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Impact of CYP2C19 genotype-predicted enzyme activity on hippocampal volume, anxiety, and depression

https://doi.org/10.1016/j.psychres.2020.112984Get rights and content

Highlights

  • CYP2C19 genetic variation is not associated with hippocampi volumes, nor depressive or anxiety symptoms.

  • Interstudy differences in CYP2C19 genotype frequencies and/or study methodology could lead to discrepant findings.

Abstract

Cytochrome P450 C19 (CYP2C19) metabolizes exogenous and endogenous compounds. Although CYP2C19 is highly expressed in the liver, it is also expressed in the brain during early life. Previous human and animal studies have linked CYP2C19 genotype-predicted enzyme activity to hippocampal volumes, depressive symptoms, and anxiety-like behaviors. We examined these promising associations in a general community sample comprising 386 Caucasian adults with no history of psychiatric or neurological illnesses. Contrary to previous findings, CYP2C19 genotype-predicted enzyme activity was not associated with hippocampal volumes, nor depressive and anxiety symptoms. Interstudy differences in CYP2C19 frequencies and/or study methodology may explain this discrepancy.

Introduction

The cytochrome P450 (CYP) family of enzymes are best known for their role in the hepatic metabolism of exogenous and endogenous compounds (Hedlund et al., 2001; Robert et al., 2010). Within this family, CYP2C19 is found in high concentration in the liver, but it is also expressed in the brain during the pre- and perinatal periods (Hedlund et al., 2001; Persson et al., 2014; Stingl and Viviani, 2015). Although CYP2C19 genetic variation is used to predict CYP2C19 enzyme activity (i.e., poor, intermediate, normal, rapid, ultrarapid) in the liver and blood levels of medications that are CYP2C19 substrates (Hicks et al., 2015, 2017), the use of CYP2C19 genetic variation to predict brain related phenotypes is less established. Clinical and preclinical studies have suggested that CYP2C19 genotype-predicted enzyme activity is associated with brain related phenotypes, such as hippocampi volumes (Jukić et al., 2017; Persson et al., 2014), depressive symptoms (Jukić et al., 2017; Sim et al., 2010), and anxiety-like behavior (Persson et al., 2014). Specifically, Jukić et al. (2017) showed in two independent cohorts of healthy adults that CYP2C19 poor metabolizers had larger hippocampi and report fewer depressive symptoms relative to non-poor metabolizers, while CYP2C19 rapid/ultrarapid metabolizers report greater suicidality. In addition, Sim and colleagues (2010) found in a cohort of healthy adults that CYP2C19 poor metabolizers reported fewer depressive symptoms relative to normal metabolizers. Finally, Persson et al. (2014) reported that CYP2C19 transgenic mice displayed more anxiety-like behaviors and smaller hippocampi compared to their littermates with no copies of CYP2C19. Thus, the current study sought to contribute to this emerging evidence base by examining these promising genotype-brain phenotype associations in an independent Australian community sample.

Section snippets

Subjects

Participants were recruited as part of a larger cross-sectional study of healthy community members (N = 1094) in the Melbourne and Brisbane areas of Australia between August 2013 and May 2017 (Pinar et al., 2018; Sabaroedin et al., 2019). The current study included 386 individuals (57% females; mean age = 23.6 years, standard deviation = 5.3 years) of European descent (all four grandparents) that had genetic and neuroimaging data available but no self-reported history of psychiatric illness,

Results

CYP2C19 genotype frequencies were in Hardy-Weinberg equilibrium and phenotype frequencies aligned with those contained in the PharmGKB, European population database (Whirl-Carrillo et al., 2012) (Table S1). The frequency of poor, intermediate, normal, rapid and ultrarapid phenotypes was 1% (n = 4), 25% (n = 97), 37% (n = 143), 32% (n = 123) and 5% (n = 19), respectively. Hippocampi volumes did not differ by CYP2C19 genotype-predicted phenotypes (Fig. 1a & b, left: F4,380 = 0.722, P = 0.577;

Discussion

In contrast to previous findings (Jukić et al., 2017; Persson et al., 2014; Sim et al., 2010), CYP2C19 genotype-predicted enzyme activity was not associated with hippocampi volumes, depressive symptoms or anxiety in the current study. The association between CYP2C19 and hippocampi volumes was first reported in a study of humanized CYP2C19 transgenic mice that showed mice with one copy of CYP2C19 (transgenic) had smaller hippocampi compared to their littermates with no copies of CYP2C19 (

CRediT authorship contribution statement

Aisouda Savadlou: Formal analysis, Writing - original draft. Aurina Arnatkeviciute: Data curation, Writing - review & editing. Jeggan Tiego: Data curation, Writing - review & editing. Ziarih Hawi: Data curation, Writing - review & editing. Mark A. Bellgrove: Methodology, Funding acquisition, Writing - review & editing. Alex Fornito: Methodology, Funding acquisition, Writing - review & editing. Chad Bousman: Conceptualization, Writing - review & editing, Methodology, Formal analysis, Supervision.

Declaration of Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

AF was supported by the National Health and Medical Research Council (NHMRC) (Grant No. 1050504), Australian Research Council (Grant No. FT130100589), and the Sylvia and Charles Viertel Charitable Foundation. MAB is supported by a NHMRC Senior Research Fellowship (Level B). Jeggan Tiego was supported by (NHMRC Project Grants1002458 and 1046054). CAB was supported by the University of Calgary, Cumming School of Medicine and Alberta Children's Hospital Foundation.

References (17)

  • B. Patenaude et al.

    A Bayesian model of shape and appearance for subcortical brain segmentation

    Neuroimage

    (2011)
  • K. Sabaroedin et al.

    Functional connectivity of corticostriatal circuitry and psychosis-like experiences in the general community

    Biol. Psychiatry

    (2019)
  • F. Grubbs

    Sample criteria for testing outlying observations

    Ann. Math. Statist.

    (1950)
  • E. Hedlund et al.

    Cytochrome P450 in the brain; a review

    Curr. Drug Metab.

    (2001)
  • J.K. Hicks et al.

    Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors

    Clin. Pharmacol. Ther.

    (2015)
  • J.K. Hicks et al.

    Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update

    Clin. Pharmacol. Ther

    (2017)
  • The jamovi project (2020). jamovi (Version 1.2)[Computer Software]. Retrieved...
  • M.M. Jukić et al.

    Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment

    Mol. Psychiatry

    (2017)
There are more references available in the full text version of this article.

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