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IOWA CITY — Autism, its variations, the people it affects, and the extent to which it affects them run a wide spectrum — which is becoming more clear — thanks to new and ongoing research into its genetics, including work by scientists at the University of Iowa.
A study published Aug. 18 in the prestigious Nature Genetics journal identified 60 genes that contribute to autism, largely via inherited genes from parents who don’t have autism or cognitive differences — including five never before implicated in the condition.
“This new study focuses on these inherited variants: gene variants passed from a non-autistic parent to an autistic child,” said UI associate psychiatry professor Jake Michaelson, who also heads the UI Michaelson Lab on computational psychiatry and genomics.
The genes at the center of this new study often have “milder effects,” Michaelson said.
“But these genes probably explain a greater proportion of the autism spectrum,” he said. “All of this points to the reality that, for most autistic people, their neurodiversity isn’t the product of a single genetic variant, but rather the confluence of multiple genetic factors passed down in unique combinations from their parents.”
Michaelson and two graduate students contributed to the study, led by researchers from Columbia University Medical Center, the Simons Foundation in New York, and Peking University Health Science Center in Beijing.
For decades, autism-related research focused on the “low-hanging fruit” of genes that — when changed — almost always resulted in autism, Michaelson said. Scientists were searching for new genetic mutations that parents didn’t have and that affected those genes important to brain development.
“That approach has powered autism genetic research for more than a decade,” Michaelson said. “But we’re starting to get into diminishing returns: it looks like most of the rest of the ‘autism genes’ probably have milder effects, are not associated with intellectual disability, and may have even been transmitted by a parent who doesn’t have autism.”
Plus, researchers report, most autistic individuals don’t have the condition because of novel mutations that their parents don’t have — meaning those who do represent only a small part of the genetic picture.
“We’re really excited about this study because it sheds light on how genes are influencing the brain over a wider band of the autism spectrum,” Michaelson said.
For the study, a massive team of scientists from about 45 institutions tapped a growing autism research cohort called SPARK, or Simons Powering Autism Research — which today is the largest autism research community, including genetic data from nearly 100,000 people with autism.
Michaelson and his students helped recruit thousands of participants and families to SPARK, created six years ago to advance the scientific understanding of autism. They also helped interpret what the autism-associated genes are doing, “essentially making a map of autism genetics that tells us what the major molecular mechanisms are,” Michaelson said.
“It feels sort of like a Lewis and Clark-type expedition, where you know there’s this huge (unexplored) territory, but its contours and variety haven’t yet been well described.”
‘Subtypes of autism’
The two-stage study assessed 19,843 people with autism, along with one or both biological parents, and found about 20 percent of those with autism had new genetic variants — not found in their parents.
Nearly 70 percent of that genetic contribution could be attributed to known autism genes or those associated with neurodevelopmental disorders — leaving others “still to be identified.”
When researchers then added another 22,764 people with autism and 236,000 without autism from the general population, a “meta-analysis” revealed 60 autism-associated genes — mostly driven by inherited variants transmitted by parents who don’t have autism or cognitive differences.
“Of these genes, five have not previously been implicated in neurodevelopmental conditions,” according to a UI summary of the study.
Michaelson said the inherited variants are “less associated with intellectual disability, and they expand our view of what developmental mechanisms are being impacted in autism.”
“Ultimately, this knowledge will help us better understand subtypes of autism that each have different support, resource, and treatment needs.”
Of the 42,607 total autism cases analyzed for the study, 35,130 new cases came via online recruitment through SPARK.
Researchers spell out in the study benefits of using a tool like SPARK, designed to recruit people from across the autism spectrum, without relying on medical centers.
“The strategy used by SPARK — to recruit and assess large numbers of individuals with autism across the spectrum and their available family members without costly, in-depth clinical phenotyping — is necessary to achieve the required sample size to fully elucidate genetic contributions to (autism spectrum disorder),” according to the study.
SPARK also allows researchers to reconnect with and track participants as part of follow-up and deeper assessment of “newly discovered genes” — as well as develop new treatments.
“As we do this kind of basic science research, we learn — little by little — what autism really is,” Michaelson said. “And, as this new research shows, there are autistic bits in undiagnosed people, and to some extent in everyone.”
‘Just the beginning’
Those “autistic bits” are just more concentrated in individuals who have been clinically diagnosed with autism — diagnoses that can be a big part of a person’s identity.
And scientists and clinicians, Michaelson said, should work toward developing more precise and respectful language to address the “deeply personal and identity-based features of autism,” while leaving behind aspects that are “objectively disabling and recognized as such by the autistic individual.”
“We want this kind of basic research to ultimately lead to the empowerment of autistic people to live full and healthy lives, free from medical, mental health, and societal barriers,” he said.
The recently published research represented the culmination of years of work — from the coordination of hundreds of thousands of participants and efforts from nearly 30 clinical recruitment centers to analysis involving thousands of hours of compute time and countless drafts.
“This is just the beginning,” Michaelson said. “We estimate that we will need three to four times as many participants as are currently in SPARK to continue to discover the inherited, moderate impact genes that underlie a majority of the autism spectrum.”
That line of inquiry and ongoing SPARK recruitment, according to Michaelson, will power related research — including several projects UI is engaged in on topics like sleep, eating habits, language ability, seizures, gender identity, and exceptional abilities.
“We recently convened a new working group that is focused on investigating autistic strengths and developing new ways to help autistic people recognize, cultivate, and capitalize on strengths that they have,” he said.
“There’s a feeling, I think, that much of the work we’ve been doing so far was ultimately leading us to this critically important theme.”
SPARK is an ongoing study and is looking for individuals and families with autism to participate. You can learn more about the study and how to enroll at sparkforautism.org/uiowa.
Vanessa Miller covers higher education for The Gazette.
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