Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families

Tourette International Collaborative Genetics Study (TIC Genetics); Xiaolong Cao; Yeting Zhang; Mohamed Abdulkadir; Li Deng; Thomas V. Fernandez; Blanca Garcia-Delgar; Julie Hagstrøm; Pieter J. Hoekstra; Robert A. King; Justin Koesterich; Samuel Kuperman; Astrid Morer; Cara Nasello; Kerstin J. Plessen; Joshua K. Thackray; Lisheng Zhou; Lawrence W. Brown; Xiaolong Cao; Barbara J. Coffey; Donald L. Gilbert; Tammy Hedderly; Isobel Heyman; Chaim Huyser; Eunjoo Kim; Young Shin Kim; Yun Joo Koh; Bennett L. Leventhal; Marcos Madruga-Garrido; Athanasios Maras; Pablo Mir; Alexander Münchau; Veit Roessner; Dong Ho Song; Matthew W. State; A. Jeremy Willsey; Samuel H. Zinner; Andrea Dietrich; Jay A. Tischfield; Gary A. Heiman; Jinchuan Xing

doi:10.1038/s41380-021-01094-1

Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families

Tourette International Collaborative Genetics Study (TIC Genetics), Xiaolong Cao, Yeting Zhang, Mohamed Abdulkadir, Li Deng, Thomas V. Fernandez, Blanca Garcia-Delgar, Julie Hagstrøm, Pieter J. Hoekstra, Robert A. King, Justin Koesterich, Samuel Kuperman, Astrid Morer, Cara Nasello, Kerstin J. Plessen, Joshua K. Thackray, Lisheng Zhou, Lawrence W. Brown, Xiaolong Cao, Barbara J. CoffeyDonald L. Gilbert, Tammy Hedderly, Isobel Heyman, Chaim Huyser, Eunjoo Kim, Young Shin Kim, Yun Joo Koh, Bennett L. Leventhal, Marcos Madruga-Garrido, Athanasios Maras, Pablo Mir, Alexander Münchau, Veit Roessner, Dong Ho Song, Matthew W. State, A. Jeremy Willsey, Samuel H. Zinner, Andrea Dietrich, Jay A. Tischfield, Gary A. Heiman, Jinchuan Xing^*

^*Corresponding author for this work

25 Citations (Scopus)

Abstract

Tourette’s Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein–protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies.

Original language	English
Journal	Molecular Psychiatry
Volume	26
Issue number	11
Pages (from-to)	6937-6951
Number of pages	15
ISSN	1359-4184
DOIs	https://doi.org/10.1038/s41380-021-01094-1
Publication status	Published - 11.2021

Funding

Funders	Funder number
Jacques und Gloria Gossweiler-Stiftung
Fundación Alicia Koplowitz
Fundación Mutua Madrileña
Sociedad Andaluza de Neurología
Comissionat per Universitats i Recerca del Departmanent d’Innovacio
Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía	CTS-7685, CVI-02526
Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya	2009SGR1119
Instituto de Salud Carlos III	PI13/01461, PI10/ 01674
National Institute of Mental Health	U24MH068457, R01MH115958, K08MH099424, R01MH115963, R01MH092293
Deutsche Forschungsgemeinschaft	MU 1692/4-1, MU 1692/3-1, FOR 2698
National Institute of Environmental Health Sciences	R01ES021462
Consejería de Salud y Bienestar Social de la Junta de Andalucía	PI-0471-2013, PI-0741/2010, PI-0437-2012
New Jersey Center for Tourette Syndrome	K08MH099424

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
Centers: Center for Rare Diseases (ZSE)

DFG Research Classification Scheme

2.23-07 Clinical Neurology, Neurosurgery and Neuroradiology
2.23-06 Molecular and Cellular Neurology and Neuropathology

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10.1038/s41380-021-01094-1

Cite this

Tourette International Collaborative Genetics Study (TIC Genetics), Cao, X., Zhang, Y., Abdulkadir, M., Deng, L., Fernandez, T. V., Garcia-Delgar, B., Hagstrøm, J., Hoekstra, P. J., King, R. A., Koesterich, J., Kuperman, S., Morer, A., Nasello, C., Plessen, K. J., Thackray, J. K., Zhou, L., Brown, L. W., Cao, X., ... Xing, J. (2021). Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families. Molecular Psychiatry, 26(11), 6937-6951. https://doi.org/10.1038/s41380-021-01094-1

