Neuroimaging Signatures of Autism In Siblings

Background:  

Siblings of individuals with autism spectrum disorder (ASD) have a greatly enhanced risk of ASD and there is accumulating evidence that apparently unaffected siblings may also display subtle impairments in comparable domains of cognitive function.  Although siblings have been the subject of relatively little neuroimaging research, their study holds great promise as a means of identifying candidate endophenotypes of autism – expressed as differences in brain structure and function that are related to the genetic liability for the condition.  This is the first report of results from a large MRC funded study of adolescents with autism and their siblings.

Objectives:  

To recruit and scan adolescents with ASD, unaffected siblings and typically developing controls – with sufficient group sizes to investigate possible neural signatures of ASD as expressed in the structural and functional neuroimaging correlates of autism and of the broader phenotype in siblings. 

Methods:  

We recruited adolescents with ASD (n=40), their unaffected siblings (n=40) and typically developing controls (n=40), group matched for age and IQ.  All ASD participants met DSM-IV criteria for autism or Asperger Syndrome and were assessed as positive on the ADI-R (Autism Diagnostic Interview – Revised) and ADOS-G (Autism Diagnostic Observation Schedule – Generic).  All participants had IQ ≥ 70.  No sibling or control participant reached the screening threshold for ASD on the Social Communication Questionnaire (SCQ).  Participants completed brain structural and functional magnetic resonance imaging (MRI) on a 3T Siemens Tim Trio scanner.  Image processing and analysis of MRI scan data was performed using SPM8 (Wellcome Department of Cognitive Neurology, London, UK), and statistical correction for multiple comparisons was performed at whole-brain level.

Results:  

Preliminary results from this cohort reveal significant differences in brain structure between unaffected siblings and typically developing controls – including an excess of occipital grey matter in unaffected siblings (p = 0.02) that is expressed differently in sisters versus brothers of people with ASD.  These results provide the first evidence of a sexual dimorphism of brain structure in the broader phenotype of autism.

Conclusions:  

We have provided the first evidence of a sexually dimorphic signature of ASD in the brain structure of apparently unaffected adolescent siblings.  These results build upon previous findings of an age-related excess of grey matter in autism and of associations between fetal testosterone and the development of autistic traits.  These findings offer key insights into potential neuroendophenotypes of ASD and contribute to our understanding of the neural basis of autism.