De Novo Coding Variants Are Strongly Associated with Tourette Disorder

A Jeremy Willsey; Thomas V Fernandez; Dongmei Yu; Robert A King; Andrea Dietrich; Jinchuan Xing; Stephan J Sanders; Jeffrey D Mandell; Alden Y Huang; Petra Richer; Louw Smith; Shan Dong; Kaitlin E Samocha; Benjamin M Neale; Giovanni Coppola; Carol A Mathews; Jay A Tischfield; Jeremiah M Scharf; Matthew W State; Gary A Heiman; Tourette International Collaborative Genetics (TIC Genetics)

doi:10.1016/j.neuron.2017.04.024

De Novo Coding Variants Are Strongly Associated with Tourette Disorder

A Jeremy Willsey, Thomas V Fernandez, Dongmei Yu, Robert A King, Andrea Dietrich, Jinchuan Xing, Stephan J Sanders, Jeffrey D Mandell, Alden Y Huang, Petra Richer, Louw Smith, Shan Dong, Kaitlin E Samocha, Benjamin M Neale, Giovanni Coppola, Carol A Mathews, Jay A Tischfield, Jeremiah M Scharf, Matthew W State, Gary A HeimanTourette International Collaborative Genetics (TIC Genetics)

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT.

Original language	English
Pages (from-to)	486-499.e9
Journal	Neuron
Volume	94
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2017.04.024
Publication status	Published - 3 May 2017
Externally published	Yes

Funding

This research was also supported in part by an Informatics Starter Grant from the PhRMA Foundation (to Y. Bromberg). We thank all of the individuals involved in recruitment and assessment of the subjects reported in this study: Denmark: Nikoline Frost and Heidi B. Biernat (Copenhagen); Germany: Stephanie Enghardt, Yvonne Friedrich, Christiane Michel (Dresden), Jenny Schmalfeld (Lübeck), Hanife Kling, and Ariane Saccarello (Ulm); Spain: María T. Cáceres, Fátima Carrillo, Marta Correa, Pilar Gómez-Garre, and Laura Vargas (Sevilla); the Netherlands: Vivian op de Beek (Amsterdam), Marieke Messchendorp (Groningen), Nicole Driessen, Nadine Schalk (Nijmegen), Noor Tromp (Alkmaar), Els van den Ban (Utrecht), Jolanda Blom, Rudi Bruggemans, and MariAnne Overdijk (Barendrecht); UK: Anup Kharod (London GOSH); USA: Sarah Jacobson (Cincinnati), Angie Cookman (Iowa City), Zoey Shaw (Mount Sinai/NKI), Julia Brillante, Daniela B. Colognori, Joseph Conerty, Alycia Davis, Joanne O'Brien, Carolyn Spiro, Donna Tischfield (Rutgers), Shannon Granillo, and JD Sandhu (Seattle Children's). Finally, we thank Adife Gulhan Ercan-Sencicek (Yale), Xin He (University of Chicago), Kathryn Roeder (CMU), Bernie Devlin (University of Pittsburgh), Helen Willsey (UCSF), the Willsey lab (UCSF), and all who may not have been mentioned.

Funders	Funder number
Angie Cookman
Hanife Kling
Helen Willsey
Kathryn Roeder
MariAnne Overdijk
Vivian op de Beek
National Institute of Mental Health	R01MH092289
Pharmaceutical Research and Manufacturers of America Foundation
University of Chicago
University of Pittsburgh
Carnegie Mellon University
University of California, San Francisco

Keywords

Adult
Cadherins
Child
Cohort Studies
Female
Fibronectins
Genetic Predisposition to Disease
Genetic Variation
Humans
Intracellular Signaling Peptides and Proteins
Journal Article
Male
Mutation
Odds Ratio
Parents
Phosphoproteins
Proteins
Receptors, Cell Surface
Sequence Analysis, DNA
Tourette Syndrome
Video-Audio Media

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10.1016/j.neuron.2017.04.024

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Willsey, A. J., Fernandez, T. V., Yu, D., King, R. A., Dietrich, A., Xing, J., Sanders, S. J., Mandell, J. D., Huang, A. Y., Richer, P., Smith, L., Dong, S., Samocha, K. E., Neale, B. M., Coppola, G., Mathews, C. A., Tischfield, J. A., Scharf, J. M., State, M. W., ... Tourette International Collaborative Genetics (TIC Genetics) (2017). De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron, 94(3), 486-499.e9. https://doi.org/10.1016/j.neuron.2017.04.024

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title = "De Novo Coding Variants Are Strongly Associated with Tourette Disorder",

abstract = "Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT.",

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author = "Willsey, {A Jeremy} and Fernandez, {Thomas V} and Dongmei Yu and King, {Robert A} and Andrea Dietrich and Jinchuan Xing and Sanders, {Stephan J} and Mandell, {Jeffrey D} and Huang, {Alden Y} and Petra Richer and Louw Smith and Shan Dong and Samocha, {Kaitlin E} and Neale, {Benjamin M} and Giovanni Coppola and Mathews, {Carol A} and Tischfield, {Jay A} and Scharf, {Jeremiah M} and State, {Matthew W} and Heiman, {Gary A} and {Tourette International Collaborative Genetics (TIC Genetics)}",

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doi = "10.1016/j.neuron.2017.04.024",

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Willsey, AJ, Fernandez, TV, Yu, D, King, RA, Dietrich, A, Xing, J, Sanders, SJ, Mandell, JD, Huang, AY, Richer, P, Smith, L, Dong, S, Samocha, KE, Neale, BM, Coppola, G, Mathews, CA, Tischfield, JA, Scharf, JM, State, MW, Heiman, GA & Tourette International Collaborative Genetics (TIC Genetics) 2017, 'De Novo Coding Variants Are Strongly Associated with Tourette Disorder', Neuron, vol. 94, no. 3, pp. 486-499.e9. https://doi.org/10.1016/j.neuron.2017.04.024

TY - JOUR

T1 - De Novo Coding Variants Are Strongly Associated with Tourette Disorder

AU - Willsey, A Jeremy

AU - Fernandez, Thomas V

AU - Yu, Dongmei

AU - King, Robert A

AU - Dietrich, Andrea

AU - Xing, Jinchuan

AU - Sanders, Stephan J

AU - Mandell, Jeffrey D

AU - Huang, Alden Y

AU - Richer, Petra

AU - Smith, Louw

AU - Dong, Shan

AU - Samocha, Kaitlin E

AU - Neale, Benjamin M

AU - Coppola, Giovanni

AU - Mathews, Carol A

AU - Tischfield, Jay A

AU - Scharf, Jeremiah M

AU - State, Matthew W

AU - Heiman, Gary A

AU - Tourette International Collaborative Genetics (TIC Genetics)

PY - 2017/5/3

Y1 - 2017/5/3

N2 - Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT.

AB - Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT.

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KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - Journal Article

KW - Male

KW - Mutation

KW - Odds Ratio

KW - Parents

KW - Phosphoproteins

KW - Proteins

KW - Receptors, Cell Surface

KW - Sequence Analysis, DNA

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SP - 486-499.e9

JO - Neuron

JF - Neuron

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ER -

De Novo Coding Variants Are Strongly Associated with Tourette Disorder

Abstract

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Keywords

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