68 What is Autism?
interviews, ASD symptom scores were higher in males than in females. ASD
males also had increased levels of inattentive and hyperactive/impulsive ADHD
symptoms. However, symptom severity was higher in females compared with
males in self‐reports. There was some association between lower IQ and higher
scores on ASD symptom measures. Overall, the individuals in the study
reflected the phenotypic heterogeneity typically observed in ASD. Although
associations were found between ASD symptoms severity and sex, age, and
assessments in ASD symptoms differed between clinicians, parents, and indi-
viduals, highlighting the critical importance of selecting appropriate measure-
ment approaches when examining ASD.
Chaste and his collaborators have carried out one of the most comprehensive
genome‐wide analyses of ASD [48]. This group carried out the full genetic
analyses of 2,576 families to attempt to uncover phenotypic heterogeneity in
autism that may be linked to certain genes. This approach is based on the
hypothesis that phenotypic heterogeneity closely maps to genetic variation,
which has not yet been shown. This study examined the impact of phenotyping
and even subphenotyping of a well‐characterized ASD sample on genetic
homogeneity and the ability to discover common genetic variants that may
contribute to ASD. Their analyses of large numbers of families revealed no
genome‐wide significant association signal. They concluded that analysis of
subphenotypes is not a productive path forward for discovering genetic risk
variants in ASD. Chaste et al. studied a large (N = 2,576 families) and behavio-
rally well‐phenotyped ASD sample (the Simons Simplex Collection) to ask
whether subgrouping to enhance phenotypic homogeneity increases the ability
to make SNP findings in ASD. The results provide a clear “no.” The authors
show that subphenotyping by many reasonable criteria, including IQ, extent of
repetitive behaviors, insistence on sameness, and more severe ASD, failed to
increase power substantially, and the subgroups showed very similar heritabil-
ity estimates (~0.4). Most importantly, allele scores from the entire sample
predicted case status equally well regardless of subgroup. In short, reducing
phenotypic heterogeneity did nothing to increase genetic homogeneity. In a
subsequent philosophic reflection, Chaste et al. [49] suggest that ASD is a
complex polygenic disorder and rare de novo and inherited variations act
within the context of a common‐variant genetic load, and this load accounts
for the largest portion of ASD liability. Obviously, missing a real common sense
point: these so called rare de novo mutations may be caused by environmental
factors, while the fetal cells are going through enormous cellular differentiation
and neurogenesis!
It is useful to consider genetic variation as either common (e.g., an allele
found in 0.5% of the population) or rare because these categories of variation
are analyzed using different approaches and have different properties. Most
importantly, for neurodevelopmental disorders, common genetic variation
(e.g., SNP) is associated with very small effect sizes given evolutionary