Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Biological Psychiatry |
| Vol/bind | 90 |
| Udgave nummer | 5 |
| Sider (fra-til) | 317-327 |
| Antal sider | 11 |
| ISSN | 0006-3223 |
| DOI | |
| Status | Udgivet - 2021 |
| Eksternt udgivet | Ja |
Bibliografisk note
Funding Information:
This work is supported by a personal grant from the Innovation Program of the Netherlands Organisation for Scientific Research (Grant No. 016-130-669 [to BF]); the European Community's Horizon 2020 Programme (H2020/2014 ? 2020) (Grant Nos. 667302 [CoCA] and 728018 (Eat2beNICE); the European Union's Seventh Framework Programme for research, technological development and demonstration (Grant No. 602805 (Aggressotype) [to SVF]); the European Union's Horizon 2020 research and innovation programme Grant Nos. 667302 (CoCA) and 728018 (Eat2beNICE) (to SVF); the National Institute of Mental Health (Grant Nos. 5R01MH101519 and U01 MH109536-01 [to SVF]); and a National Science Foundation grant (Grant No. 1715202 [to PP]). ZY performed experiments and wrote the manuscript. PP designed the study, coordinated analysis, and wrote the manuscript. HW generated figures and tables for main and supplementary content. All authors participated in study design and analysis, interpretation of results, and critical review of the manuscript. We thank the Psychiatric Genomics Consortium Cross-disorder Working Group, the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), the Psychiatric Genomics Consortium ADHD Working Group, the Psychiatric Genomics Consortium ASD Working Group, and the Psychiatric Genomics Consortium TS/OCD Working Group. A previous version of this article was published as a preprint on bioRxiv: https://www.biorxiv.org/content/10.1101/770222v1. BF has received educational speaking fees from Medice. BN is a member of the scientific advisory board at Deep Genomics. In the past year, SVF received income, potential income, travel expenses, continuing education support, and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili Interactive Labs, Enzymotec, Sunovion, Supernus, and Genomind. With his institution, SVF holds US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. SVF also receives royalties from books published by Guilford Press (Straight Talk about Your Child's Mental Health), Oxford University Press (Schizophrenia: The Facts), and Elsevier (ADHD: Non-Pharmacologic Interventions). SVF is the principal investigator of www.adhdinadults.com. JWS is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. CAM is the cochair of the Scientific Advisory Board of the Tourette Association of America and is on the Scientific Advisory Board of the International OCD Foundation. All other authors report no biomedical financial interests or potential conflicts of interest.
Publisher Copyright:
© 2021
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