Familiar autism-linked genes emerge from first analysis of Latin American cohort

Ancestry has little bearing on the genes strongly linked to autism, according to the first genetic analysis of the largest cohort of autistic Latin Americans and their families to date. The results were posted on medRxiv on 6 January and have not yet been peer reviewed.

Of the 35 genes linked to autism in the cohort, which is managed by a consortium called Genomics of Autism in Latin America (GALA), 19 are strongly associated with autism in a separate dataset of people of European ancestry. “We conclude that the biology of ASD is universal and not impacted to any detectable degree by ancestry,” the investigators wrote in the preprint.

“It has been an open discussion in the field,” says the study’s principal investigator, Joseph Buxbaum, director of the Seaver Autism Center for Research and Treatment at the Icahn School of medicine at Mount Sinai. “And this provides a fairly clear answer.”

Diversifying autism genetics databases is “critical” work, says Maria Chahrour, associate professor of neuroscience at the University of Texas Southwestern Medical Center, who was not involved in the study. But Buxbaum’s conclusion may be premature, she says.

Although the fundamental biology of autism is likely consistent across people of various ancestries, saying ancestry has no impact is “a little bit of an overreach,” she says.

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ost genetic studies to date primarily include people of European ancestry. To address this gap, Buxbaum and other scientists affiliated with the Autism Sequencing Consortium (ASC) started GALA—which includes existing data as well as funding to sequence additional families—in 2022.

GALA has a total of 10 sites, located in São Paulo, Brazil; Bogota, Colombia; Central Valley, Costa Rica; Mexico City, Mexico; and Lima, Peru; as well as in California, Florida and New York. In contrast with other international gene-sequencing projects, the GALA cohort comprises a greater proportion of people who have admixed American heritage, which can include Indigenous, European, African and East Asian ancestry. The new analysis includes 1,613 Latin American people—707 of whom have autism—whose sequences have not previously been reported.

The new analysis looked at the exomes—or, in a few cases, whole genomes—of 4,450 autistic people from Latin America, along with 1,459 of their neurotypical siblings and 8,450 parents. (Data from two sites were not yet ready for analysis.)

The researchers looked for de novo variants—which are not inherited but rather occur spontaneously in a parent’s egg or sperm, or in an embryo after conception—in the GALA cohort, as well as in a previously published cohort that combined data from the ASC, the Simons Simplex Collection and SPARK, from which Buxbaum’s team removed people with admixed American heritage. (The Simons Simplex Collection and SPARK are funded by the Simons Foundation, Spectrum’s parent organization.)

One gene that emerged, MARK2, has not been definitively linked to autism but has emerged in datasets of severe developmental delay. This finding demonstrates the scientific value of expanding genetics research beyond people with European backgrounds, Buxbaum says.

The 35 genes Buxbaum and his team found tend to be involved in gene expression regulation, neuronal communication and the structure and function of cells, roles that align with those seen in autism-linked genes in European cohorts.

The investigators’ conclusion—that ancestry has no detectable impact on autism—is “fair to say” based on the findings, says Dennis Lal, associate professor of neurogenetics at McGovern Medical School at UT Health Houston, who was not involved in the work.

But the 35 genes highlighted in the new analysis are typically linked specifically to autistic people with high support needs, or what is sometimes called profound autism. That leaves open the possibility that ancestry and environment could have a greater effect on other forms of autism, Lal says.

Still, he says, the work underscores the consistency of the underlying pathways involved in autism: “At the end, it’s the same biology, but it comes in different flavors.”

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any known autism-linked genes don’t show the typical accumulation of variants that occurs over the course of evolution. This tendency implies that the genes are crucial for survival, and variants in them are typically not passed from one generation to the next.

There’s no reason to expect a higher rate of such random variants in one ancestry than in another, Buxbaum says. But without the genomes of more non-European people, researchers were stuck looking for a hypothetical black cat in a dark room.

“We’ve shown there is no cat,” Buxbaum says, “and that’s not a bad thing.”

But it’s possible that variants that are inherited could interact with the identified genes in ways that ultimately affect a person’s traits, Chahrour says. Another limitation, she notes, is that the study accounts for only the protein-coding portion of the genome.

“Even if core gene sets overlap, the expression or penetrance may be modulated by population-specific genetic backgrounds,” she says.

In a 2023 analysis of 129 people from East Africa, for example, Chahrour identified areas of the genome where variants are more likely to be passed from parents to children in people of African ancestry than in those of European ancestry; those regions contained genes linked to autism and other neurodevelopmental conditions.

Buxbaum agrees that genetic background matters. But most of the variants identified in the study have significant impacts on a gene’s function—the variants essentially never occur in controls.

Ultimately, cohorts such as GALA could improve clinical genetic testing, particularly—but not only—for people of non-European ancestry, agree Lal, Chahrour and Buxbaum.

“Without precision diagnostics, there’s no precision medicine,” Lal says.