Investigation of gene-environment interactions in relation to tic severity

Mohamed Abdulkadir^{1

2}, Dongmei Yu^{3

4}, Lisa Osiecki⁴, Robert A King⁵, Thomas V Fernandez⁵, Lawrence W Brown⁶, Keun-Ah Cheon⁷, Barbara J Coffey^{8

9

10}, Blanca Garcia-Delgar¹¹, Donald L Gilbert¹², Dorothy E Grice⁸, Julie Hagstrøm¹³, Tammy Hedderly¹⁴, Isobel Heyman¹⁵, Hyun Ju Hong¹⁶, Chaim Huyser¹⁷, Laura Ibanez-Gomez¹⁸, Young Key Kim¹⁹, Young-Shin Kim²⁰, Yun-Joo Koh²¹, Sodahm Kook²², Samuel Kuperman²³, Bennett Leventhal²⁰, Marcos Madruga-Garrido²⁴, Athanasios Maras²⁵, Pablo Mir²⁶, Astrid Morer²⁷, Alexander Münchau²⁸, Kerstin J Plessen¹³, Veit Roessner²⁹, Eun-Young Shin⁷, Dong-Ho Song³⁰, Jungeun Song³¹, Frank Visscher³², Samuel H Zinner³³, Carol A Mathews³⁴, Jeremiah M Scharf^{3

4}, Jay A Tischfield³⁵, Gary A Heiman³⁵, Andrea Dietrich^#³⁶, Pieter J Hoekstra^#³⁶

Affiliations

¹ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. mohamedabdulkadir@gmail.com.
² Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. mohamedabdulkadir@gmail.com.
³ Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
⁴ Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
⁵ Yale Child Study Center, Yale University School of Medicine, New Haven, CT, 06510, USA.
⁶ Pediatric Neuropsychiatry Program, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
⁷ Yonsei University College of Medicine, Severance Hospital, Seoul, 120-752, South Korea.
⁸ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
¹⁰ University of Miami Miller School of Medicine, Miami, FL, 33146, USA.
¹¹ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain.
¹² Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹³ Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Evelina London Children's Hospital GSTT, Kings Health Partners AHSC, London, UK.
¹⁵ Psychological Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.
¹⁶ Department of Psychiatry, Hallym University Sacred Heart Hospital, Anyang, Gyeonggi, 14068, South Korea.
¹⁷ Academic Center for Child and Adolescent Psychiatry De Bascule, 1105 AZ, Amsterdam, The Netherlands.
¹⁸ Family Health Centers at NYU Langone, Brooklyn, NY, 11220, USA.
¹⁹ Department of Psychiatry, Yonsei Bom Clinic, Seoul, 03330, South Korea.
²⁰ University of California San Francisco Medical Center, San Francisco, CA, 94143, USA.
²¹ Korea Institute for Children's Social Development, Seoul, South Korea.
²² Yonsei-Nuri Mental Health Clinic, Seoul, 08005, South Korea.
²³ Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa, IA, 52242, USA.
²⁴ Sección de Neuropediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
²⁵ Yulius Academy, Yulius Mental Health Organization, 3311 JG, Dordrecht, The Netherlands.
²⁶ Unidad de Trastornos del MovimientoInstituto de Biomedicina de Sevilla (IBiS). Hospital Universitario Virgen del Rocío/CSICUniversidad de Sevilla, Seville, Spain.
²⁷ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari Barcelona, Spain; Institut d'Investigacions Biomediques August Pi i Sunyer (IDIPABS) and Centro de Investigacion en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
²⁸ Institute of Systems of Motor Science, University of Lübeck, 23562, Lübeck, Germany.
²⁹ Department of Child and Adolescent Psychiatry, TU Dresden, Dresden, Germany.
³⁰ Yonsei University Severance Hospital, Seoul, 03722, South Korea.
³¹ Department of Psychiatry, National Health Insurance Service Ilsan Hospital, Goyang, Gyeonggi, 10444, South Korea.
³² Admiraal De Ruyter Ziekenhuis, Department of Neurology, Goes, The Netherlands.
³³ Department of Pediatrics, Division of Developmental Medicine, University of Washington School of Medicine, 1925 NE Pacific Street, Box 356524, Seattle, WA, 98195, USA.
³⁴ Department of Psychiatry, Center for OCD, Anxiety and Related Disorders, and Genetics Institute, University of Florida College of Medicine, Gainesville, FL, 32611, USA.
³⁵ Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.
³⁶ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

^# Contributed equally.

PMID: 34389898
PMCID: PMC8536549
DOI: 10.1007/s00702-021-02396-y

Meta-Analysis

Investigation of gene-environment interactions in relation to tic severity

Mohamed Abdulkadir et al. J Neural Transm (Vienna). 2021 Nov.

