TY - JOUR
T1 - Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum
AU - Yang, Zhiyu
AU - Wu, Hanrui
AU - Lee, Phil H.
AU - Tsetsos, Fotis
AU - Davis, Lea K.
AU - Yu, Dongmei
AU - Lee, Sang Hong
AU - Dalsgaard, Søren
AU - Haavik, Jan
AU - Barta, Csaba
AU - Zayats, Tetyana
AU - Eapen, Valsamma
AU - Wray, Naomi R.
AU - Devlin, Bernie
AU - Daly, Mark
AU - Neale, Benjamin
AU - Børglum, Anders D.
AU - Crowley, James J.
AU - Scharf, Jeremiah
AU - Mathews, Carol A.
AU - Faraone, Stephen V.
AU - Franke, Barbara
AU - Mattheisen, Manuel
AU - Smoller, Jordan W.
AU - Paschou, Peristera
N1 - Publisher Copyright:
© 2021
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Background: Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum. Methods: Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers). Results: As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism–based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD. Conclusions: Our work underlines the value of redefining the framework for research across traditional diagnostic categories.
AB - Background: Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum. Methods: Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers). Results: As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism–based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD. Conclusions: Our work underlines the value of redefining the framework for research across traditional diagnostic categories.
KW - ADHD
KW - ASD
KW - Cross-disorder genetic analysis
KW - GWAS meta-analysis
KW - OCD
KW - Tourette syndrome
UR - https://www.scopus.com/pages/publications/85103041205
U2 - 10.1016/j.biopsych.2020.12.028
DO - 10.1016/j.biopsych.2020.12.028
M3 - Article
C2 - 33714545
AN - SCOPUS:85103041205
SN - 0006-3223
VL - 90
SP - 317
EP - 327
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 5
ER -