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Glutamatergic and HPA-axis pathway genes in bipolar disorder comorbid with alcohol- and substance use disorders

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Abstract

Glutamatergic neurotransmission has been shown to be dysregulated in bipolar disorder (BD), alcohol use disorder (AUD) and substance use disorder (SUD). Similarly, disruption in the hypothalamic-pituitary-adrenal (HPA)-axis has also been observed in these conditions. BD is often comorbid with AUD and SUD. The effects of the glutamatergic and HPA systems have not been extensively examined in individuals with BD-AUD and BD-SUD comorbidity. The aim of this investigation was to determine whether variants in the glutamatergic pathway and HPA-axis are associated with BD-AUD and BD-SUD comorbidity. The research cohort consisted of 498 individuals with BD type I from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). A subset of the cohort had comorbid current AUD and current SUD. A total of 1935 SNPs from both the glutamatergic and HPA pathways were selected from the STEP-BD genome-wide dataset. To identify population stratification, IBS clustering was performed using the program Plink 1.07. Single SNP association and gene-based association testing were conducted using logistic regression. A pathway analysis of glutamatergic and HPA genes was performed, after imputation using IMPUTE2. No single SNP was associated with BD-AUD or BD-SUD comorbidity after correction for multiple testing. However, from the gene-based analysis, the gene PRKCI was significantly associated with BD-AUD. The pathway analysis provided overall negative findings, although several genes including GRIN2B showed high percentage of associated SNPs for BD-AUD. Even though the glutamatergic and HPA pathways may not be involved in BD-AUD and BD-SUD comorbidity, PRKCI deserves further investigation in BD-AUD.

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Acknowledgments

The authors acknowledge the support of the National Research Foundation (NRF), the Medical Research Council of South Africa and the University of Cape Town (UCT). The authors declare no conflict of interest.

The STEP-BD project was funded in whole or in part with Federal Funds from the National Institute of Mental Health (NIMH), under contract N01MH8001.

Collection of DNA from consenting participants in STEP-BD was supported by N01MH80001 (Gary S. Sachs, M.D., principal investigator). Sample collection funding was supported by NIH grants (MH067288, Pamela Sklar; MH063445, Jordan W. Smoller; MH63420, Vish Nimgaonkar). Genotyping was funded by grants from NIH (MH067288 Pamela Sklar, PI), Johnson & Johnson Pharmaceutical Research and Development, Sylvan C. Herman Foundation, Stanley Medical Research Foundation, and Merck Genome Research Institute (Edward Scolnick, PI).

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Authors and Affiliations

  1. MRC/UCT Human Genetics Research Unit, Division of Human Genetics, University of Cape Town, Observatory, Cape Town, South Africa

    Shareefa Dalvie & Raj Ramesar

  2. Institute of Psychiatry, University of Bologna, Viale Carlo Pepoli 5, Bologna, Italy

    Chiara Fabbri & Alessandro Serretti

  3. Department of Psychiatry and Mental Health, University of Cape Town, Observatory, Cape Town, South Africa

    Dan J. Stein

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  1. Shareefa Dalvie
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  2. Chiara Fabbri
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Correspondence to Shareefa Dalvie.

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Dalvie, S., Fabbri, C., Ramesar, R. et al. Glutamatergic and HPA-axis pathway genes in bipolar disorder comorbid with alcohol- and substance use disorders. Metab Brain Dis 31, 183–189 (2016). https://doi.org/10.1007/s11011-015-9762-1

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