Autism spectrum disorder (ASD) remains a complex puzzle, its pieces scattered across the landscape of genetics and neurobiology. In the quest to uncover its secret, large-scale genomic studies have been conducted on North American and European populations, but a crucial gap remained: the genetic tapestry of the Korean demographic.

That is until Professor Yoo Hee-jeong collaborated with Professor An Joon-yong in a groundbreaking study that unveiled a novel chapter in ASD genetics — the first to identify a novel genetic variant responsible for ASD in Korea.

Dr. Yoo, from the Department of Neuropsychiatry at Seoul National University Bundang Hospital (SNUBH) is a leading authority in the field of adolescent psychiatry, with her research spanning across ASD, ADHD, and various emotional and behavioral disorders. 

According to Dr. An, a professor in the Department of Biosystem and Biomedical Science at Korea University, previous large-scale genomic studies primarily focused on Europeans and did not fully reflect the genetic traits of Koreans. Dr. An serves as the principal investigator of An Lab at Korea University, leading research into the genetic roots of developmental and neurological disorders. 

This study stands as the first and most comprehensive evidence of STR expansion associated with ASD in Korea to date, particularly in individuals of non-European descent, according to SNUBH.

The research team discovered that a variation in a part of a genome known as short tandem repeats (STR) affects a network of genes specific to cortical layers that regulate brain development and is associated with ASD, potentially being a genetic risk factor for the disorder.

ASD is a complex neurodevelopmental condition characterized by repetitive and restricted behaviors (RRBs), sensory-related RRBs being the most common. These behaviors include restricted interests, fixation on objects, resistance to change, and repetitive body movements, alongside communication deficits and atypical social functioning. While ASD is known to be highly hereditary, many genetic studies have failed to pinpoint specific genetic factors associated with the disorder, and research on Korean populations remains limited.

To identify the genetic causes of ASD in Korean populations, Dr. Yoo and her research team used deep learning models, a subset of machine learning (ML) within the broader field of artificial intelligence (AI). They investigated the genetic link between STR expansions and ASF using whole genome sequencing, a technology that reveals the complete DNA make-up of an organism, to identify risk loci associated with ASD phenotypes. 

They conducted an analysis involving 12,929 genes for a group of 2,104 individuals. This group included 641 individuals diagnosed with ASD, 634 non-autistic mothers, 634 non-autistic fathers, and 195 non-autistic siblings.

The research revealed that STR variants play a significant role in influencing gene expression and regulating chromosomes from the moment of fertilization to birth. This developmental window is crucial as it marks a period of extensive growth, especially in the brain. These variants were detected in genes spread throughout the prefrontal cortex, which is responsible for governing adaptive behaviors and cognitive functions closely linked with ASD.

STRs are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in ASD remains largely unexplored. 

The genome encompasses the entirety of genes and chromosomes within the cell nucleus, primarily composed of repetitive DeoxyriboNucleic Acid (DNA), including tandem repeats, which may be used as genetic markers to track inheritance in families. Among these, STRs constitute approximately 6.8% of the genome and are one of the genetic variations that contribute to trait differences.

In ASD cases, rare STR expansions predominantly occurred in genes specific to layers of neurons in the cerebral cortex involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. 

Using deep learning prediction models, they demonstrated that these STR expansions disrupt the regulatory functions of enhancers and promoters, suggesting a potential pathway contributing to ASD pathogenesis. They found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers.

Due to the rapid growth of the brain during early development, timely diagnosis and early intervention for autism can significantly improve outcomes. 

“If we can detect autism spectrum disorders early and start treatment quickly, we can achieve positive results,” said Dr. Yoo. “We plan to conduct a comprehensive study of genetic variation in ASDs in the Korean population to identify the specific genes responsible for causing these disorders.”

The study underscored a notable discrepancy between the genetic signatures identified in previous studies on North American and European populations and the genetic makeup observed within the Korean demographic. “This incongruity suggests the  importance of considering the distinct patterns of gene expression among diverse ethnic groups, particularly in the context of complex neurodevelopmental disorders like autism,” Dr. Yoo said. 

To gain a more comprehensive understanding of the genome, she said, it’s crucial to grasp how genes have been passed down from ancestors to the present day and consider this within the context of the diversity inherent in the genome. “It is believed that research conducted in Asia will contribute to filling the gaps in autism genomic research,” she said.

The research received support and funding from the Institute for Basic Science, Ministry of Science and ICT, and KISTI’s Supercomputing Center.

The study is published in the international journal Psychiatry and Clinical Neuroscience (IF 11.9).