New research reveals autism risk genes are shared across ancestries
The Mount Sinai Hospital / Mount Sinai School of Medicine
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Map of GALA collection sites across the Americas.
view moreCredit: Marina Natividad Avila, MSc
A new study, co-led by researchers at the Icahn School of Medicine at Mount Sinai and published March 30 in Nature Medicine [https://doi.org/ 10.1038/s41591-026-04228-6], demonstrates that genes associated with autism risk are largely the same across people of different ancestries.
The findings, based on one of the largest genomic studies of Latin American individuals to date, provide strong evidence that the genetic architecture of autism is consistent across diverse populations. They underscore the importance of expanding genetic research beyond individuals of European ancestry.
Over the past decade, scientists have identified numerous rare genetic variants that confer substantial risk for autism and other neurodevelopmental disorders. However, most of these discoveries were made in cohorts composed predominantly of individuals of European ancestry, leaving open the question of whether autism’s genetic underpinnings differ across populations. This knowledge gap has contributed to disparities in genetic testing, including higher rates of inconclusive results among non-European individuals due to limited reference data.
To address this issue, the research team analyzed exome and genome sequencing data from more than 15,000 Latin American individuals across North, Central, and South America, including approximately 4,700 individuals diagnosed with autism. Latin American populations represent the largest recently mixed-ancestry group globally, with heritage that frequently includes Indigenous American, West African, and European origins. This rich genetic diversity provides a powerful opportunity to refine gene-disease associations, which can improve health outcomes for all populations.
The study examined more than 18,000 genes for enrichment of rare, deleterious coding variants—genetic changes that can have immediate and profound clinical implications for diagnosis, treatment, and family counseling.
Consistent with prior research, rare, deleterious variants in highly conserved genes—genes that remain similar across species and populations over long periods of time—were disproportionately observed in individuals with autism. Researchers identified 35 genes significantly associated with autism in the Latin American cohort. These genes showed extensive overlap with those previously identified in genome-wide studies of individuals of European ancestry. The findings also provide support for several recently identified “emerging” autism-associated genes.
“Our results indicate that the core genetic architecture of autism is shared across ancestries,” said study senior author Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center for Research and Treatment at Mount Sinai. “This suggests that the biology underlying autism is universal and reinforces the importance of ensuring that diverse populations are represented in genetic research.”
The study also evaluated widely used metrics that assess evolutionary conservation of genes, an important tool for prioritizing genes in clinical genetic analyses of neurodevelopmental disorders. The researchers found that these metrics, which were again largely derived from European-ancestry datasets, may overestimate conservation overall due to limited ancestral diversity in European populations. However, the metrics remain highly accurate for the most strongly conserved genes—including those most relevant to autism and other neurodevelopmental disorders.
The authors note that continued sequencing of diverse populations will further improve conservation metrics, particularly for less conserved genes, ultimately enhancing the accuracy of clinical genetic testing.
“These findings provide a road map for improving genetic diagnosis across ancestral groups,” said Dr. Buxbaum. “Expanding genomic research in underrepresented populations is essential to reducing health disparities and advancing precision medicine for autism and related conditions across all ancestral populations.”
The study’s results align with growing evidence that both rare and common genetic risk factors for complex disorders are shared across diverse populations. By demonstrating broad overlap in autism risk genes across ancestries, the research supports more inclusive approaches to genomic medicine and reinforces the universal biological foundations of autism.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across seven hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 9,000 primary and specialty care physicians and 10 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals” and by U.S. News & World Report’s® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report® “Best Hospitals” Honor Roll for 2025-2026.
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Journal
Nature Medicine
Method of Research
Observational study
Subject of Research
People
Article Title
Deleterious coding variation associated with autism is shared across ancestries
Article Publication Date
30-Mar-2026
A new lens on autism’s sex bias
Whitehead Institute for Biomedical Research
Autism has a significant and enduring sex bias, with roughly four boys diagnosed for every girl. For many years, experts have believed this disparity arises primarily from diagnostic inequities because much of autism research — and the screening tools that grew out of it — has historically focused on boys, effectively setting a male standard for what autism “looks like.” As a result, girls and women are more likely to be overlooked, misdiagnosed, or diagnosed much later in life.
