Cortical Surface Architecture Endophenotype and Correlates of Clinical Diagnosis of Autism Spectrum Disorder

Background: Autism spectrum disorder (ASD) is a developmental disorder that shows cortical abnormality in the brain. Because of its genetic heritability, both individuals with ASD and their unaffected siblings present the endophenotype. Some prior MRI studies compared individuals with ASD, their unaffected siblings and typically developing (TD) people and recognized abnormalities shared by individuals with ASD and their unaffected siblings as the endophenotype.

Objectives: However, such prior studies have two major concerns. First, because they did not enroll siblings of TD people, they underestimated the difference between individuals with ASD and their unaffected siblings, which might have resulted in not identifying the difference for the diagnostic status. Second, although they demonstrated atypical gray matter characteristics, they did not clarify which aspect of gray matter presents the endophenotype. The aim of this cross-sectional study is to address these two concerns.

Methods: We recruited not only 15 pairs of adult male siblings with an ASD endophenotype but 15 pairs of TD siblings to account for the similarity between siblings. We focused on four gray matter parameters: cortical volume and three surface-based parameters (cortical thickness, fractal dimension, and sulcal depth [SD]). First, we sought to identify a pattern of an ASD endophenotype, comparing the four parameters. Then, we compared individuals with ASD and their unaffected siblings in the cortical parameters to identify neural correlates for the clinical diagnosis accounting for the difference between TD siblings.

Results: A sparse logistic regression with a leave-one-pair-out cross-validation showed the highest accuracy for the identification of an ASD endophenotype (73.3%) with the SD compared with the other three parameters. Focusing on SD, a bootstrapping analysis accounting for the difference in the SD between TD siblings showed a significantly large difference between individuals with ASD and their unaffected siblings in six out of 68 regions-of-interest accounting for multiple comparisons.

Conclusions: These findings suggest that an ASD endophenotype emerges in SD and that neural correlates for the clinical diagnosis can be dissociated from the endophenotype when we accounted for the difference between TD siblings.