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; Csaba Barta; Peter Nagy; Luca Farkas; Karen Brøndum-Nielsen; Renata Rizzo; Mariangela Gulisano; Dan Rujescu; Lambertus A Kiemeney; Sarah Tosato; Muhammad Sulaman Nawaz; Andrés 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

doi:10.1016/j.biopsych.2015.08.027

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, Csaba Barta, Peter Nagy, Luca Farkas, Karen Brøndum-Nielsen, Renata Rizzo, Mariangela Gulisano, Dan Rujescu, Lambertus A Kiemeney, Sarah Tosato, Muhammad Sulaman NawazAndrés 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

23 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 language	English
Journal	Biological Psychiatry
Volume	79
Issue number	5
Pages (from-to)	383–391
Number of pages	9
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2015.08.027
Publication status	Published - 1 Mar 2016

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Bertelsen, B., Stefánsson, H., Riff Jensen, L., Melchior, L., Debes, N. M., 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, L. A., Tosato, S., ... Tümer, Z. (2016). Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort. Biological Psychiatry, 79(5), 383–391. https://doi.org/10.1016/j.biopsych.2015.08.027

Bertelsen, B, Stefánsson, H, Riff Jensen, L, Melchior, L, Debes, NM, 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 2016, 'Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort', Biological Psychiatry, vol. 79, no. 5, pp. 383–391. https://doi.org/10.1016/j.biopsych.2015.08.027

@article{d9c3abd7cc7f48bbac4db802fb6a3a74,

title = "Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort",

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.",

author = "Birgitte Bertelsen and Hreinn Stef{\'a}nsson and {Riff Jensen}, Lars and Linea Melchior and Debes, {Nanette Mol} and Camilla Groth and Liselotte Skov and Thomas Werge and Iordanis Karagiannidis and Zsanett Tarnok and Csaba 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 Andr{\'e}s 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",

year = "2016",

month = mar,

day = "1",

doi = "10.1016/j.biopsych.2015.08.027",

language = "English",

volume = "79",

pages = "383–391",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

number = "5",

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TY - JOUR

T1 - Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort

AU - Bertelsen, Birgitte

AU - Stefánsson, Hreinn

AU - Riff Jensen, Lars

AU - Melchior, Linea

AU - Debes, Nanette Mol

AU - Groth, Camilla

AU - Skov, Liselotte

AU - Werge, Thomas

AU - Karagiannidis, Iordanis

AU - Tarnok, Zsanett

AU - Barta, Csaba

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, Andrés

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 - 2016/3/1

Y1 - 2016/3/1

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.

U2 - 10.1016/j.biopsych.2015.08.027

DO - 10.1016/j.biopsych.2015.08.027

M3 - Journal article

C2 - 26444075

SN - 0006-3223

VL - 79

SP - 383

EP - 391

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 5

ER -

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

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