On the Spectrum

General discussion
study, it has proven difficult to make a meaningful and reproducible distinction between
Asperger syndrome and high-functioning autism (Witwer and Lecavalier 2008). And even
while some classifications may seem meaningful on the behavioral level, they do not always
lead to better results in neurobiological research. Notably, a genetic study performed in the
Simons Simplex Collection sample showed that reducing phenotypic heterogeneity, based
on IQ and symptom profiles, did not have much impact on genetic homogeneity and did
not aid the discovery of genetic risk variants of ASD (Chaste, Klei, Sanders, Hus, Murtha et
al. 2015). Of note, identification of more homogeneous sub-classifications may also refer to
symptom dimensions within a continuously defined phenotype. A recent study pointed to an
intrinsic latent structure of continuous measures of autistic traits, comprising a systemizing
and an empathizing factor (Grove, Baillie, Allison, Baron-Cohen and Hoekstra 2013). It would
be worthwhile to assess whether the distinction of such continuous factors contributes to the
neurobiological understanding of ASD.
Another source of behavioral heterogeneity is presented by comorbidity. This alludes to
the concept of symptoms or diagnoses that are co-occurring with the symptom dimension
of interest. The Social Responsiveness Scale has been criticized for showing associations
with other types of behavioral symptoms, such as aggression or internalizing problems (Hus,
Bishop, Gotham, Huerta and Lord 2013). These can be interpreted as potential confounding
factors, suggesting that any associations with the Social Responsiveness Scale in fact involve
‘non-ASD-specific factors’. A way to deal with that would be to statistically adjust for other
symptom scores. However, since comorbidity is often indicative of severity, this would
potentially adjust for true autistic trait variation of interest (Constantino and Frazier 2013).
In fact, the term ‘comorbidity’ may be somewhat misleading as it suggests that different
conditions or symptoms are etiologically distinct entities, while they may in fact show
considerable overlap and represent different aspects of the same phenotype (Lilienfeld,
Sauvigne, Lynn, Cautin, Latzman et al. 2015). If ASD symptoms are indeed closely related to
other, less specific impairments, then controlling for such symptoms results in an artificial,
non-life-like phenotype. This phenomenon is reminiscent of the discussion of adjusting
for general intelligence as a confounder in the relation between early psychopathology
and cognitive functioning. As discussed in chapter 6, this should probably only be done to
assess more specific relations between psychopathology and cognitive subdomains. In the
context of developmental psychopathology, it is often unclear what came first: the cognitive
impairments or the behavioral symptoms. In fact, they may well belong to a common
underlying etiology. As such, general intelligence should not be a default covariate in the
relation between developmental psychopathology and cognition. However, it should be
noted that IQ can influence associations between symptoms of autism and the brain. Highly
intelligent people with ASD likely have more resources to compensate their social difficulties.
This may lead to more beneficial patterns of interaction, while subjects with low cognitive
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