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Autistic traits in simplex and multiplex autism families Focus on unaffected relatives.

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LETTER TO THE EDITOR
Autistic Traits in Simplex and Multiplex Autism
Families: Focus on Unaffected Relatives
Rosa A. Hoekstra* and Sally Wheelwright
Department of Psychiatry, Autism Research Centre, University of Cambridge, Cambridge, UK
Received 4 December 2008; Accepted 10 February 2009
TO THE EDITOR:
Virkud et al. [2009] recently published findings from a very
interesting dataset on the aggregation of autistic traits in families
in which more than one individual is affected with autism
(multiplex autism, MA) compared to families with only one
affected individual (simplex autism, SA). Recent studies suggest
that individuals from MA families may have a stronger genetic
predisposition to autism compared to SA families, due to
common genetic variants running in these families. Conversely,
autism in SA families may be more often induced by relatively rare
gene mutations of large effect or by copy number variations that are
unshared with the other family members [Sebat et al., 2007; Weiss et
al., 2008]. Advancing our knowledge about how genetic transmission may be different in these two types of families is of utmost
importance to our understanding of the etiology of autism spectrum conditions. We therefore read the article of Virkud et al.
[2009] with great interest and would like to share our thoughts on
their results and offer some suggestions for future analyses in
similar datasets.
If the hypothesis that genetic predisposition for autism is different in MA and SA families holds true, not only would individuals
from MA families be at increased risk for autism compared to SA
family members, but they may also show increased expression of
sub-threshold autistic traits measured on a dimensional scale. To
test this hypothesis, it is of interest to see if unaffected members of
MA families show increased expression of autistic traits compared
to unaffected relatives of SA families. Some evidence for this is
presented in Virkud et al.’s article. Mean quantitative autistic traits
(QAT) scores as assessed using the Social Responsiveness Scale
(SRS) seem to be somewhat higher (on a trend level, P ¼ 0.075) in
unaffected male siblings from MA families compared to male
siblings from SA families. This result is promising. However, it
remains unclear whether this trend holds when the significantly
higher QAT-scores in the affected brothers of MA families compared to SA brothers (Mean SRS score 104.7 vs. 87.8, P ¼ 0.0001)
are taken into account. It is not unconceivable that the autism
observed in the MA families is simply of a more severe kind (hence
leading to increased QAT expression in siblings) than in SA families.
A second test of the hypothesis would be to compare the
resemblance between siblings from MA and SA families. Virkud
et al. reported the intraclass correlation (ICC) between all male
Ó 2009 Wiley-Liss, Inc.
How to Cite this Article:
Hoekstra RA, Wheelwright S. 2010. Autistic
Traits in Simplex and Multiplex Autism
Families: Focus on Unaffected Relatives.
Am J Med Genet Part B 153B:356–358.
siblings from SA families (of which per definition one is affected and
the other is unaffected) and all male siblings from MA families (in
which a substantial amount of the sibling pairs are both affected and
only a small proportion consists of affected–unaffected sibling
pairs). The sibling correlations were found to be non-significant
(ICC ¼ 0.0) in SA families, and significant (ICC ¼ 0.46) in MA
families. Although this result is promising, the more interesting
question would be whether unaffected siblings from MA families
resemble their affected sibling more closely than affected– unaffected sibling pairs do from SA families. To answer this, the ICC should
be computed for affected–unaffected sibling pairs from MA families only. Unfortunately, this association was not tested by Virkud
et al. [2009].
Thirdly, Virkud et al. present the distribution of QAT in respectively all boys from SA families, all boys from MA families, and all
girls from MA families. The distribution of the scores in boys from
MA families appears to follow a markedly different distribution
than the scores from both other groups. Whilst the graphs depicting
scores from SA siblings and from MA female siblings follow
bimodal distributions, the distribution of scores from boys from
MA families appears continuous. However it is important to realize
that there are marked differences in the number of affected and
Grant sponsor: Netherlands Organisation for Scientific Research (NWO
Rubicon).
Comment on ‘‘Familial aggregation of quantitative autistic traits in
multiplex versus simplex autism’’ by Virkud et al., 2009 in the
American Journal of Medical Genetics Part B: Neuropsychiatric
Genetics 150B: 328–334.
*Correspondence to:
Dr. Rosa A. Hoekstra, Department of Psychiatry, Autism Research Centre,
University of Cambridge, Douglas House, 18b Trumpington Road,
Cambridge CB2 8AH, UK. E-mail: rah58@medschl.cam.ac.uk
Published online 14 April 2009 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.b.30947
356
ROSA A. HOEKSTRA AND SALLY WHEELWRIGHT
unaffected siblings in each of the graphs. The graph for SA families
(80 families in total) includes 80 affected males and 89 unaffected
males. The affected:unaffected ratio is thus approximately 1 (which
follows directly from the criterion for SA families set by Virkud et al.
that each affected male should have at least 1 unaffected brother).
This is in strong contrast to the graphs of MA families, which
include many more affected than unaffected boys (ratio ¼ 262:29,
or 9:1) and more affected than unaffected girls (ratio ¼ 81:45 or
1.8:1).
Therefore, the distribution of QAT scores in MA male siblings
may mainly look unimodal because there are so few unaffected
siblings in these families. Moreover, the distribution in MA girls
could appear to be bimodal because the unaffected MA girls have
autistic brothers (who are left out of the graph) rather than sisters.
To illustrate this point, we have amended the original Figure 1 from
Virkud et al. [2009] and displayed the distribution of QAT scores
as the proportion of the number of available siblings (Fig. 1) and
357
FIG. 2. Distribution of raw social responsiveness scale scores for
all boys and girls from multiplex autism families. Each line
represents the total number of affected or unaffected siblings
obtaining the score. [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]
we have grouped all siblings (both boys and girls) from MA
families together (Fig. 2). What these figures illustrate is that,
depending on the way you portray the data, the distribution looks
bimodal (for graphs representing proportions) for both male and
female siblings or unimodal (for graphs representing total number
of individuals).
We think more evidence is needed to establish whether
the aggregation of autistic traits is attenuated in female siblings of
autistic individuals. Of course it remains intriguing that the
sibling recurrence rate for autism is found to be much higher
in boys than in girls. To further study possible differences
in vulnerability for autism between the sexes, it would be
interesting to compare the resemblance in affected–unaffected
sibling pairs from MA families for male–male sibling pairs with
the resemblance in female–female sibling pairs and in opposite-sex
pairs.
In sum, studies exploring the differential aggregation of
QAT in relatives from MA and SA families are of great value to
further our understanding of the etiology of autism spectrum
conditions. We suggest that in future comparisons between these
two types of autism families the attention should focus on the
aggregation of autistic traits in unaffected relatives from MA
families.
ACKNOWLEDGMENTS
Dr. Hoekstra is financially supported by the Netherlands Organisation for Scientific Research (NWO Rubicon).
FIG. 1. A–C: Distribution of raw social responsiveness scale scores
for all boys from simplex autism families (A), for all boys from
multiples autism families (B), and for all girls from multiplex
autism families (C). Each line represents the proportion of
affected or unaffected siblings obtaining the score. [Color figure
can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
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