Whole-brain functional hypoconnectivity as an endophenotype of autism in adolescents

• Adolescents with autism and genetic relatives show weaker functional connectivity.
• This appears at a whole-brain level in several task contexts.
• Connectivity in autism and in siblings is much more variable than in controls.
• Local endophenotypes also appear in default mode network and visual network.
• Hypoconnectivity is a feature of the broader and the diagnosable autism spectrum in adolescents.

Endophenotypes are heritable and quantifiable markers that may assist in the identification of the complex genetic underpinnings of psychiatric conditions. Here we examined global hypoconnectivity as an endophenotype of autism spectrum conditions (ASCs). We studied well-matched groups of adolescent males with autism, genetically-related siblings of individuals with autism, and typically-developing control participants. We parcellated the brain into 258 regions and used complex-network analysis to detect a robust hypoconnectivity endophenotype in our participant group. We observed that whole-brain functional connectivity was highest in controls, intermediate in siblings, and lowest in ASC, in task and rest conditions. We identified additional, local endophenotype effects in specific networks including the visual processing and default mode networks. Our analyses are the first to show that whole-brain functional hypoconnectivity is an endophenotype of autism in adolescence, and may thus underlie the heritable similarities seen in adolescents with ASC and their relatives.