On the Spectrum

General discussion
Pourcain, Anttila, Kosmicki, Bulik-Sullivan et al. 2016). It is estimated that around 10-20% of
cases with ASD are so-called “syndromic cases”, where a known single-gene mutation can
be established (Folstein and Rosen-Sheidley 2001; Abrahams and Geschwind 2008). While
the genetics of ASD are very complicated and not very well understood yet, some genetic
findings lend support to the framework of ASD as a continuously distributed trait in the
general population.
According to the so-called quantitative locus theory, ASD may be polygenic, and there
are many different genes, each with a very modest effect size, that influence the entire
range of variation in the autistic phenotype (Plomin, Haworth and Davis 2009). Within this
framework, it is hypothesized that risk genes for ASD also give rise to autistic traits. There is a
number of studies that found evidence for this, either by using heritability estimates (Ronald,
Happe, Bolton, Butcher, Price et al. 2006; Robinson, Koenen, McCormick, Munir, Hallett et
al. 2011; Lundstrom, Chang, Rastam, Gillberg, Larsson et al. 2012) or specific genetic ASD
risk variants (St Pourcain, Wang, Glessner, Golding, Steer et al. 2010). Taken together, this
work provides evidence for a related genetic etiology of autistic traits at the extreme end
and in the rest of the population. In other words, genetic factors that underlie individual
differences in autistic traits show considerable overlap with genetic influences on clinically
diagnosed ASD (Constantino 2011). Recently, this body of evidence was strengthened by an
important novel study by Robinson and colleagues that involved several large ASD consortia
and population-based samples. They found that both inherited and de novo variants for ASD
influence a continuum of autistic traits, as well as other behavioral and developmental traits.
At the severe tail of this continuum, there are people with either ASD or other psychiatric
disorders, such as schizophrenia (Robinson et al. 2016).
Importantly, the notions of rare structural changes and quantitative risk scores are not
mutually exclusive. It is thought that most of the genetic risk factors for ASD are not rare,
but common variants, that can be found in many unaffected people as well (Gaugler, Klei,
Sanders, Bodea, Goldberg et al. 2014). Quite strikingly, there are several studies that show
that phenotypic penetrance of chromosomal deletions, traditionally assumed to operate
through a classical “hit-or-miss” mechanism, are in fact modulated by the background genetic
ASD risk load (Hanson, Bernier, Porche, Jackson, Goin-Kochel et al. 2015; Moreno-De-Luca,
Evans, Boomer, Hanson, Bernier et al. 2015).
It is likely that genetic aspects play an important role in the heterogeneity of
neurobiological findings in ASD. There is a large group of genetic pathways that all lead to a
globally overlapping behavioral phenotype, although the levels at which the brain is affected
could differ profoundly (Kendler 2013). Since there are different forms of genetic liability
for ASD, that probably operate at least partly in distinct ways in the brain, it is unlikely that
they together point to one underlying mechanism, or that there is even such a unifying
mechanism at all (Kendler 2013). While this is probably true to some degree in almost all
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