Scientists have identified the first “high-confidence” risk gene for Tourette syndrome (or Tourette disorder) as well as three other probable risk genes. Their findings, published in the journal Neuron, are a step forward in understanding the biology of the disorder and may aid in the search for better treatments.
Tourette syndrome, a disorder which features debilitating symptoms such as involuntary motor and vocal tics, affects approximately one in a hundred people worldwide. So far, treatments have only limited effectiveness, in part because the genetics underlying the disorder have remained largely a mystery.
“In the clinic, I have seen again and again the frustration that patients and families experience because of our lack of understanding and the limitations of our current treatments. But we have now taken a major initial step forward in changing this reality, thanks to new genomic technologies and a very successful long term collaboration between clinicians and geneticists,” said Matthew State, M.D., Ph.D., Oberndorf Family Distinguished Professor and chair of the Department of Psychiatry at University of California San Francisco (UCSF) and a co-senior author on the new paper.
For the study, a consortium of top scientists, led by the UCSF, Rutgers University, Massachusetts General Hospital, the University of Florida, and Yale School of Medicine, tried a genetic approach previously used to study autism spectrum disorders (ASD).
As in the previous ASD research, the scientists in the new study compared the protein-coding regions of the genomes of children with Tourette syndrome to the genomes of their parents to identify so-called de novo variants — rare genetic mutations that are not inherited from parents, but rather occur spontaneously at conception.
De novo variants often have stronger biological effects than inherited variants passed from generation to generation, said Jeremy Willsey, Ph.D., an assistant professor of psychiatry at UCSF and co-lead author of the new paper.
“We study de novo variants even though they are rare because they generally have more extreme effects than inherited mutations and can provide us much information about the underlying causes of a disease,” Willsey said.
“This also translates to developing therapies: if these variants greatly increase a child’s risk of Tourette disorder, we would expect that understanding these changes could potentially lead to very effective treatments for the disorder.”
The researchers analyzed genomic data from 311 “trios” — children with Tourette disorder and their parents, most of whom were unaffected by the disorder — collected by the Tourette International Collaborative Genetics group (TIC Genetics). They found strong evidence that de novo variants can play a significant role in triggering the disorder.
To confirm their findings, the team conducted a replication study in 173 trios from the Tourette Association of America International Consortium for Genetics (TAAICG), and found the same results.
The researchers then estimated that approximately 12 percent of Tourette syndrome cases are likely to involve de novo variants and that these variants probably strike about 400 different key risk genes.
Through further analysis, the researchers were able to zero in on four genes expressed in the brain in which de novo variants were significantly associated with the disorder.
This analysis identified variants of a gene known as KIBRA (for “KIdney- and BRAin-expressed protein) — which is involved in brain development, memory, and the brain’s response to the hormone estrogen — as having a greater than 90 percent probability of contributing to Tourette syndrome.
Three other genes were flagged as having at least 70 percent probability of contributing to the disorder. Of these, two are also known to be involved in the development of brain circuitry. The third is involved in regulation of gene expression in the brain, and has previously been associated with the developmental disorder Cornelia de Lange syndrome, as well as anxiety, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder in humans.
The researchers anticipate that future studies of de novo variants in a larger number of families affected by Tourette disorder will result in dozens more promising genetic leads.