetes), or as the late manifestation of an independent causal influence on ASD (eg, attention-deficit/hyperactivity disorder). Here, we review evidence for the latter, that is, the role of nonspecific causal influences on the development of ASD itself. The notion that nonspecific insults to neural development, either inherited or acquired, might augment the impact of ASD-specific genetic susceptibilities in contributing to its cause has not been appreciated in the literature on comorbidity, and has significant implications for both personalized intervention and future research. Prior biomarker studies of ASD have typically not accounted for variation in such traits. The statistical power of future studies, particularly in autism genetics and neuroimaging, can be enhanced by more comprehensive attention to the measurement of comorbid behavioral traits that index causal influences on the disorder, among not only cases but (importantly) controls.