A large-scale new genetic analysis reveals that the biological characteristics underlying autism risk are the same among people of different ancestral backgrounds. By testing the DNA of thousands of Latin Americans, researchers have shown that the rare genetic changes associated with autism occur in the exact same genes across different populations. The results were published in a magazine natural medicinepoints to a universal genetic basis for autism and emphasizes the need for more comprehensive medical testing.
Over the past decade, researchers have identified dozens of genetic variations that increase the likelihood of developing autism. These mutations tend to appear in highly conserved genes. Highly conserved genes are segments of DNA that remain nearly identical across species over vast evolutionary history.
These specific genes perform basic cellular functions and are therefore subject to rigorous natural selection. Their naturally occurring mutations disrupt essential biological processes and are usually eliminated over time. When these rare mutations occur in humans, they often cause significant neurodevelopmental changes.
Most of the DNA databases used to discover these autism-related genes rely almost entirely on people of European descent. This lack of global representation leaves major questions about whether genetic traits associated with autism look different in other parts of the world. Problems also arise in the real world when patients seek genetic counseling in the clinic. When people of non-European descent undergo genetic testing, results are often inconclusive simply because the genetic variant does not appear in standard reference databases.
To fill this gap, an international team of researchers established the “Genomics of Autism in Latin American Ancestry” consortium. Marina Nativida Avila, the researcher who led the study, collaborated with Joseph D. Buxbaum, director of the Seaver Center for Autism Research and Treatment at Mount Sinai. The research team wanted to determine whether genetic risk factors for autism differ depending on a person’s ancestry. They specifically focused on Latin American populations, which represent large and genetically diverse populations with Native American, African, and European heritage.
Researchers collected and analyzed genetic material from more than 15,000 individuals in North, Central and South America. The group included approximately 4,700 people diagnosed with autism, as well as their parents and healthy siblings. By comparing the DNA of autistic children with that of their parents, the researchers were able to identify natural mutations.
These natural mutations are newly occurring genetic changes that are present in the child but not in the parents. To find the specific genes involved, the research team used advanced DNA sequencing techniques that read the genetic code. They focused on the exome, a specific part of the genome that provides instructions for building proteins. Although the exome makes up only a small portion of our total DNA, it contains the majority of known disease-causing mutations.
The researchers carefully looked for rare, naturally occurring mutations that change or disrupt protein function. They then compared the rates of these disruptive mutations in children with autism to the rates in children without autism. Through this mathematical analysis, the research team identified 35 specific genes that are strongly linked to autism within the Latin American group. When they compared these 35 genes with genes previously found in European populations, they found significant overlap.
The biological pathways affected by these genes were completely consistent between the two groups. For example, both populations had mutations in genes that control how neurons communicate with each other in the brain. They also discovered disruption of genes that control the cytoskeleton, the scaffolding of a cell’s internal structures. These findings show that the subtle cellular mechanisms that cause autism are essentially the same around the world.
The underlying biology appears to operate completely independent of a person’s ethnic background. The research team also evaluated the mathematical tools scientists use to measure how conserved genes are. Because these tools were originally built using European DNA data, the researchers wanted to test their accuracy on diverse groups in Latin America. They found that these tools maintained high accuracy for the most important genes associated with autism.
This means that mutations in highly conserved genes have the same biological weight regardless of a person’s ancestry. As it turns out, the genetic changes that promote the likelihood of autism were not limited to a particular ancestral group. “Our results show that the core genetic structure of autism is shared across ancestry,” Buxbaum said. “This suggests that the biology underlying autism is universal and highlights the importance of ensuring diverse populations are represented in genetic research.”
Despite these obvious biological similarities, the researchers found some important limitations to their study. When the research team used standard clinical software to interpret the mutations they found, the software flagged fewer mutations as definitively harmful in Latin Americans than in Europeans. In clinical genetics, mutations that are definitively deleterious are known as pathogenic mutations. This diagnostic discrepancy arises because current clinical tools rely heavily on historical data, which is heavily biased toward European genomes.
As a result, non-Europeans may still not get a clear answer from standard genetic testing. Additionally, this study primarily relied on sequencing only the protein-coding regions of the genome, rather than the entire DNA sequence. This approach makes it difficult to know exactly which specific ancestral background a particular genetic variation originates from. In highly admixed populations, complete genomic data is required to trace the exact origin of small DNA segments.
Unmapped structural changes in the DNA of less studied populations may also harbor specific genetic risk factors. To correct these clinical blind spots, researchers must continue to sequence the DNA of diverse populations around the world. Adding more non-European genomes to medical databases will help improve the tools used to diagnose neurodevelopmental conditions. As these databases grow, physicians will be able to provide better and more accurate genetic counseling to families of all backgrounds.
Future efforts like these will help ensure that the benefits of precision medicine reach everyone. Medical testing needs to catch up with the reality that there is a common basis in human biology. “These findings provide a roadmap for improving genetic diagnosis across ancestry groups,” Buxbaum added. “Expanding genomic research in underrepresented populations is essential to reducing health disparities and advancing precision medicine for autism and related diseases across all ancestry populations.”
The study, “Detrimental coding mutations associated with autism are shared across ancestry,” was authored by Marina Natividad Avila, Seulgi Jung, F. Kyle Satterstrom, Jack M. Fu, Tess Levy, Laura G. Sloofman, Lambertus Klei, Thariana Pichardo, Dalia Marquez, Christine R. Stevens, Caroline M. Cusick, and Jennifer L. Ames. Gabriele S. Campos, Hilda Cerros, Roberto Chasquel, Claudia IS Costa, Michael L. Cuccaro, Andrea del Pilar López, Magdalena Fernandez, Eugenio Ferro, Liliana Galeano, Ana Cristina de Girardi, Anthony J. Griswold, Luis C. Hernandez, Nyla Lourenço, Eunin Rudena, Diana Nuñez-Rios, Rosa Oyama, Catherine P. Peña, Isaac Pessa, Rebecca Schmidt, Holly M. Sweeney, Lizbeth Tolentino, Jacqueline Y.T. Wang, Lilia Alborez-Gallo, Lisa A. Croen, Carlos S. Cruz-Fuentes, Ylva Herz-Picciotto, Alexander Corebzon, Maria Claudia Lattig, Liliana Mayo, Maria Rita Passos-Bueno, Margaret A. Pericak-Vance, Paige M. Siper, Flora Tassone, M. Pilar Trelles, GALA Consortium, The Autism Sequencing Consortium (ASC), Michael E. Talkowski, Mark J. Daly, Behrang Mahjani, Silvia De Rubeis, Edwin H. Cook, Kathryn Lauder, Catalina Betancourt, Bernie Devlin, and Joseph D. Buxbaum.
