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Eur Arch Psychiatry Clin Neurosci. 2018 Apr;268(3):301-316. doi: 10.1007/s00406-017-0808-8. Epub 2017 May 29.

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.

Author information

1
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. abdulkadir@dls.rutgers.edu.
2
Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. abdulkadir@dls.rutgers.edu.
3
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
4
Department of Psychiatry, Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
5
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
6
Yonsei University College of Medicine, Yonsei Yoo & Kim Mental Health Clinic, Seoul, South Korea.
7
Division of Tics, OCD and Related Disorders, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
9
Yulius Academy and Division Child and Adolescent Psychiatry, Yulius Mental Health Organization, Barendrecht, The Netherlands.
10
Medizinische Hochschule Hannover Klinik für Psychiatrie, Sozialpsychiatrie und Psychotherapie, Hannover, Germany.
11
University Hospital Medical Center Hamburg-Eppendorf, Hamburg, Germany.
12
Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain.
13
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
14
Evelina London Children's Hospital GSTT, Kings Health Partners AHSC, London, UK.
15
Great Ormond Street Hospital for Children, and UCL Institute of Child Health, London, UK.
16
Hallym University Sacred Heart Hospital, Anyang, South Korea.
17
De Bascule, Amsterdam, The Netherlands.
18
AMC Department of Child and Adolescent Psychiatry, Amsterdam, The Netherlands.
19
Yonsei Bom Clinic, Seoul, South Korea.
20
Department of Psychiatry, University of California, San Francisco, USA.
21
Korea Institute for Children's Social Development, Seoul, South Korea.
22
Kangbuk Samsung Hospital, Seoul, South Korea.
23
University of Iowa Carver College of Medicine, Iowa City, IA, USA.
24
Department of Child and Adolescent Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany.
25
Sección de Neuropediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
26
Department of Child and Adolescent Psychiatry, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
27
Unidad de Trastornos del Movimiento, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
28
Institut d'Investigacions Biomediques August Pi i Sunyer (IDIPABS) and Centro de Investigacion en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
29
Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
30
Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
31
Department of Child and Adolescent Psychiatry, TU Dresden, Dresden, Germany.
32
National Health Insurance Service Ilsan Hospital, Goyang-Si, South Korea.
33
Youth Division, Altrecht, Institute for Mental Health, Utrecht, The Netherlands.
34
Department of Neurology, Admiraal De Ruyter Ziekenhuis, Goes, The Netherlands.
35
Department of Pediatrics, University of Washington, Seattle, WA, USA.
36
Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Abstract

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

KEYWORDS:

Attention-deficit/hyperactivity disorder; Candidate gene study; Obsessive–compulsive disorder; Tourette syndrome; Transmission Disequilibrium Test

PMID:
28555406
PMCID:
PMC5708161
DOI:
10.1007/s00406-017-0808-8
[Indexed for MEDLINE]
Free PMC Article

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