A group of researchers has identified the first "high-confidence" risk gene for Tourette disorder, also known as Tourette Syndrome, as well as three other probable risk genes.
Tourette disorder afflicts as many as one person in a hundred worldwide with potentially disabling symptoms including involuntary motor and vocal tics. Treatments had only limited effectiveness, in part because the genetics underlying the disorder have remained largely a mystery.
Published online in Neuron on May 3, the new findings are a step forward in understanding the biology of the disorder and in the search for better treatments, said the researchers at the University of California, San Francisco, Rutgers University, Massachusetts General Hospital, the University of Florida and Yale School of Medicineare.
The researchers used an approach that Matthew State, chair of the Department of Psychiatry at UCSF and a co-senior author on the paper, and his colleagues have pioneered in studies of the genetic basis of autism spectrum disorders.
They 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, namely 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, an assistant professor of psychiatry at UCSF and co-lead author of the 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 explained.
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.
They then combined the genetic data from the TIC Genetics and TAAICG cohorts, and the resulting dataset allowed them to zero in on four genes expressed in the brain in which de novo variants were significantly associated with the disorder.
The analysis identified variants of the gene WWC1, also called KIBRA, 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 disorder. Three other genes, FN1, CELSR3 and NIPBL were flagged as having at least 70 percent probability of contributing to the disorder.
"These findings show that Tourette disorder has same path forward, which means there is a very bright future for understanding genetics of the disorder," State was quoted as saying in a news release from UCSF. "The very first study I did as a geneticist was of Tourette disorder, so this has been a 20-year odyssey. It is deeply gratifying to see this long-term effort across multiple sites and countries lead to real progress."