Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort

Birgitte Bertelsen, Hreinn Stefánsson, Lars Riff Jensen, Linea Melchior, Nanette Mol Debes, Camilla Groth, Liselotte Skov, Thomas Werge, Iordanis Karagiannidis, Zsanett Tarnok, C. Barta, Peter Nagy, Luca Farkas, Karen Brøndum-Nielsen, Renata Rizzo, Mariangela Gulisano, Dan Rujescu, Lambertus A. Kiemeney, Sarah Tosato, Muhammad Sulaman Nawaz & 14 others Andres Ingason, Unnur Unnsteinsdottir, Stacy Steinberg, Pétur Ludvigsson, Kari Stefansson, Andreas Walter Kuss, Peristera Paschou, Danielle Cath, Pieter J. Hoekstra, Kirsten Müller-Vahl, Manfred Stuhrmann, Asli Silahtaroglu, Rolph Pfundt, Zeynep Tümer

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. Methods: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. Results: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10-4; odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. Conclusions: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

Original languageEnglish
JournalBiological Psychiatry
DOIs
Publication statusAccepted/In press - Jan 29 2015

Fingerprint

Tourette Syndrome
Genes
Meta-Analysis
Iceland
Gene Duplication
Hungary
Brain
Netherlands
Italy
Reverse Transcription
In Situ Hybridization
Germany
Exons
Central Nervous System
Odds Ratio
RNA
Confidence Intervals
Pathology
Gene Expression
Polymerase Chain Reaction

Keywords

  • AADAC
  • Association study
  • CNV
  • Copy number variation
  • Gilles de la Tourette syndrome
  • Neuropsychiatric disorder

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Bertelsen, B., Stefánsson, H., Riff Jensen, L., Melchior, L., Mol Debes, N., Groth, C., ... Tümer, Z. (Accepted/In press). Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2015.08.027

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort. / Bertelsen, Birgitte; Stefánsson, Hreinn; Riff Jensen, Lars; Melchior, Linea; Mol Debes, Nanette; Groth, Camilla; Skov, Liselotte; Werge, Thomas; Karagiannidis, Iordanis; Tarnok, Zsanett; Barta, C.; Nagy, Peter; Farkas, Luca; Brøndum-Nielsen, Karen; Rizzo, Renata; Gulisano, Mariangela; Rujescu, Dan; Kiemeney, Lambertus A.; Tosato, Sarah; Nawaz, Muhammad Sulaman; Ingason, Andres; Unnsteinsdottir, Unnur; Steinberg, Stacy; Ludvigsson, Pétur; Stefansson, Kari; Kuss, Andreas Walter; Paschou, Peristera; Cath, Danielle; Hoekstra, Pieter J.; Müller-Vahl, Kirsten; Stuhrmann, Manfred; Silahtaroglu, Asli; Pfundt, Rolph; Tümer, Zeynep.

In: Biological Psychiatry, 29.01.2015.

