New Tourette disorder genes come to light

September 25, 2018, University of California, San Francisco
Credit: CC0 Public Domain

In the largest DNA sequencing study of Tourette Disorder (TD) to date, UC San Francisco researchers and their collaborators have unearthed new data suggesting a potential role for disruptions in cell polarity in the development of this condition.

The researchers focused on "de novo" mutations, or rare mutations that arise anew at conception, rather than being inherited from parents. They observed that these mutations tend to affect with a role in cell "polarity," which is the process by which cells differentiate "top" and "bottom." This is particularly important in the brain, where neurons must form with specialized information gathering and transmitting sides to function properly.

"You might expect that mutations in these genes would affect things like neurons getting to the right place in the brain, or forming the right connections, with the appropriate directionality," said Jeremy Willsey, Ph.D., an expert on psychiatric genetics in the UCSF Weill Institute for Neurosciences and a senior author of the paper. "Our group has already started experiments modeling the effect of mutations in these cell polarity genes during early brain development."

Such disruptions to neuronal wiring may eventually explain the uncontrollable chronic vocal and motor tics that mark TD. Although as many as one percent of children worldwide develop TD, the condition has been relatively neglected in studies compared to other child-onset psychiatric disorders, such as autism, intellectual disability, and epilepsy.

Referring to the relatively small number of studies on TD genetics, Matthew State, MD, Ph.D., professor and chair of the UCSF Department of Psychiatry, said, "Tourette disorder has tended to be marginalized in psychiatric research, but with the promise of these genetic findings and a major recent investment by the National Institute of Mental Health, we can deepen our understanding of TD and potentially use the new insights to develop improved treatments."

State and Jay Tischfield, Ph.D., of Rutgers University, founded the Tourette International Collaborative Genetics (TIC Genetics) consortium in 2009 to collect, study and share genetic data from TD patients and their families across multiple U.S. and international sites. Willsey now serves alongside them, and several other authors of the new paper, on the executive board.

Collaboration was at the heart of the new study, too, with TIC Genetics joining forces with the Tourette Association of America International Consortium for Genetics (TAAICG), and the Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE); the researchers also received samples from the Uppsala Tourette Cohort, based in Sweden.

This pooling of resources allowed researchers to amass genetic data from much larger samples of TD patients, and their unaffected parents, than would otherwise be possible. With this data in hand, the researchers conducted a powerful approach, known in genetics as trio analysis, in order to identify de novo mutations, by determining which mutations were present in patients but not in their parents. These are very rare events, occurring one or two times for every 100 million DNA base pairs sequenced.

De novo mutations arise spontaneously in a sperm or egg cell, or in a zygote soon after fertilization. Unlike inherited mutations, these de novo events are subject to natural selection over only a very short period of time, and mutations that have large effects are thus overrepresented or "enriched" among de novo mutations. De novo mutations have already been strongly linked to autism, epilepsy, and intellectual disability.

Last year, the TIC Genetics group found the same is true for TD, based on analysis of 511 trios (1,533 total samples). The new study, published online September 25 in Cell Reports, expands on the 2017 study with 291 more trios (873 new samples), for a total of 802 trios (2,406 samples).

First author Sheng Wang, a graduate student in both the State and Willsey labs, and colleagues set about sequencing the exome—the protein-coding parts of the genome—in DNA samples from each person with TD, plus each of their parents. By focusing on the coding parts of the genomes, the researchers can easily identify mutations that disrupt the corresponding proteins encoded by these sequences.

The researchers then compared the exome sequences between parents and their affected child. This painstaking process identified 309 new de novo sequence mutations, or accidental genetic "typos" that alter a few "letters" of the DNA code.

First and foremost, the new independent sample of 291 trios allowed the authors to independently confirm the 2017 results. Namely, that de novo mutations deemed to be damaging to protein function were present more often in individuals with TD than in unaffected control samples—a suspicious enrichment that suggests these variants directly contribute to the disorder.

"It cannot be overstated that in psychiatric genetics it's critical for replication to happen. It should not be taken for granted," Willsey said, acknowledging that some results that have not been replicated have stymied the field for years.

But in addition to replicating their earlier findings, the researchers arrived at several key new insights. First, de novo variants tend to be enriched in families without any history of TD, suggesting, as expected, that future studies should match the types of genetic analyses conducted with the type of families recruited.

They also observed some evidence for an enrichment of de novo variants in females affected with TD, as compared to males affected with TD. This indicates that females may be more resilient to developing TD. Similar findings have been observed in autism. Understanding the basis of this biological difference in susceptibility holds promise for developing new treatments. Finally, they identified a new, high-confidence risk gene, CELSR3, adding to the first high-confidence gene they identified in 2017, WWC1.

