Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 217-227 |
| Number of pages | 11 |
| Journal | American Journal of Psychiatry |
| Volume | 176 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Psychiatry and Mental health
Cite this
Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies. / Tourette Association of America International Consortium for Genetics; Gilles de la Tourette GWAS Replication Initiative; Tourette International Collaborative Genetics Study; Psychiatric Genomics Consortium Tourette Syndrome Working Group.
In: American Journal of Psychiatry, Vol. 176, No. 3, 01.01.2019, p. 217-227.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies
AU - Tourette Association of America International Consortium for Genetics
AU - Gilles de la Tourette GWAS Replication Initiative
AU - Tourette International Collaborative Genetics Study
AU - Psychiatric Genomics Consortium Tourette Syndrome Working Group
AU - Yu, Dongmei
AU - Sul, Jae Hoon
AU - Tsetsos, Fotis
AU - Nawaz, Muhammad S.
AU - Huang, Alden Y.
AU - Zelaya, Ivette
AU - Illmann, Cornelia
AU - Osiecki, Lisa
AU - Darrow, Sabrina M.
AU - Hirschtritt, Matthew E.
AU - Greenberg, Erica
AU - Muller-Vahl, Kirsten R.
AU - Stuhrmann, Manfred
AU - Dion, Yves
AU - Rouleau, Guy
AU - Aschauer, Harald
AU - Stamenkovic, Mara
AU - Schlögelhofer, Monika
AU - Sandor, Paul
AU - Barr, Cathy L.
AU - Grados, Marco
AU - Singer, Harvey S.
AU - Nöthen, Markus M.
AU - Hebebrand, Johannes
AU - Hinney, Anke
AU - King, Robert A.
AU - Fernandez, Thomas V.
AU - Barta, Csaba
AU - Tarnok, Zsanett
AU - Nagy, Peter
AU - Depienne, Christel
AU - Worbe, Yulia
AU - Hartmann, Andreas
AU - Budman, Cathy L.
AU - Rizzo, Renata
AU - Lyon, Gholson J.
AU - McMahon, William M.
AU - Batterson, James R.
AU - Cath, Danielle C.
AU - Malaty, Irene A.
AU - Okun, Michael S.
AU - Berlin, Cheston
AU - Woods, Douglas W.
AU - Lee, Paul C.
AU - Jankovic, Joseph
AU - Robertson, Mary M.
AU - Gilbert, Donald L.
AU - Brown, Lawrence W.
AU - Coffey, Barbara J.
AU - Barzilai, Nir
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85063063105&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063063105&partnerID=8YFLogxK
U2 - 10.1176/appi.ajp.2018.18070857
DO - 10.1176/appi.ajp.2018.18070857
M3 - Article
C2 - 30818990
AN - SCOPUS:85063063105
VL - 176
SP - 217
EP - 227
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
SN - 0002-953X
IS - 3
ER -