Tourette disorder afflicts as many as one person in a hundred worldwide with potentially disabling symptoms including involuntary motor and vocal tics. However, researchers have so far failed to determine the cause of the disorder, and treatments have only limited effectiveness, in part because the genetics underlying the disorder have remained largely a mystery.

Now, as reported online May 3, 2017, in the journal Neuron, a consortium of top researchers – led by scientists at UC San Francisco, Rutgers University, Massachusetts General Hospital, the University of Florida and Yale School of Medicine – has made a significant advance, identifying the first “high–confidence” risk gene for Tourette disorder as well as three other probable risk genes. These findings are a step forward in understanding the biology of the disorder, the authors said, which will aid in the search for better treatments.

For their new paper, the researchers used an approach that State and colleagues have pioneered in studies of the genetic basis of autism spectrum disorders, and which has led to important discoveries in that field over the past five years.

As in this earlier research, the scientists involved in the Neuron study compared the protein–coding regions of the genomes of children with Tourette disorder 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, PhD, 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 team 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), and found strong evidence that de novo variants can play a significant role in triggering the disorder. To be certain of what they were seeing, 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.

Extrapolating from the number of de novo variants they observed in these relatively small datasets, the researchers were able to estimate that approximately 12 percent of Tourette disorder cases are likely to involve de novo variants, and that these variants probably strike about 400 different key risk genes.