# 3/7-Administrative Supplement due to COVID-19 Impact to Collaborative genomic studies of Tourette Disorder

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $164,757

## Abstract

PROJECT SUMMARY
Despite strong evidence for a genetic contribution to Tourette disorder (TD), progress in the identification of
specific risk genes has been, until quite recently, halting. However, building upon NIMH’s support for our initial
efforts to ascertain TD trios as well as our highly successful experience with genomic investigations of autism
spectrum disorders (ASD), we have now demonstrated a clear path forward for reliable, systematic gene
discovery in TD. Our TD work, recently published in Neuron and in Cell Reports, identified two high confidence
and three probable novel TD risk genes, and collectively, pointed to neurite outgrowth and axon pathfinding as
potential pathological mechanisms5,6. More importantly, however, our findings demonstrated, for the first time, a
clear excess of de novo damaging point mutations and copy number variants (CNV) in individuals with TD, with
effect sizes that rival our recent findings in ASD. This discovery strongly suggests that sequencing of larger
cohorts will reliably and rapidly lead to the identification of many more highly penetrant risk genes. Moreover,
our recent work suggests an increased yield of highly penetrant damaging de novo variants in probands who are
affected both with TD and OCD or ADHD, suggesting that our efforts may well also offer avenues to study the
overlap in genetic risks for these often-comorbid conditions. Our current application proposes to: (1) expand our
well characterized TD trio cohort by an additional 1,000 simplex trios and make the phenotypic data and
biological materials widely and rapidly available to the broad scientific community; (2) accelerate gene and locus
discovery, via whole exome sequencing (to identify rare and/or de novo sequence variants) and genotyping (to
identify rare and/or de novo CNVs) of these additional TD trios, making these data rapidly and widely available
as well (e.g., we have a long history of sharing our genotyping data with the Psychiatric Genomics Consortium
or PGC1 in order to facilitate common variant studies of TD and related disorders); (3) extend the process of in
silico and in vitro genomics investigations to elaborate the biology of TD with the long term goal of developing
novel and more effective treatment strategies; and (4) begin biological characterization of TD variants using
iPSC-derived neuronal cells. Given the debilitating nature of TD alone, and a population prevalence of
approximately 1 in 100 individuals, such advances would confer a significant public health benefit. The study
design again rests heavily on the collaborative R01 mechanism that will bring together deep experience with the
TD phenotype at multiple sites across the globe with scientists with a strong track record of success and
collaboration in rare variant human genomics and gene discovery. Specifically, the proposal includes seven
primary US sites, four direct subcontracts (two USA sites for clinical supervision and data analysis and two
foreign c...

## Key facts

- **NIH application ID:** 10598794
- **Project number:** 3R01MH115960-05S1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Alyssa Rosen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $164,757
- **Award type:** 3
- **Project period:** 2022-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598794

## Citation

> US National Institutes of Health, RePORTER application 10598794, 3/7-Administrative Supplement due to COVID-19 Impact to Collaborative genomic studies of Tourette Disorder (3R01MH115960-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10598794. Licensed CC0.

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