JTwo of the largest DNA sequence analyzes of people with autism have discovered genes linked to the condition across a range of variant types. the work, published in two studies today in Natural geneticsprovides a more complete picture of the genetic architecture of the disease and indicates how it may differ from that of other neurodevelopmental conditions.
Scientists typically search for de novo variants in sequences to spot genes linked to autism – an approach that has yielded around 100 genes. But alterations in these genes tend to have global effects on cognition and brain function, and people who carry them often represent only part of the autism spectrum.
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“I think we were biased in terms of the genes we identified,” says Wendy Chung, a professor of pediatrics and medicine at Columbia University, who co-led one of the studies. To better understand the biology underlying brain function, behavior and autism, researchers need to look at genetic variation across the spectrum, she says.
Besides de novo variants, several other types, such as legacy variants and large DNA duplications or deletions known as copy number variants (NVC) – may contribute to autism. But insufficient sample sizes have limited researchers’ ability to detect genes strongly linked to disease by these types of alterations.
The two new studies come from international collaborations that have amassed treasure troves of genetic data. An analysis considers both de novo and inherited variants to uncover five new autism-linked genes, four of which are linked to a lower likelihood of cognitive impairment than five well-established autism-linked genes. The other study integrates data on single-letter changes in DNA, small insertions or deletions called indels, and CNVs to detect 373 genes linked to autism and other neurodevelopmental conditions, as well as 36 genes that exhibit increased autism variation.
Together, the studies expand the list of genes broadly linked to neurodevelopment, which researchers can use to build on previous work which aims to find out how genes are linked to specific conditions or traits, says Varun Warriorpostdoctoral researcher in Simon Baron Cohenfrom the University of Cambridge laboratory in the UK, which was not involved in the research.
“We don’t know exactly what these genes are actually associated with,” says Warrier, but the work points to differences that could help researchers untangle heterogeneity in neurodevelopmental conditions.
VShung and his colleagues analyzed the genetic sequences of more than 42,607 people with autism and 79,670 of their parents and siblings. The team relied on previously published data from three projects – the Autism Sequencing Consortium, MSSNG and the Simons Simplex collection–as well as new footage from 35,130 people collected through an online registry called SPARK. (As Spectrumthe Simons Simplex Collection and SPARK are both funded by the Simons Foundation Autism Research Initiative, where Chung is also Director of Clinical Research.)
The researchers used a two-step approach: they first searched for genes enriched with de novo alterations. They also defined 25 sets of genes based on existing genetic or functional evidence for autism, such as genes expressed in neurons or those predicted by machine learning tools to be related to the condition. They then identified genes harboring variants that people with autism inherit more often than expected by chance in gene sets enriched with rare and inherited loss-of-function variants.
Overall, autism showed links to de novo variants in 159 genes and rare and inherited variants in another 260 genes. The team found that known genes linked to autism and neurodevelopment account for approximately 70% of autism risk attributed to de novo variants, while these genes explain less than 20% of the likelihood conferred by rare and neurodevelopmental variants. hereditary.
“This means that it is very useful to identify new risk genes through rare and inherited variants,” says Yufeng Shenassociate professor of systems biology at Columbia University, who co-led the work.
Another round of statistical tests incorporated 8,116 additional samples from autistic children and their parents, again looking for genes enriched for de novo variants or harboring over-inherited alterations in autism among 367 genes on non-sex chromosomes . The analysis also compared the rates of loss-of-function variants in 15,780 people with autism and 236,000 population controls.
The approach uncovered 60 genes strongly linked to autism, including 5 new ones: ITSN1, SCAF1, HNRNPUL2, MARK 2 and NAV3. The first three genes in this list are linked to autism through several types of variants. NAV3however, is primarily linked to the disease through rare and inherited variants, the researchers report.
All new genes, but MARK 2 have modest effects, the researchers found, and autistic people who carry variants are less likely to have cognitive impairment than people who harbor variants in a comparison set of five well-established autism-linked genes: CHD8, SCN2A, DNAP, FOXP1 and STEM3. Genes with modest effects may be more closely linked to core autism traits than to brain development, the researchers say.
Although assessing cognition in people with autism can be difficult, the study is a step toward better understanding the complexity of the condition, says Thomas Bourgeron, a professor of genetics at the Institut Pasteur in Paris, France, who was not involved in the research. Taking cognitive disorders into account brings more nuances than simply comparing autistic people with controls. “It’s a little more specific,” he said.
IIn the other study, a team co-led by Michael Talkowskidirector of the Center for Genomic Medicine at Massachusetts General Hospital in Boston, looked for single-letter changes in the DNA and indels in the exome sequences of 63,237 people, including 20,627 with autism.
They also used a method developed several years ago to detect CNVs in exome data – drawn from various repositories, including the Autism Sequencing Consortium, the Simons Simplex Collection, iPSYCH and SPARK – and calibrated the approach using whole genome sequences from 7,165 people.
In total, this method yielded 17,774 rare, inherited and 662 de novo CNVs spanning three or more exons. The team used a statistical framework called TADA combine information about CNVs, indels, and single-letter DNA changes with a score that measures a gene’s tolerance to variants that alter its function. This process revealed 72 genes associated with autism – a significant increase from a previous study which found 32 genes linked to the condition at the same level of statistical significance, the researchers reported.
Another analysis that combined sequences from people with autism and 91,605 people from Deciphering developmental disorders study – of which 31,058 have a developmental condition – detected 373 genes linked to neurodevelopment. The genes identified among people with autism and among those with other developmental disabilities overlapped, with 70-90% of the genes identified in both groups.
Assessing variation among 464 genes associated with either condition through de novo mutations that likely affect gene function revealed 36 genes that harbor more variation in people with autism than in people with other developmental conditions. Another 82 genes are more often altered in people with developmental disabilities.
These results provide insight into some of the genes that might contribute to autism compared to other developmental conditions, Talkowski said. Expression of genes linked to other developmental conditions is enriched in early neurodevelopmental cell types, according to an analysis of single-cell gene expression data from the developing brain. Genes primarily associated with autism, on the other hand, are widely expressed in maturing neurons.
The results are interesting, Warrier says, but children with other developmental disabilities may have undiagnosed or concurrent autism, and vice versa. “These are not watertight compartments,” he says, and better characterizing people in each group can help link genes to distinct traits, which is an ongoing challenge in the field.
Talkowski, too, notes that the two conditions are difficult to disentangle. Which genes are linked to autism versus other neurodevelopmental conditions may change as research continues, he says. Nonetheless, as more data becomes available, the study provides a framework to better understand how genes and classes of variants contribute to various neurodevelopmental conditions and traits.