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Scientists Identify 36 Genes Linked To OCD And Tourette Syndrome
For 20 years, researchers collected DNA from families affected by obsessive-compulsive disorder and chronic tic disorders without having the technology to fully read what those samples contained. Now, a new study has identified 36 large-effect risk genes linked to OCD and tic disorders, dramatically expanding a genetic map that previously contained only four confirmed genes.
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The findings also uncovered overlap with genes previously associated with autism and schizophrenia. Researchers stress that this does not mean they discovered the genetic cause of autism, but it does suggest that several conditions traditionally treated as separate may share some of the same biological pathways.
Researchers Finally Have A Much Bigger Genetic Map
The study began with DNA samples collected over two decades ago by Rutgers geneticist Gary Heiman and his colleagues. Families affected by OCD and chronic tic disorders, including Tourette disorder, provided samples in the hope that future technology would eventually reveal information hidden inside them.
“When we began collecting these samples 20 years ago, we did not yet have the rapid and cost-effective technologies we have today,” Heiman said, according to Rutgers. The samples continued accumulating while genetic sequencing technology advanced enough to make a much deeper analysis possible.
OCD and chronic tic disorders affect an estimated 1% to 2% of the population, yet researchers previously had only four genes that had cleared the statistical evidence needed to establish a strong connection with both conditions. Those genes were CHD8, SCUBE1, CELSR3 and WWC1, leaving researchers with a surprisingly small genetic map for conditions affecting millions of people.
“In the past we knew about a couple of strong genes, so there were few opportunities for the pharmaceutical industry to develop drugs,” Rutgers geneticist Jay Tischfield said. The new research has now given scientists dozens more biological targets to investigate.
Nearly 4,000 People Took Part In The Study
The research team, led by Rutgers, used whole-exome sequencing to examine 3,964 people diagnosed with OCD, a chronic tic disorder, or both. Whole-exome sequencing focuses on the protein-coding sections of DNA, where damaging mutations can have significant effects on how cells function.
The researchers also studied 2,418 parent-child trios, which allowed them to identify mutations appearing in a child but not either parent. This approach can help researchers distinguish potentially important new mutations from ordinary genetic variation passed through families.
The results produced 36 large-effect risk genes connected to obsessions, compulsions and tics. The authors described the result as a “tenfold increase” in the number of bona fide large-effect risk genes contributing to these symptoms.
That expansion gives researchers considerably more material to study. Instead of examining a handful of isolated genes, scientists can now begin looking for relationships between groups of genes and the biological systems they influence.
Heiman compared the discovery to increasing the magnification of a microscope, because the larger genetic list allows researchers to see patterns that were previously difficult to identify. “With only a handful of genes, we could see isolated pieces of the puzzle; with 36 genes, we can begin to identify the broader cellular pathways and brain networks disrupted in both conditions,” he said.
The researchers found evidence that many of the risk genes are active in the cortex and striatum, brain regions involved in functions including movement, decision-making and habit formation. Those findings provide a potential biological connection between the genetic results and some of the symptoms associated with OCD and tic disorders.
The overlap between the two conditions was also substantial within the genetic data. Roughly 83% of the 36 genes had supporting evidence from both OCD cases and tic disorder cases, strengthening the case for studying their biological relationship rather than treating them as completely separate conditions.
“We have long known that chronic tic disorders, including Tourette disorder, frequently co-occur with obsessive-compulsive disorder, yet the functional basis for this overlap remained unclear,” Heiman said. The new findings give researchers another route for investigating that long-standing question.
Autism Appeared In The Findings, But There Is A Big Caveat
Several of the 36 genes identified in the study had previously appeared in research involving autism and schizophrenia. That overlap is one of the most intriguing parts of the findings, but it needs to be interpreted carefully.
The researchers did not study autism as the primary condition, and the study did not identify the genetic cause of autism. Instead, some genes associated with OCD and tic disorder risk were already known from research into other neurodevelopmental or psychiatric conditions.
That suggests there may be biological pathways shared across conditions that are usually separated into different diagnostic categories. A genetic connection also does not mean that a particular mutation produces the same condition or symptoms in every person who carries it.
The finding therefore raises questions rather than providing a final explanation. Researchers can now investigate whether certain cellular pathways contribute to multiple conditions and why changes in those pathways can produce very different symptoms.
The Study Still Captured Only Part Of The Genetic Picture
Despite the size of the discovery, the researchers were looking through a limited window of the genome. Their analysis focused on rare single-letter changes and small insertions and deletions within coding DNA, while copy-number variants, noncoding DNA and mitochondrial DNA were outside the study’s scope.
The researchers also found that fewer than one in 10 people in the study carried one of the newly identified damaging mutations. That means the majority of people with OCD or chronic tic disorders do not have one of these particular large-effect mutations.
These findings therefore should not be treated as a genetic diagnosis. The genes indicate increased risk, and researchers still need to determine exactly how the mutations affect cells and brain function before knowing whether they can be used to guide treatment.
Thirty-Six Genes Could Open New Treatment Research
The expanded genetic list could eventually help researchers investigate new therapies, but the study is still an early step in that process. Scientists first need to establish what each gene does, how a damaging mutation disrupts its normal function, and whether correcting the resulting biological pathway changes symptoms.
Tischfield believes the larger list gives researchers more targets to investigate because the genes appear to operate within connected biological networks. “These genes don’t act individually. They act in networks. And now you can target whole networks, which will make it easier to design new therapies,” he said.
He added that researchers now have “over 30 targets” that could potentially be explored for treatment development. That does not mean dozens of new medications are imminent, but it does give drug researchers a much broader starting point than the field had before.
The next stage will require laboratory experiments, protein studies and other research to determine whether these genetic discoveries translate into useful treatment targets. There is still a long road between identifying a risk gene and developing something that helps patients.
The DNA Samples Were Waiting For Better Technology
Perhaps the most striking part of the research is how long the evidence had to wait before scientists could properly examine it. Families provided their DNA decades ago, when researchers lacked the rapid and affordable sequencing tools needed to extract this level of information.
Heiman credited those families for making the study possible, saying, “None of this would have been possible without the extraordinary commitment of individuals with CTDs and OCD and their families.” Their samples eventually became part of a study that expanded the known list of large-effect risk genes from four to 36.
Much of the genome remains outside the scope of this particular analysis, so the researchers are far from having a complete genetic explanation for OCD or tic disorders. For now, they have something far more useful than a simple headline: a much larger map showing where scientists can look next.