@article{c20de31b72984b49af6e8349505ee332,

title = "Whole-exome sequencing identifies genes associated with Tourette{\textquoteright}s disorder in multiplex families",

abstract = "Tourette{\textquoteright}s Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7\% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein–protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies.",

author = "\{Tourette International Collaborative Genetics Study (TIC Genetics)\} and Xiaolong Cao and Yeting Zhang and Mohamed Abdulkadir and Li Deng and Fernandez, \{Thomas V.\} and Blanca Garcia-Delgar and Julie Hagstr{\o}m and Hoekstra, \{Pieter J.\} and King, \{Robert A.\} and Justin Koesterich and Samuel Kuperman and Astrid Morer and Cara Nasello and Plessen, \{Kerstin J.\} and Thackray, \{Joshua K.\} and Lisheng Zhou and Brown, \{Lawrence W.\} and Xiaolong Cao and Coffey, \{Barbara J.\} and Gilbert, \{Donald L.\} and Tammy Hedderly and Isobel Heyman and Chaim Huyser and Eunjoo Kim and Kim, \{Young Shin\} and Koh, \{Yun Joo\} and Leventhal, \{Bennett L.\} and Marcos Madruga-Garrido and Athanasios Maras and Pablo Mir and Alexander M{\"u}nchau and Veit Roessner and Song, \{Dong Ho\} and State, \{Matthew W.\} and Willsey, \{A. Jeremy\} and Zinner, \{Samuel H.\} and Andrea Dietrich and Tischfield, \{Jay A.\} and Heiman, \{Gary A.\} and Jinchuan Xing",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = nov,

doi = "10.1038/s41380-021-01094-1",

language = "English",

volume = "26",

pages = "6937--6951",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "11",

}

Tourette International Collaborative Genetics Study (TIC Genetics), Cao, X, Zhang, Y, Abdulkadir, M, Deng, L, Fernandez, TV, Garcia-Delgar, B, Hagstrøm, J, Hoekstra, PJ, King, RA, Koesterich, J, Kuperman, S, Morer, A, Nasello, C, Plessen, KJ, Thackray, JK, Zhou, L, Brown, LW, Cao, X, Coffey, BJ, Gilbert, DL, Hedderly, T, Heyman, I, Huyser, C, Kim, E, Kim, YS, Koh, YJ, Leventhal, BL, Madruga-Garrido, M, Maras, A, Mir, P, Münchau, A, Roessner, V, Song, DH, State, MW, Willsey, AJ, Zinner, SH, Dietrich, A, Tischfield, JA, Heiman, GA & Xing, J 2021, 'Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families', Molecular Psychiatry, vol. 26, no. 11, pp. 6937-6951. https://doi.org/10.1038/s41380-021-01094-1

TY - JOUR

T1 - Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families

AU - Tourette International Collaborative Genetics Study (TIC Genetics)

AU - Cao, Xiaolong

AU - Zhang, Yeting

AU - Abdulkadir, Mohamed

AU - Deng, Li

AU - Fernandez, Thomas V.

AU - Garcia-Delgar, Blanca

AU - Hagstrøm, Julie

AU - Hoekstra, Pieter J.

AU - King, Robert A.

AU - Koesterich, Justin

AU - Kuperman, Samuel

AU - Morer, Astrid

AU - Nasello, Cara

AU - Plessen, Kerstin J.

AU - Thackray, Joshua K.

AU - Zhou, Lisheng

AU - Brown, Lawrence W.

AU - Cao, Xiaolong

AU - Coffey, Barbara J.

AU - Gilbert, Donald L.

AU - Hedderly, Tammy

AU - Heyman, Isobel

AU - Huyser, Chaim

AU - Kim, Eunjoo

AU - Kim, Young Shin

AU - Koh, Yun Joo

AU - Leventhal, Bennett L.

AU - Madruga-Garrido, Marcos

AU - Maras, Athanasios

AU - Mir, Pablo

AU - Münchau, Alexander

AU - Roessner, Veit

AU - Song, Dong Ho

AU - State, Matthew W.

AU - Willsey, A. Jeremy

AU - Zinner, Samuel H.

AU - Dietrich, Andrea

AU - Tischfield, Jay A.

AU - Heiman, Gary A.

AU - Xing, Jinchuan

PY - 2021/11

Y1 - 2021/11

N2 - Tourette’s Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein–protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies.

AB - Tourette’s Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein–protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies.

UR - https://www.scopus.com/pages/publications/85104282852

U2 - 10.1038/s41380-021-01094-1

DO - 10.1038/s41380-021-01094-1

M3 - Journal articles

C2 - 33837273

AN - SCOPUS:85104282852

SN - 1359-4184

VL - 26

SP - 6937

EP - 6951

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 11

ER -

Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

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