Both of the proteins these genes encode have known roles in cell polarity. This inspired the team to look at the rest of the genes with de novo mutations in TD patients. Consulting a database of gene function, the authors noted that 15 other cell polarity genes had damaging de novo , almost three times as many as would be expected, which suggests that disruption of cell polarity during brain development may be a central biological mechanism in the development of TD.

When looking at all the genes hit by damaging de novo variants in TD, the researchers also found an overlap with genes implicated in obsessive-compulsive disorder (OCD), which suggests the biology of these conditions is intertwined. People with TD often also have OCD, yet when the researchers excluded these cases from their samples, the gene overlap remained. This suggests that the same genes can give rise to TD or OCD, and that pursuing the biology of these genes may offer insights on multiple disorders.

"While tics are the defining feature of TD, there are many other symptoms that tend to go along with the disorder, like attention problems, learning difficulties, OCD, depression, and anxiety," State said. "If we knew exactly what was going wrong and could target this more specifically, not only could we do a better job of decreasing tics, but we could potentially simultaneously address multiple symptoms that accompany TD, and that in many children are more debilitating than the tics themselves."

The researchers also detected, for the first time, a statistically significant enrichment of larger-scale de novo alterations, called copy number variants (CNVs), in TD. A role for CNVs, which are deletions or duplications of sections of DNA, in TD had been suspected from previous studies, but the enlarged sample in the new study allowed researchers to clearly establish the association for the first time.

The success of the TD collaboration spurred the National Institute of Mental Health to fund a $10 million dollar grant earlier this year to help the research team pursue their findings. The award will go to seven U.S. and 14 international sites to enroll more than 1,000 parent-child trios (3,000 samples), genetically characterize them, and identify new genes. The researchers expect this will generate new biological insights and potentially opportunities for new and improved treatments.

Explore further: First clear-cut risk genes for Tourette disorder revealed

Related Stories

First clear-cut risk genes for Tourette disorder revealed

May 3, 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 ...

Mutations in gene TRAF7 are associated with a multisystem disorder

June 28, 2018
A group of seven patients presenting with a similar disorder of unknown origin now know of a possible genetic root of their condition. A team of researchers sequenced all the protein-coding genes in the patients' genomes ...

Autism study finds de novo mutations associated with motor skill deficiencies

February 7, 2018
A team of researchers affiliated with several institutions in the U.S. has found an association between de novo mutations and motor skills in people with autism. In their paper published in Proceedings of the National Academy ...

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Intellectual disabilities caused by protein defect

September 4, 2017
Intellectual disabilities are often caused by a mutation that damages a gene, preventing the associated protein from functioning properly. However, a mutation can also change the function of a gene. As a result, the gene ...

Genetic analysis finds rare, damaging variants contribute to the risk of schizophrenia

June 27, 2017
(Medical Xpress)—Via genetic analysis, a large international team of researchers has found rare, damaging gene variants that they believe contribute to the risk of a person developing schizophrenia. In their paper published ...

Recommended for you

Scientists identify method to study resilience to pain

December 14, 2018
Scientists at the Yale School of Medicine and Veterans Affairs Connecticut Healthcare System have successfully demonstrated that it is possible to pinpoint genes that contribute to inter-individual differences in pain.

CRISPR joins battle of the bulge, fights obesity without edits to genome

December 13, 2018
A weighty new study shows that CRISPR therapies can cut fat without cutting DNA. In a paper published Dec. 13, 2018, in the journal Science, UC San Francisco researchers describe how a modified version of CRISPR was used ...

Noncoding mutations contribute to autism risk

December 13, 2018
A whole-genome sequencing study of nearly 2,000 families has implicated mutations in 'promoter regions' of the genome—regions that precede the start of a gene—in autism. The study, which appears in the December 14 issue ...

New method for studying ALS more effectively

December 13, 2018
The neurodegenerative disease ALS causes motor neuron death and paralysis. However, long before the cells die, they lose contact with muscles as their axons atrophy. Researchers at Karolinska Institutet in Sweden have now ...

Paternal grandfather's high access to food may indicate higher mortality risk in grandsons

December 12, 2018
A paternal grandfather's access to food during his childhood is associated with mortality risk, especially cancer mortality, in his grandson, shows a large three-generational study from Stockholm University. The reason might ...

New genetic study could lead to better treatment of severe asthma

December 12, 2018
The largest-ever genetic study of people with moderate-to-severe asthma has revealed new insights into the underlying causes of the disease which could help improve its diagnosis and treatment.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.