: Publication 11395

Publication 11395

Title:	Assessment of Neuroanatomical Endophenotypes of Autism Spectrum Disorder and Association With Characteristics of Individuals With Schizophrenia and the General Population
Journal:	JAMA Psychiatry
Published:	1 May 2023
Pubmed:	https://pubmed.ncbi.nlm.nih.gov/37017948/
DOI:	https://doi.org/10.1001/jamapsychiatry.2023.0409
URL:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10157419

Abstract

Importance: Autism spectrum disorder (ASD) is associated with significant clinical, neuroanatomical, and genetic heterogeneity that limits precision diagnostics and treatment.

Objective: To assess distinct neuroanatomical dimensions of ASD using novel semisupervised machine learning methods and to test whether the dimensions can serve as endophenotypes also in non-ASD populations.

Design, Setting, and Participants: This cross-sectional study used imaging data from the publicly available Autism Brain Imaging Data Exchange (ABIDE) repositories as the discovery cohort. The ABIDE sample included individuals diagnosed with ASD aged between 16 and 64 years and age- and sex-match typically developing individuals. Validation cohorts included individuals with schizophrenia from the Psychosis Heterogeneity Evaluated via Dimensional Neuroimaging (PHENOM) consortium and individuals from the UK Biobank to represent the general population. The multisite discovery cohort included 16 internationally distributed imaging sites. Analyses were performed between March 2021 and March 2022.

Main Outcomes and Measures: The trained semisupervised heterogeneity through discriminative analysis models were tested for reproducibility using extensive cross-validations. It was then applied to individuals from the PHENOM and the UK Biobank. It was hypothesized that neuroanatomical dimensions of ASD would display distinct clinical and genetic profiles and would be prominent also in non-ASD populations.

Results: Heterogeneity through discriminative analysis models trained on T1-weighted brain magnetic resonance images of 307 individuals with ASD (mean [SD] age, 25.4 [9.8] years; 273 [88.9%] male) and 362 typically developing control individuals (mean [SD] age, 25.8 [8.9] years; 309 [85.4%] male) revealed that a 3-dimensional scheme was optimal to capture the ASD neuroanatomy. The first dimension (A1: aginglike) was associated with smaller brain volume, lower cognitive function, and aging-related genetic variants (FOXO3; Z = 4.65; P = 1.62 × 10-6). The second dimension (A2: schizophrenialike) was characterized by enlarged subcortical volumes, antipsychotic medication use (Cohen d = 0.65; false discovery rate-adjusted P = .048), partially overlapping genetic, neuroanatomical characteristics to schizophrenia (n = 307), and significant genetic heritability estimates in the general population (n = 14 786; mean [SD] h2, 0.71 [0.04]; P < 1 × 10-4). The third dimension (A3: typical ASD) was distinguished by enlarged cortical volumes, high nonverbal cognitive performance, and biological pathways implicating brain development and abnormal apoptosis (mean [SD] β, 0.83 [0.02]; P = 4.22 × 10-6).

Conclusions and Relevance: This cross-sectional study discovered 3-dimensional endophenotypic representation that may elucidate the heterogeneous neurobiological underpinnings of ASD to support precision diagnostics. The significant correspondence between A2 and schizophrenia indicates a possibility of identifying common biological mechanisms across the 2 mental health diagnoses.

32 Authors

Gyujoon Hwang

Junhao Wen

Susan Sotardi

Edward S. Brodkin

Ganesh B. Chand

Dominic B. Dwyer

Guray Erus

Jimit Doshi

Pankhuri Singhal

Dhivya Srinivasan

Erdem Varol

Aristeidis Sotiras

Paola Dazzan

Rene S. Kahn

Hugo G. Schnack

Marcus V. Zanetti

Eva Meisenzahl

Geraldo F. Busatto

Benedicto Crespo-Facorro

Christos Pantelis

Stephen J. Wood

Chuanjun Zhuo

Russell T. Shinohara

Haochang Shou

Yong Fan

Adriana Di Martino

Nikolaos Koutsouleris

Raquel E. Gur

Ruben C. Gur

Theodore D. Satterthwaite

Daniel H. Wolf

Christos Davatzikos