Nav: Home

First clear-cut risk genes for Tourette disorder revealed

May 03, 2017

Tourette disorder (also known as Tourette syndrome) 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 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.

"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, MD, PhD, Oberndorf Family Distinguished Professor and chair of the Department of Psychiatry at UCSF and a co-senior author on the new paper.

Studying Rare Variants to Illuminate Disease Biology

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.

Four Brain-Expressed Genes are Likely Tourette Disorder Risk Factors

In order to gain sufficient statistical power to identify specific genes in which de novo variants disrupt function and contribute to risk of Tourette disorder, the researchers combined the genetic data from the TIC Genetics and TSAICG cohorts -- a complex effort led by State, Willsey, and their team at UCSF. The resulting dataset allowed the researchers 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 the gene WWC1, also called 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 disorder. Three other genes were flagged as having at least 70 percent probability of contributing to the disorder. Of these, two -- FN1 and CELSR3 -- are also known to be involved in the development of brain circuitry. The third probable risk gene, called NIPBL or Delangin, 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 authors 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, just as State and colleagues have been able to generate for autism spectrum disorders: those findings are driving an explosion in research into the biology of autism that was not possible before the identification of these molecular clues.

"We've now done in Tourette disorder what we began five years ago in autism spectrum disorders. These findings shows that Tourette disorder has same path forward, which means there is a very bright future for understanding genetics of the disorder," said State, who is also director of the Langley Porter Psychiatric Institute and Hospital at UCSF and a member of the Steering Committee for the UCSF Weill Institute for Neurosciences. "The very first study I did as a geneticist was of Tourette disorder, so this has been a 20-year odyssey -- and it is deeply gratifying to see this long-term effort across multiple sites and countries lead to real progress."

Close Collaboration Between Geneticists, Clinicians Made Study Possible

The new study represents a collaborative effort across the two international Tourette disorder genetics consortia: TIC Genetics, founded by State and Jay Tischfield, PhD, of Rutgers, and now led by State, Tischfield and Gary Heiman, PhD, also at Rutgers; and the TSAICG, led by Jeremiah Scharf, MD, PhD, of Massachusetts General Hospital and Carol Mathews, MD, of the University of Florida. Tischfield, Heiman, Scharf, and Mathews are all co-senior authors of the new paper.

"The success of this project, and the identification of an increased burden of rare variants in Tourette disorder reinforces the importance of collaborative science and open data sharing, to which both consortia are strongly committed," Scharf and Matthews wrote in an email.

The study also depended on a tight collaboration between genetic researchers and the clinicians who work directly with the patients and families whose DNA were central to the new findings, State said. "Our collaborators in this effort are all clinical experts, deeply devoted to Tourette patients and families, in the U.S., Europe and Asia, all of whom have tenaciously worked to keep this project moving forward over the last seven years."
-end-
Thomas V. Fernandez, MD, of the Yale School of Medicine's Child Study Center and Department of Psychiatry was co-lead author, with Willsey, of the new study.

The research was funded by the National Institute of Mental Health (R01MH092290, R01MH092291, R01MH092292, R01MH092293, R01MH092513, R01MH092516, R01MH092520, R01MH092289, K23MH085057, K08MH099424) and the National Institute of Neurological Disorders and Stroke (U01NS40024-09S1, K02 NS085048) of the U.S. National Institutes of Health, as well as the Harvard Clinical and Translational Science Center, the Tourette Association of America, the New Jersey Center for Tourette Syndrome and Associated Disorders, and the Overlook International Fund.

About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit http://www.ucsf.edu/news.

University of California - San Francisco

Related Autism Articles:

Autism-cholesterol link
Study identifies genetic link between cholesterol alterations and autism.
National Autism Indicators Report: the connection between autism and financial hardship
A.J. Drexel Autism Institute released the 2020 National Autism Indicators Report highlighting the financial challenges facing households of children with autism spectrum disorder (ASD), including higher levels of poverty, material hardship and medical expenses.
Autism risk estimated at 3 to 5% for children whose parents have a sibling with autism
Roughly 3 to 5% of children with an aunt or uncle with autism spectrum disorder (ASD) can also be expected to have ASD, compared to about 1.5% of children in the general population, according to a study funded by the National Institutes of Health.
Adulthood with autism
The independence that comes with growing up can be scary for any teenager, but for young adults with autism spectrum disorder and their caregivers, the transition from adolescence to adulthood can seem particularly daunting.
Brain protein mutation from child with autism causes autism-like behavioral change in mice
A de novo gene mutation that encodes a brain protein in a child with autism has been placed into the brains of mice.
Autism and theory of mind
Theory of mind, or the ability to represent other people's minds as distinct from one's own, can be difficult for people with autism.
Potential biomarker for autism
A study of young children with autism spectrum disorder published in JNeurosci reveals altered brain waves compared to typically developing children during a motor control task.
Autism often associated with multiple new mutations
Most autism cases are in families with no previous history of the disorder.
State laws requiring autism coverage by private insurers led to increases in autism care
A new study led by researchers at the Johns Hopkins Bloomberg School of Public Health has found that the enactment of state laws mandating coverage of autism spectrum disorder (ASD) was followed by sizable increases in insurer-covered ASD care and associated spending.
Autism's gender patterns
Having one child with autism is a well-known risk factor for having another one with the same disorder, but whether and how a sibling's gender influences this risk has remained largely unknown.
More Autism News and Autism Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.