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The World Journal of Biological Psychiatry Volume 22, 2021 - Issue 6
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Review Articles

Genetics of human startle reactivity: A systematic review to acquire targets for an anxiety endophenotype

Julia Tomasia Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada;b Institute of Medical Science, University of Toronto, Toronto, CanadaCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0003-2464-5471View further author information
ORCID Icon,
Clement C. Zaia Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada;b Institute of Medical Science, University of Toronto, Toronto, Canada;c Department of Psychiatry, University of Toronto, Toronto, Canada;d Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, CanadaView further author information
,
Gwyneth Zaia Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada;b Institute of Medical Science, University of Toronto, Toronto, Canada;c Department of Psychiatry, University of Toronto, Toronto, Canada;e General Adult Psychiatry and Health Systems Division, CAMH, Toronto, CanadaView further author information
,
James L. Kennedya Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada;b Institute of Medical Science, University of Toronto, Toronto, Canada;c Department of Psychiatry, University of Toronto, Toronto, CanadaORCID Iconhttps://orcid.org/0000-0002-8733-3806View further author information
ORCID Icon &
Arun K. Tiwaria Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada;c Department of Psychiatry, University of Toronto, Toronto, CanadaView further author information
Pages 399-427 | Received 05 Aug 2020, Accepted 01 Oct 2020, Published online: 12 Nov 2020
 
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Abstract

Objectives

Startle response is an objective physiological measure integral to the human defense system and a promising target for endophenotype investigations of anxiety. Given the alterations in startle reactivity observed among anxiety and related disorders, we searched for genetic variants associated with startle reactivity as they may be further involved in pathological anxiety risk.

Methods

A systematic literature review was performed to identify genetic variants associated with startle reactivity in humans, specifically baseline and fear- or anxiety-potentiated startle.

Results

The polymorphisms Val66Met (rs6265) from brain-derived neurotrophic factor (BDNF), Val158Met (rs4680) from catechol-O-methyltransferase (COMT), and the serotonin transporter-linked polymorphic region (5-HTTLPR) from the serotonin transporter gene (SLC6A4) were most commonly studied in human startle. In addition, several other genetic variants have also been identified as potential candidates that warrant further research, especially given their novelty in in the context of anxiety.

Conclusions

Similar to psychiatric genetic studies, the studies on startle reactivity primarily focus on candidate genes and are plagued by non-replication. Startle reactivity is a promising endophenotype that requires concerted efforts to collect uniformly assessed, large, well-powered samples and hypothesis-free genome-wide strategies. To further support startle as an endophenotype for anxiety, this review suggests advanced genetic strategies for startle research.

Acknowledgements

None.

Disclosure statement

JLK is a member of the Scientific Advisory Board of Myriad Neuroscience (unpaid). JLK, AKT, and CCZ are authors on several patents relating to pharmacogenetic tests for psychiatric medications. The remaining authors have no conflicts of interest to declare.

Additional information

Funding

JT is supported by the Ontario Graduate Scholarship and Institute of Medical Science Open Fellowship Award. JLK receives support from the Larry and Judy Tanenbaum Centre for Pharmacogenetics (CAMH), the Ontario Ministry of Research and Innovation, the Canadian Institutes for Health Research, and the Brain & Behavior Research Foundation (NARSAD). AKT is supported by the Granville Nickerson fellowship in pharmacogenetics and McLaughlin Centre Accelerator Grant (2019–2020). AKT and CCZ have both received NARSAD (BBRF) Young Investigator Awards.

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