The largest analysis to date of whole-genome sequences from people with autism links new genes and variants to the disease. The results and sequences – from 5,100 people with autism and 6,212 without – are on a cloud-based platform and are available to trained researchers.
This effort is the latest advancement of the ongoing MSSNG project and doubles the number of participants compared to the previous version of the research collaboration in 2017.
It also expands the types of variants considered, to include inherited or non-hereditary, common or rare single-nucleotide variants; brief insertions and deletions; structural variants; additional repeating pieces of DNA called tandem repeats; and mitochondrial DNA variants.
Collecting data on so many different types of variants at once is useful to a large community of autism researchers — and required a wide range of expertise, says lead researcher Stephen Scherer, professor of molecular genetics at the University of Toronto in Canada. More than 100 researchers collaborated on this study for about two years.
“If you just took two random authors from this list and asked yourself if the first author would have been able to do what the second author did, and vice versa, in most cases the answer was no”, explains Brett Trost, postdoctoral researcher in the Scherer Laboratory.
Other autism geneticists have been eagerly awaiting the latest version of MSSNG, says Maria Chahrour, an associate professor of neuroscience and human growth and development at the University of Texas Southwestern Medical Center in Dallas, who was not involved in the the study. As of July, more than 300 researchers from 65 institutions and 20 countries had access to the database, according to the document. The findings were published in Cell in November.
ANearly 3,500 of the autistic participants are from simplex families, which have only one autistic child, and 777 are from multiplex families, which have at least two children on the spectrum. A quarter of the participants are of non-European descent.
Autism was strongly linked to 134 genes – including 67 not previously reported – in an analysis of de novo coding variants in data from MSSNG plus two other projects: the Autism Sequencing Consortium and SPARK. (SPARK is funded by the Simons Foundation, Spectrum‘s parent organization.) Many of the new genes contribute to cellular functions implicated in autism, including synaptic signaling, chromatin remodeling, and control of gene expression and protein translation.
Across the entire dataset, about 14% of people with autism carry rare variants. The team found a similar percentage among footage from 9,205 people in the Simons Simplex Collection, a cohort of autistic simplex families. (This collection is also funded by the Simons Foundation.)
“We have a pretty good picture of rare genetic variation,” Scherer says. “Now is the time to focus on what is happening in the remaining 85% of families.” This will require studying hundreds of thousands of entire family genomes, he adds.
ATo take a step in that direction, Scherer’s team calculated a polygenic autism risk score — a sum of common variants linked to the condition — for each MSSNG participant. People with autism score higher than their nonautistic siblings, the team found, consistent with previous research. But autistic people from multiplex families do not have above-average scores, suggesting that rare hereditary variants play a greater role in multiplex autism – a finding that complements an unpublished analysis of multiplex families presented. at the American Society of Human Genetics conference in October. .
The new analysis of polygenic risk scores is an important contribution, says Chahrour.
“I think it’s dangerous to overstate polygenic risk scores when we know so little about them and rely primarily on European ancestry to calculate these scores,” says Chahrour, whose own genetics research focus on diverse ancestral cohorts.
The study also provided information to the thousands of families who participated. Vicky Garbutt – who signed up, her husband, their autistic son Jeffrey and their non-autistic son Luke – says she wanted to “give back” to the researchers who helped Jeffrey. And she was curious.
“We wanted to know if this was a genetic trait that we passed on to Jeff, and if it would affect his brother having children,” Garbutt says. “Knowledge is power.”
Jeffrey’s genome showed a de novo spontaneous genetic mutation that was not inherited from his parents.
“We knew nothing was going to change,” Garbutt says, “but knowing it was a ‘typo’ gives us peace of mind.”
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