. 2021 Nov;128(11):1757-1765.

doi: 10.1007/s00702-021-02396-y. Epub 2021 Aug 13.

Authors

Affiliations

¹ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. mohamedabdulkadir@gmail.com.
² Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA. mohamedabdulkadir@gmail.com.
³ Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
⁴ Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
⁵ Yale Child Study Center, Yale University School of Medicine, New Haven, CT, 06510, USA.
⁶ Pediatric Neuropsychiatry Program, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
⁷ Yonsei University College of Medicine, Severance Hospital, Seoul, 120-752, South Korea.
⁸ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
¹⁰ University of Miami Miller School of Medicine, Miami, FL, 33146, USA.
¹¹ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain.
¹² Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹³ Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Evelina London Children's Hospital GSTT, Kings Health Partners AHSC, London, UK.
¹⁵ Psychological Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.
¹⁶ Department of Psychiatry, Hallym University Sacred Heart Hospital, Anyang, Gyeonggi, 14068, South Korea.
¹⁷ Academic Center for Child and Adolescent Psychiatry De Bascule, 1105 AZ, Amsterdam, The Netherlands.
¹⁸ Family Health Centers at NYU Langone, Brooklyn, NY, 11220, USA.
¹⁹ Department of Psychiatry, Yonsei Bom Clinic, Seoul, 03330, South Korea.
²⁰ University of California San Francisco Medical Center, San Francisco, CA, 94143, USA.
²¹ Korea Institute for Children's Social Development, Seoul, South Korea.
²² Yonsei-Nuri Mental Health Clinic, Seoul, 08005, South Korea.
²³ Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa, IA, 52242, USA.
²⁴ Sección de Neuropediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
²⁵ Yulius Academy, Yulius Mental Health Organization, 3311 JG, Dordrecht, The Netherlands.
²⁶ Unidad de Trastornos del MovimientoInstituto de Biomedicina de Sevilla (IBiS). Hospital Universitario Virgen del Rocío/CSICUniversidad de Sevilla, Seville, Spain.
²⁷ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari Barcelona, Spain; Institut d'Investigacions Biomediques August Pi i Sunyer (IDIPABS) and Centro de Investigacion en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
²⁸ Institute of Systems of Motor Science, University of Lübeck, 23562, Lübeck, Germany.
²⁹ Department of Child and Adolescent Psychiatry, TU Dresden, Dresden, Germany.
³⁰ Yonsei University Severance Hospital, Seoul, 03722, South Korea.
³¹ Department of Psychiatry, National Health Insurance Service Ilsan Hospital, Goyang, Gyeonggi, 10444, South Korea.
³² Admiraal De Ruyter Ziekenhuis, Department of Neurology, Goes, The Netherlands.
³³ Department of Pediatrics, Division of Developmental Medicine, University of Washington School of Medicine, 1925 NE Pacific Street, Box 356524, Seattle, WA, 98195, USA.
³⁴ Department of Psychiatry, Center for OCD, Anxiety and Related Disorders, and Genetics Institute, University of Florida College of Medicine, Gainesville, FL, 32611, USA.
³⁵ Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.
³⁶ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

^# Contributed equally.

PMID: 34389898
PMCID: PMC8536549
DOI: 10.1007/s00702-021-02396-y

Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

Keywords: Gene–environment interaction; Pre- and perinatal complications; Tic severity; Tourette syndrome.

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Conflict of interest statement

Drs. Mathews and Scharf are on the scientific advisory board of the Tourette Association of America (TAA) and have received travel and Grant support from the TAA. Dr. Mathews is also on the scientific advisory board of the International Obsessive–Compulsive Disorder Foundation and the Family Foundation for OCD Research. Dr. Scharf is on the scientific advisory board of the TLC Foundation for Body-Focused Repetitive Behaviors and has received consulting fees from Nuvelution Pharma and Abide Pharmaceuticals. Dr. Coffey is co-Chair of the TAA Medical Advisory Board and has received honoraria from the TAA-CDC partnership She has also received honoraria from the American Academy of Child and Adolescent Psychiatry, Partners Health Care, Harvard Medical School/Psychiatry Academy; consulting fees fromTeva/Nuvelution, and Skyland Trail, and research support from NIMH and Emalex Pharmaceuticals. The remaining authors reported no biomedical financial interest or potential conflict of interest.

Figures

**Fig. 1**
Interaction analyses of rs6539267 with a cumulative pre- and perinatal adversity score in relation to lifetime tic severity

See this image and copyright information in PMC

References

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Investigation of gene-environment interactions in relation to tic severity

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Investigation of gene-environment interactions in relation to tic severity

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