Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum

Zhiyu Yang; Hanrui Wu; Phil H Lee; Fotis Tsetsos; Lea K Davis; Dongmei Yu; Sang Hong Lee; Søren Dalsgaard; Jan Haavik; Csaba Barta; Tetyana Zayats; Valsamma Eapen; Naomi R Wray; Bernie Devlin; Mark Daly; Benjamin Neale; Anders D Børglum; James J Crowley; Jeremiah Scharf; Carol A Mathews; Stephen V Faraone; Barbara Franke; Manuel Mattheisen; Jordan W Smoller; Peristera Paschou

doi:10.1016/j.biopsych.2020.12.028

Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum

Zhiyu Yang, Hanrui Wu, Phil H Lee, Fotis Tsetsos, Lea K Davis, Dongmei Yu, Sang Hong Lee, Søren Dalsgaard, Jan Haavik, Csaba Barta, Tetyana Zayats, Valsamma Eapen, Naomi R Wray, Bernie Devlin, Mark Daly, Benjamin Neale, Anders D Børglum, James J Crowley, Jeremiah Scharf, Carol A MathewsStephen V Faraone, Barbara Franke, Manuel Mattheisen, Jordan W Smoller, Peristera Paschou^*

^*Corresponding author for this work

80 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Biological Psychiatry
Volume	90
Issue number	5
Pages (from-to)	317-327
Number of pages	11
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2020.12.028
Publication status	Published - 1 Sept 2021
Externally published	Yes

Access to Document

10.1016/j.biopsych.2020.12.028

Cite this

Yang, Z., Wu, H., Lee, P. H., Tsetsos, F., Davis, L. K., Yu, D., Lee, S. H., Dalsgaard, S., Haavik, J., Barta, C., Zayats, T., Eapen, V., Wray, N. R., Devlin, B., Daly, M., Neale, B., Børglum, A. D., Crowley, J. J., Scharf, J., ... Paschou, P. (2021). Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum. Biological Psychiatry, 90(5), 317-327. https://doi.org/10.1016/j.biopsych.2020.12.028

Yang, Z, Wu, H, Lee, PH, Tsetsos, F, Davis, LK, Yu, D, Lee, SH, Dalsgaard, S, Haavik, J, Barta, C, Zayats, T, Eapen, V, Wray, NR, Devlin, B, Daly, M, Neale, B, Børglum, AD, Crowley, JJ, Scharf, J, Mathews, CA, Faraone, SV, Franke, B, Mattheisen, M, Smoller, JW & Paschou, P 2021, 'Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum', Biological Psychiatry, vol. 90, no. 5, pp. 317-327. https://doi.org/10.1016/j.biopsych.2020.12.028

@article{6d1b0c5781e746a5856f996bd2d67e42,

title = "Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum",

abstract = "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.",

author = "Zhiyu Yang and Hanrui Wu and Lee, \{Phil H\} and Fotis Tsetsos and Davis, \{Lea K\} and Dongmei Yu and Lee, \{Sang Hong\} and S{\o}ren Dalsgaard and Jan Haavik and Csaba Barta and Tetyana Zayats and Valsamma Eapen and Wray, \{Naomi R\} and Bernie Devlin and Mark Daly and Benjamin Neale and B{\o}rglum, \{Anders D\} and Crowley, \{James J\} and Jeremiah Scharf and Mathews, \{Carol A\} and Faraone, \{Stephen V\} and Barbara Franke and Manuel Mattheisen and Smoller, \{Jordan W\} and Peristera Paschou",

note = "Published by Elsevier Inc.",

year = "2021",

month = sep,

day = "1",

doi = "10.1016/j.biopsych.2020.12.028",

language = "English",

volume = "90",

pages = "317--327",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Inc.",

number = "5",

}

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 - Published by Elsevier Inc.

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.

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 - Journal article

C2 - 33714545

SN - 0006-3223

VL - 90

SP - 317

EP - 327

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 5

ER -

Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum

Abstract

Access to Document

Other files and links

Fingerprint

Cite this