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Gene–brain–behavior mechanisms underlying autism spectrum disorder: implications for precision psychiatry

Neuropsychopharmacology volume 49, pages 343–344 (2024)Cite this article

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Since “autism” was first systematically described by Leo Kanner in 1943, the genetic and neurobiological etiologies underlying its diverse clinical presentations of social affect (SA) impairment, restricted/repetitive behaviors/interests (RRBs), and other atypical behaviors have remained elusive—a major barrier to developing effective and personalized therapies. This highlights a need for new approaches aimed at explaining individual differences in autism spectrum disorder (ASD) and defining neurobiological subtypes [1]. One approach is combining dimensional, clustering, and transcriptomic analyses to link gene pathways to neurobiological and phenotypic heterogeneity, and reveal subtype-specific gene-brain-behavior associations [2]. The brainwide spatial organization of gene expression can then be used to predict neuropsychiatric-related changes in brain structure and function within subtypes.

ASD Subgroups 3 and 4 differed along axes of imbalanced SA–to–RRB and social-brain-related connections: visual–to–salience network connectivity was strengthened in Subgroup 3 (SA > RRB) but weakened in Subgroup 4 (RRB > SA). Oxytocin-related genes implicated in immune signaling were enriched for Subgroups 2 and 3 (high SA) while serotonergic-related genes that regulate spine remodeling were enriched in Subgroups 2 and 4 (high RRBs). These diverging gene–brain–behavior associations may contribute to inconsistent outcomes of preclinical and clinical trials: for example, personalizing therapies might reconcile whether intranasal oxytocin can improve SA and whether serotonin-modulating pharmacotherapeutics can reduce RRBs [3, 5].

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Fig. 1: Multimodal machine learning approach for investigating gene–brain–behavior mechanisms underlying phenotypic heterogeneity in autism spectrum disorder (ASD).

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Funding

Funding

AMB was supported by a Ford Foundation Postdoctoral Fellowship. Additionally, this work was supported by grants from the NIMH (MH118388, MH114976, MH123154, MH118451, MH109685, and MH109685-04S1), the National Institute on Drug Abuse (DA047851), the Hope for Depression Research Foundation, the Pritzker Neuropsychiatric Disorders Research Consortium, the Klingenstein–Simons Foundation Fund, the One Mind Institute, the Rita Allen Foundation, the Dana Foundation, the Foundation for OCD Research, the Hartwell Foundation, and the Brain and Behavior Research Foundation (NARSAD).

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  1. Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medicine, 413 East 69th Street, Box 240, New York, NY, 10021, USA

    Amanda M. Buch & Conor Liston

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  1. Amanda M. Buch
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  2. Conor Liston
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AMB and CL wrote, edited, and approved the article. AMB illustrated Fig. 1.

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Correspondence to Amanda M. Buch or Conor Liston.

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Competing interests

CL is listed as an inventor for Cornell University patent applications on neuroimaging biomarkers for depression that are pending or in preparation. CL has served as a scientific advisor or consultant to Compass Pathways, Delix Therapeutics, and Brainify.AI. The authors declare no other competing interests.

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Buch, A.M., Liston, C. Gene–brain–behavior mechanisms underlying autism spectrum disorder: implications for precision psychiatry. Neuropsychopharmacol. 49, 343–344 (2024). https://doi.org/10.1038/s41386-023-01722-0

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