Jun Egawa ^1* Vance P. Lemmon ^2* Toshiyuki Someya ¹

• ¹ Niigata University, Niigata, Japan
• ² The Miami Project to Cure Paralysis, Miami, Florida, United States

Autism spectrum disorder (ASD) is a highly complex neurodevelopmental disorder characterized by a broad range of behavioral and cognitive manifestations.Genetic research has identified approximately 1,000 risk genes linked to ASD.Many of these genes are involved in critical processes of neuronal development, such as synapse formation, axonal growth, and synaptic pruning during the prenatal and early postnatal stages. However, the exact contributions of these risk genes to the clinical heterogeneity observed in ASD remain poorly understood.This problem is further compounded by risk genes altering molecular functions and cellular processes that change brain circuitry and, ultimately, behavior (Fig. 1). Given this complexity, understanding how individual risk genes influence phenotypes at successive hierarchical levels is essential for advancing ASD research and therapeutic development.The Research Topic Effects of Autism Spectrum Disorder (ASD) Risk Genes on Phenotypes of Each Hierarchy was conceived to address these gaps. This collection of studies focuses on elucidating the hierarchical impact of ASD risk genes by examining their effects at various levels, including molecular, cellular, circuit, and behavioral phenotypes. By investigating how changes at each level contribute to the broader ASD phenotype, these studies aim to identify convergent pathways that may underlie the disorder's diverse presentations. This editorial highlights four studies that exemplify this approach, each shedding light on different hierarchical levels and offering insights into potential therapeutic Together, these four studies highlight the value of a hierarchical approach to studying ASD risk genes. By examining how risk genes impact phenotypes at multiple levels-from proteins and cells to circuits and behaviors-these studies contribute to a more nuanced understanding of the biological underpinnings of ASD. Such research is crucial for the development of precision therapies that can address the specific needs of ASD subgroups. For instance, while targeting molecular pathways like Trio or PANK2 may benefit some individuals, others may require interventions that normalize circuit-level dysfunctions or modulate earlylife environmental factors.The implications of these findings extend beyond ASD. Many neurodevelopmental disorders, such as schizophrenia and ADHD, share overlapping genetic and phenotypic features with ASD, suggesting that insights gained from ASD research could inform the broader field of neurodevelopmental disorders. Future studies should focus on integrating data across hierarchical levels to create a comprehensive framework for understanding the complex relationships between genetic risk, neurodevelopmental processes, and behavior.Additionally, cross-species research using animal models and human subjects will be essential for validating and translating these findings into clinical practice.In conclusion, this Research Topic has highlighted the diverse effects of ASD risk genes across hierarchical phenotypes. By taking a multidisciplinary approach, the studies in this collection provide new perspectives on how genetic and environmental factors interact to shape the ASD phenotype. We hope that this Research Topic will stimulate further research into the hierarchical impact of ASD risk genes, ultimately paving the way for the development of more effective and targeted therapeutic strategies.Author contributions JE, VPL, and TS: Writing -original draft, Writing -review & editing.