Research output: Contribution to journalArticle

Bertelsen, B, Stefánsson, H, Riff Jensen, L, Melchior, L, Mol Debes, N, Groth, C, Skov, L, Werge, T, Karagiannidis, I, Tarnok, Z, Barta, C, Nagy, P, Farkas, L, Brøndum-Nielsen, K, Rizzo, R, Gulisano, M, Rujescu, D, Kiemeney, LA, Tosato, S, Nawaz, MS, Ingason, A, Unnsteinsdottir, U, Steinberg, S, Ludvigsson, P, Stefansson, K, Kuss, AW, Paschou, P, Cath, D, Hoekstra, PJ, Müller-Vahl, K, Stuhrmann, M, Silahtaroglu, A, Pfundt, R & Tümer, Z 2015, 'Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2015.08.027
Bertelsen, Birgitte ; Stefánsson, Hreinn ; Riff Jensen, Lars ; Melchior, Linea ; Mol Debes, Nanette ; Groth, Camilla ; Skov, Liselotte ; Werge, Thomas ; Karagiannidis, Iordanis ; Tarnok, Zsanett ; Barta, C. ; Nagy, Peter ; Farkas, Luca ; Brøndum-Nielsen, Karen ; Rizzo, Renata ; Gulisano, Mariangela ; Rujescu, Dan ; Kiemeney, Lambertus A. ; Tosato, Sarah ; Nawaz, Muhammad Sulaman ; Ingason, Andres ; Unnsteinsdottir, Unnur ; Steinberg, Stacy ; Ludvigsson, Pétur ; Stefansson, Kari ; Kuss, Andreas Walter ; Paschou, Peristera ; Cath, Danielle ; Hoekstra, Pieter J. ; Müller-Vahl, Kirsten ; Stuhrmann, Manfred ; Silahtaroglu, Asli ; Pfundt, Rolph ; Tümer, Zeynep. / Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort. In: Biological Psychiatry. 2015.
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abstract = "Background: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. Methods: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. Results: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10-4; odds ratio = 1.9; 95{\%} confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. Conclusions: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.",
keywords = "AADAC, Association study, CNV, Copy number variation, Gilles de la Tourette syndrome, Neuropsychiatric disorder",
author = "Birgitte Bertelsen and Hreinn Stef{\'a}nsson and {Riff Jensen}, Lars and Linea Melchior and {Mol Debes}, Nanette and Camilla Groth and Liselotte Skov and Thomas Werge and Iordanis Karagiannidis and Zsanett Tarnok and C. Barta and Peter Nagy and Luca Farkas and Karen Br{\o}ndum-Nielsen and Renata Rizzo and Mariangela Gulisano and Dan Rujescu and Kiemeney, {Lambertus A.} and Sarah Tosato and Nawaz, {Muhammad Sulaman} and Andres Ingason and Unnur Unnsteinsdottir and Stacy Steinberg and P{\'e}tur Ludvigsson and Kari Stefansson and Kuss, {Andreas Walter} and Peristera Paschou and Danielle Cath and Hoekstra, {Pieter J.} and Kirsten M{\"u}ller-Vahl and Manfred Stuhrmann and Asli Silahtaroglu and Rolph Pfundt and Zeynep T{\"u}mer",
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AU - Bertelsen, Birgitte

AU - Stefánsson, Hreinn

AU - Riff Jensen, Lars

AU - Melchior, Linea

AU - Mol Debes, Nanette

AU - Groth, Camilla

AU - Skov, Liselotte

AU - Werge, Thomas

AU - Karagiannidis, Iordanis

AU - Tarnok, Zsanett

AU - Barta, C.

AU - Nagy, Peter

AU - Farkas, Luca

AU - Brøndum-Nielsen, Karen

AU - Rizzo, Renata

AU - Gulisano, Mariangela

AU - Rujescu, Dan

AU - Kiemeney, Lambertus A.

AU - Tosato, Sarah

AU - Nawaz, Muhammad Sulaman

AU - Ingason, Andres

AU - Unnsteinsdottir, Unnur

AU - Steinberg, Stacy

AU - Ludvigsson, Pétur

AU - Stefansson, Kari

AU - Kuss, Andreas Walter

AU - Paschou, Peristera

AU - Cath, Danielle

AU - Hoekstra, Pieter J.

AU - Müller-Vahl, Kirsten

AU - Stuhrmann, Manfred

AU - Silahtaroglu, Asli

AU - Pfundt, Rolph

AU - Tümer, Zeynep

PY - 2015/1/29

Y1 - 2015/1/29

N2 - Background: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. Methods: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. Results: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10-4; odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. Conclusions: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

AB - Background: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. Methods: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. Results: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10-4; odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. Conclusions: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

KW - AADAC

KW - Association study

KW - CNV

KW - Copy number variation

KW - Gilles de la Tourette syndrome

KW - Neuropsychiatric disorder

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