Evidence for Cognitive Endophenotypes in Multiplex, but Not Simplex ASD and ADHD Families? A Focus On Unaffected Siblings

Background: Autism Spectrum Disorders (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are both highly heritable neurodevelopmental disorders that frequently co-occur. Research suggests that about 50-70% of the covariance of ASD and ADHD might be explained by shared additive genetic factors. For both disorders, a polygenic mode of inheritance has been proposed in most cases, supported by findings that similar (yet milder) abnormalities are present in unaffected relatives who carry susceptibility genes for the disorder. However, in some families in which ASD or ADHD affects only one individual in the family (simplex families), it is likely that causal factors not shared between family members (such as  rare single gene mutations or CNVs) may play a role. Therefore, we hypothesize that unaffected siblings from ASD and ADHD multiplex families, but not simplex families, display (mild) cognitive deficits similar to their ASD/ADHD affected sibling and have elevated levels of ASD (in ADHD cohort) and ADHD (in ASD cohort) symptoms.

Objectives: This study has two main objectives: (1) to examine if the etiology is indeed different in simplex versus multiplex families based on cognitive and symptom presentation of unaffected siblings and (2) whether ASD and ADHD share etiological underpinnings based on overlap of cognitive problems in ASD and ADHD affected children and increased symptoms of ASD in relatives of ADHD multiplex probands and vice versa.

Methods: The current study used a large sample of simplex and multiplex families from two family- genetic cohorts. A total of 186 ASD families (431 children), 184 ADHD families (545 children) and 209 control families (414 children) were included. Multiplex families were defined as two or more ASD affected individuals in ASD families and two or more ADHD affected individuals in ADHD families. Simplex families were required to have a single-affected child and a minimum of one male unaffected sibling. Several cognitive domains were examined, such as executive functions, social cognition, motor function, and central coherence.

Results: We are currently in to process of running our analyses. We plan on conducting linear mixed models to examine group differences on neuropsychological measures and symptom presentation in children with ASD and ADHD and their unaffected siblings. Groups will be defined as: (1) affected children vs. unaffected siblings vs. controls (analyses separate for ASD and ADHD cohort), (2) affected children from simplex families vs. affected children from multiplex families vs. controls, (3) unaffected siblings from simplex families vs. unaffected siblings from multiplex families vs. controls, (4) ASD affected children vs. ADHD affected children vs. controls, and (5) ASD unaffected siblings vs. ADHD unaffected siblings vs. controls.

Conclusions: This is the first study to examine differences in cognitive performances and behavioral symptoms between simplex and multiplex families in both ASD and ADHD families. We expect to find (mild) cognitive impairments and higher rates of comorbid ASD or ADHD symptoms in unaffected siblings from multiplex, but not simplex families. Our findings may provide new insights into the mechanisms of inheritance and the shared etiological underpinnings of ASD and ADHD.