Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.
- Authors
- Yu, Dongmei; Sul, Jae Hoon; Tsetsos, Fotis; Nawaz, Muhammad S; Huang, Alden Y; Zelaya, Ivette; Illmann, Cornelia; Osiecki, Lisa; Darrow, Sabrina M; Hirschtritt, Matthew E; Greenberg, Erica; Muller-Vahl, Kirsten R; Stuhrmann, Manfred; Dion, Yves; Rouleau, Guy; Aschauer, Harald; Stamenkovic, Mara; SchlΓΆgelhofer, Monika; Sandor, Paul; Barr, Cathy L; Grados, Marco; Singer, Harvey S; NΓΆthen, Markus M; Hebebrand, Johannes; Hinney, Anke; King, Robert A; Fernandez, Thomas V; Barta, Csaba; Tarnok, Zsanett; Nagy, Peter; Depienne, Christel; Worbe, Yulia; Hartmann, Andreas; Budman, Cathy L; Rizzo, Renata; Lyon, Gholson J; McMahon, William M; Batterson, James R; Cath, Danielle C; Malaty, Irene A; Okun, Michael S; Berlin, Cheston; Woods, Douglas W; Lee, Paul C; Jankovic, Joseph; Robertson, Mary M; Gilbert, Donald L; Brown, Lawrence W; Coffey, Barbara J; Dietrich, Andrea; Hoekstra, Pieter J; Kuperman, Samuel; Zinner, Samuel H; LuΓ°vigsson, PΓ©tur; SΓ¦mundsen, Evald; Thorarensen, Γlafur; Atzmon, Gil; Barzilai, Nir; Wagner, Michael; Moessner, Rainald; Ophoff, Roel; Pato, Carlos N; Pato, Michele T; Knowles, James A; Roffman, Joshua L; Smoller, Jordan W; Buckner, Randy L; Willsey, A Jeremy; Tischfield, Jay A; Heiman, Gary A; Stefansson, Hreinn; Stefansson, KΓ‘ri; Posthuma, Danielle; Cox, Nancy J; Pauls, David L; Freimer, Nelson B; Neale, Benjamin M; Davis, Lea K; Paschou, Peristera; Coppola, Giovanni; Mathews, Carol A; Scharf, Jeremiah M; Tourette Association of America International Consortium for Genetics, the Gilles de la Tourette GWAS Replication Initiative, the Tourette International Collaborative Genetics Study, and the Psychiatric Genomics Consortium Tourette Syndrome Working Group
- Year
- 2019
- Journal
- The American journal of psychiatry
- PMID
- 30818990
- DOI
- 10.1176/appi.ajp.2018.18070857
- PMCID
- PMC6677250
OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.
Results of the primary Tourette Syndrome GWAS meta-analysis of 4,819 cases and 9,488 controls.
| Name | Type |
|---|---|
| 1000 Genomes Project Phase 1 integrated haplotypes local | cohort |
| 39 top LD-independent SNPs local | variant |
| ADHD | phenotype |
| affected sib-pair families local | cohort |
| ancestry-adjusted PRS local | drug |
| Ancestry-matched controls local | cohort |
| Ashkenazi Jewish samples local | cohort |
| attention deficit hyperactivity disorder | phenotype |
| autism spectrum disorder | phenotype |
| case-control sample | cohort |
| cases | cohort |
| caudate nucleus | anatomy |
| CELSR3 | gene |
| cerebellum | anatomy |
| chronic motor or vocal tic disorder local | phenotype |
| Chronic motor or vocal tic disorder local | phenotype |
| chronic tic local | phenotype |
| clinic-based cases local | cohort |
| CNS cell types local | anatomy |
| CNTN6 local | gene |
| complex symmetry local | phenotype |
| complex symmetry tics local | phenotype |
| controls | cohort |
| cortex | anatomy |
| deCODE controls local | cohort |
| deCODE sample local | cohort |
| deCODE samples local | cohort |
| deCODE tic spectrum cases local | cohort |
| deCODE Tourette cases local | cohort |
| dorsolateral pre-frontal cortex local | anatomy |
| dorsolateral prefrontal cortex | anatomy |
| EU cases local | cohort |
| EU controls local | cohort |
| Evolutionarily-conserved SNPs local | variant |
| family-based analysis local | cohort |
| family-based sample | cohort |
| family history of Tourette local | phenotype |
| family-history positive Tourette cases local | cohort |
| first-degree relatives | cohort |
| FLT3 local | gene |
| frontal cortex | anatomy |
| GTEx RNA-seq data local | cohort |
| GWAS1 local | cohort |
| GWAS1_AJ local | cohort |
| GWAS1 cases local | cohort |
| GWAS1_EU local | cohort |
| GWAS1_FC local | cohort |
| GWAS1 sample local | cohort |
| GWAS1_TIC local | cohort |
| GWAS2 local | cohort |
| GWAS2 analyses local | cohort |
| GWAS2 cases (email recruitment) local | cohort |
| GWAS2 cases (specialty clinics) local | cohort |
| GWAS2 FAM local | cohort |
| GWAS2 FAM sample local | cohort |
| GWAS2 sample local | cohort |
| HDC local | gene |
| Icelandic deCODE sample local | cohort |
| Icelandic sample local | cohort |
| Icelandic Tourette syndrome cases local | cohort |
| index SNP | cohort |
| MAGMA | drug |
| Motor tics local | phenotype |
| multiplex families | cohort |
| multiplex Tourette syndrome cases local | cohort |
| non-European ancestry | cohort |
| NRXN1 | gene |
| nucleus accumbens | anatomy |
| obsessive-compulsive disorder | phenotype |
| OCD | phenotype |
| Other tic disorder cases local | cohort |
| participants (age >=18) local | cohort |
| Persistent tic disorders local | phenotype |
| PGC Tourette Syndrome Workgroup local | cohort |
| polygenic risk score | cohort |
| polygenic risk score (aPRS) local | drug |
| primary meta-analysis local | cohort |
| probands | cohort |
| Psychiatric Genomics Consortium | cohort |
| putamen | anatomy |
| rs13407215 local | variant |
| rs1933437 local | variant |
| rs2504235 local | variant |
| schizophrenia | phenotype |
| screened controls | cohort |
| simplex families | cohort |
| SLITRK1 | gene |
| SNP | cohort |
| SNP-based heritability | phenotype |
| socially inappropriate tics local | phenotype |
| TIC local | cohort |
| TIC Genetics sample local | cohort |
| tic persistence local | phenotype |
| Tic persistence local | phenotype |
| tics | phenotype |
| TIC sample local | cohort |
| tic severity | phenotype |
| Tic spectrum disorder local | phenotype |
| Tic spectrum disorders local | phenotype |
| top SNPs | cohort |
| Tourette aPRS local | drug |
| Tourette Association of America local | cohort |
| Tourette/chronic tic family-history positive cases local | cohort |
| Tourette/chronic tic simplex cases local | cohort |
| Tourette GWAS1 local | cohort |
| Tourette GWAS cases with chronic tic-affected parent/sibling local | cohort |
| Tourette PRS local | drug |
| Tourette syndrome | phenotype |
| Transient tic disorder local | phenotype |
| transient tics local | phenotype |
| Transient tics local | phenotype |
| UCLA Neuroscience Genomics Core local | cohort |
| UNGC local | cohort |
| Unscreened population-matched controls local | cohort |
| unspecified tic disorder local | phenotype |
| Vocal tics local | phenotype |
| web-based cases local | cohort |
No uploaded files.
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