Faculty Collaboration Database

Assessment of Neuroanatomical Endophenotypes of Autism Spectrum Disorder and Association With Characteristics of Individuals With Schizophrenia and the General Population. JAMA Psychiatry 2023 May 01;80(5):498-507

Date

04/06/2023

Pubmed ID

37017948

Pubmed Central ID

PMC10157419

DOI

10.1001/jamapsychiatry.2023.0409

Scopus ID

2-s2.0-85159060372 (requires institutional sign-in at Scopus site)   3 Citations

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.

Author List

Hwang G, Wen J, Sotardi S, Brodkin ES, Chand GB, Dwyer DB, Erus G, Doshi J, Singhal P, Srinivasan D, Varol E, Sotiras A, Dazzan P, Kahn RS, Schnack HG, Zanetti MV, Meisenzahl E, Busatto GF, Crespo-Facorro B, Pantelis C, Wood SJ, Zhuo C, Shinohara RT, Shou H, Fan Y, Di Martino A, Koutsouleris N, Gur RE, Gur RC, Satterthwaite TD, Wolf DH, Davatzikos C

Author

Gyujoon Hwang PhD Assistant Professor in the Psychiatry and Behavioral Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Autism Spectrum Disorder
Brain
Cross-Sectional Studies
Endophenotypes
Female
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Neuroanatomy
Reproducibility of Results
Schizophrenia
Young Adult