Mood-Stabilizing Antiepileptic Treatment Response in Bipolar Disorder: A Genome-Wide Association Study

Ada Man Choi Ho; Brandon J. Coombes; Thanh Thanh L. Nguyen; Duan Liu; Susan L. McElroy; Balwinder Singh; Malik Nassan; Colin L. Colby; Beth R. Larrabee; Richard M. Weinshilboum; Mark A. Frye; Joanna M. Biernacka

doi:10.1002/cpt.1982

Mood-Stabilizing Antiepileptic Treatment Response in Bipolar Disorder: A Genome-Wide Association Study

Ada Man Choi Ho, Brandon J. Coombes, Thanh Thanh L. Nguyen, Duan Liu, Susan L. McElroy, Balwinder Singh, Malik Nassan, Colin L. Colby, Beth R. Larrabee, Richard M. Weinshilboum, Mark A. Frye, Joanna M. Biernacka^*

^*Corresponding author for this work

Psychiatry and Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED-MSs). To identify genetic polymorphisms that contribute to the variability in AED-MS response, we performed a discovery genome-wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED-MS valproate/divalproex and/or lamotrigine. AED-MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome-wide significant single-nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, P = 7.1E-09) and SLC35F3 (rs114872993, P = 3.2E-08) genes. We also identified two genes with statistically significant gene-level associations: ABCC1 (P = 6.7E-07; top SNP rs875740, P = 2.0E-6), and DISP1 (P = 8.9E-07; top SNP rs34701716, P = 8.9E-07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders, including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/γ-aminobutyric acidergic (GABAergic) neurons, which are targets of AED-MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED-MS treatment response, and may facilitate precision medicine in BD.

Original language	English (US)
Pages (from-to)	1233-1242
Number of pages	10
Journal	Clinical pharmacology and therapeutics
Volume	108
Issue number	6
DOIs	https://doi.org/10.1002/cpt.1982
State	Published - Dec 2020

Funding

We thank the participants in the Mayo Clinic Bipolar Disorder Biobank for their contribution to this research program. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 03/25/20. Recruitment and genotyping for the Mayo Clinic Bipolar Disorder Biobank was supported by the Marriott Family Foundation and the Mayo Clinic Center for Individualized Medicine. This pharmacogenomics study was supported by a gift from Kent and Liz Dauten. R.M.W.’s effort was supported by NIH R01 AA27486.

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

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10.1002/cpt.1982

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Ho, A. M. C., Coombes, B. J., Nguyen, T. T. L., Liu, D., McElroy, S. L., Singh, B., Nassan, M., Colby, C. L., Larrabee, B. R., Weinshilboum, R. M., Frye, M. A., & Biernacka, J. M. (2020). Mood-Stabilizing Antiepileptic Treatment Response in Bipolar Disorder: A Genome-Wide Association Study. Clinical pharmacology and therapeutics, 108(6), 1233-1242. https://doi.org/10.1002/cpt.1982

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title = "Mood-Stabilizing Antiepileptic Treatment Response in Bipolar Disorder: A Genome-Wide Association Study",

abstract = "Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED-MSs). To identify genetic polymorphisms that contribute to the variability in AED-MS response, we performed a discovery genome-wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED-MS valproate/divalproex and/or lamotrigine. AED-MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome-wide significant single-nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, P = 7.1E-09) and SLC35F3 (rs114872993, P = 3.2E-08) genes. We also identified two genes with statistically significant gene-level associations: ABCC1 (P = 6.7E-07; top SNP rs875740, P = 2.0E-6), and DISP1 (P = 8.9E-07; top SNP rs34701716, P = 8.9E-07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders, including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/γ-aminobutyric acidergic (GABAergic) neurons, which are targets of AED-MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED-MS treatment response, and may facilitate precision medicine in BD.",

author = "Ho, {Ada Man Choi} and Coombes, {Brandon J.} and Nguyen, {Thanh Thanh L.} and Duan Liu and McElroy, {Susan L.} and Balwinder Singh and Malik Nassan and Colby, {Colin L.} and Larrabee, {Beth R.} and Weinshilboum, {Richard M.} and Frye, {Mark A.} and Biernacka, {Joanna M.}",

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AU - Nassan, Malik

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Mood-Stabilizing Antiepileptic Treatment Response in Bipolar Disorder: A Genome-Wide Association Study

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