This disparity has also shaped the science around autism. When fewer females with the condition are identified, fewer are included in research studies, creating a feedback loop where scientific understanding of autism in females remains limited. Because of this underrepresentation of females, it has been difficult for scientists to disentangle how much of the sex bias in autism reflects social inequities versus underlying biological differences between the sexes.
While the search for biological explanations has largely lagged behind, one leading theory, known as the “female protective effect,” proposes that females may be biologically buffered against developing autism in a way males aren’t.
The idea can be traced back to studies showing that females diagnosed with autism tend to carry a higher number of genetic mutations or “hits” than males with the condition, meaning that they require a higher load of the same genetic mutations for autism to manifest. But, until now, there’s been little clarity on the exact biological mechanism behind this apparent resilience.
Now, a perspective from the lab of Whitehead Institute Member David Page, published March 30 in Nature Genetics, proposes a genetic explanation for the female protective effect and suggests that biological differences between males and females contribute to autism’s strong sex bias.
The work is one of many projects from the Page lab uncovering the biological underpinnings of sex bias in everything from heart health and autoimmune disease to certain cancers.
“The fact that we see sex biases in disease all across the body gives credence to the notion that the sex bias in autism isn’t simply emerging from diagnostic inequities and gendered expectations of what the conditions looks like,” says Page, who is also a professor of biology at Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute (HHMI).
The researchers propose that this protective effect extends beyond autism, and could help explain why 17 other congenital and developmental disorders predominately affect males. By characterizing the biological factors that make one sex more or less likely to develop certain health conditions, scientists see an opportunity to improve how these conditions are diagnosed and how people receive care.
Page and Harvard-MIT MD-PhD student Maya Talukdar trace the female protective effect to the X chromosome. Talukdar is a graduate student in Page’s lab and the lead author of the perspective.
Most females have two X chromosomes (XX) while most males have one X and one Y chromosome (XY). Sex chromosomes can dial up and down the expression of thousands of genes on the other 22 pairs of chromosomes in a cell, impacting cell function across the entire body.
Historically, scientists believed that the second X chromosome in females is largely inactive. But, in recent years, research out of the Page lab has shown that the so-called “inactive X,” also called Xi, plays a crucial role in regulating gene expression on the active X chromosome, and the rest of the chromosomes.
In this perspective, the researchers point to a subset of genes that are expressed from both the active and inactive X chromosome — often known as genes that “escape” X chromosome inactivation. Many of these genes are dosage-sensitive regulators of key cellular processes. These processes influence thousands of other genes across the genome, including many linked to autism.
Because females have an extra copy of these regulatory genes expressed from Xi, Page and Talukdar propose that they may be better able to buffer the effects of autism-associated mutations than males.
The female protective effect beyond autism
This mechanism, the researchers say, extends beyond autism to a range of congenital and developmental diseases with a male bias.
“Many of the other congenital or developmental conditions we’re pointing to aren’t subject to diagnostic inequities in the way autism is,” says Talukdar. “This strengthens the idea that the female protective effect is emerging from genetic differences in males and females.”
One example is pyloric stenosis, which like autism, affects four boys for every girl. Infants with the condition experience severe vomiting due to thickening of the pyloric sphincter, the passage between the stomach and small intestine. As with autism, girls with pyloric stenosis appear to require more genetic “hits” in order to develop the condition.
The researchers’ new framework of looking at Xi to understand sex differences in disease could impact treatment and care not just for conditions that predominately affect males, but also for those that are more common in women, such as autoimmune diseases.
“Our biology isn’t one-size-fits-all,” Talukdar says “Sex differences clearly play a huge role in health, and it’s so important that we understand them.”
ABOUT WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH
Whitehead Institute is a nonprofit, independent biomedical research institute founded in 1982. The institute advances pioneering research in cancer, developmental biology, genetics, genomics, and related fields, with a mission to pursue bold, curiosity-driven science that deepens our understanding of life and improves human health. Led by 24 principal investigators and a global community of trainees and scholars, Whitehead Institute maintains a teaching affiliation with Massachusetts Institute of Technology (MIT) but is fully independent in its research programs, governance, and finances.
Journal
Nature Genetics
Subject of Research
Cells
Article Title
The inactive X chromosome as a female protector in autism and beyond
Article Publication Date
30-Mar-2026
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