. 2023 Aug 1;13(1):12467.

doi: 10.1038/s41598-023-38984-z.

Exome-wide association study of treatment-resistant depression suggests novel treatment targets

Shrey B Shah^#^{1

2}, Teja N Peddada^#^{3

4}, Christopher Song³, Maame Mensah³, Heejong Sung³, Mani Yavi⁵, Peixiong Yuan⁵, Carlos A Zarate Jr⁵, Brian J Mickey^{6

7}, Margit Burmeister^{7

8}, Nirmala Akula³, Francis J McMahon⁹

Affiliations

¹ Human Genetics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. sbs201@njms.rutgers.edu.
² Rutgers New Jersey Medical School, Newark, NJ, USA. sbs201@njms.rutgers.edu.
³ Human Genetics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
⁴ Stanford University School of Medicine, Stanford, CA, USA.
⁵ Experimental Therapeutics and Pathophysiology Branch and Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
⁶ Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT, USA.
⁷ Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
⁸ Michigan Neuroscience Institute and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁹ Human Genetics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. mcmahonf@mail.nih.gov.

^# Contributed equally.

PMID: 37528149
PMCID: PMC10394052
DOI: 10.1038/s41598-023-38984-z

Exome-wide association study of treatment-resistant depression suggests novel treatment targets

Shrey B Shah et al. Sci Rep. 2023.

. 2023 Aug 1;13(1):12467.

doi: 10.1038/s41598-023-38984-z.

Authors

Affiliations

¹ Human Genetics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. sbs201@njms.rutgers.edu.
² Rutgers New Jersey Medical School, Newark, NJ, USA. sbs201@njms.rutgers.edu.
³ Human Genetics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
⁴ Stanford University School of Medicine, Stanford, CA, USA.
⁵ Experimental Therapeutics and Pathophysiology Branch and Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
⁶ Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT, USA.
⁷ Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
⁸ Michigan Neuroscience Institute and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁹ Human Genetics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. mcmahonf@mail.nih.gov.

^# Contributed equally.

PMID: 37528149
PMCID: PMC10394052
DOI: 10.1038/s41598-023-38984-z

Abstract

Treatment-resistant depression (TRD) is a severe form of major depressive disorder (MDD) with substantial public health impact and poor treatment outcome. Treatment outcome in MDD is significantly heritable, but genome-wide association studies have failed to identify replicable common marker alleles, suggesting a potential role for uncommon variants. Here we investigated the hypothesis that uncommon, putatively functional genetic variants are associated with TRD. Whole-exome sequencing data was obtained from 182 TRD cases and 2021 psychiatrically healthy controls. After quality control, the remaining 149 TRD cases and 1976 controls were analyzed with tests designed to detect excess burdens of uncommon variants. At the gene level, 5 genes, ZNF248, PRKRA, PYHIN1, SLC7A8, and STK19 each carried exome-wide significant excess burdens of variants in TRD cases (q < 0.05). Analysis of 41 pre-selected gene sets suggested an excess of uncommon, functional variants among genes involved in lithium response. Among the genes identified in previous TRD studies, ZDHHC3 was also significant in this sample after multiple test correction. ZNF248 and STK19 are involved in transcriptional regulation, PHYIN1 and PRKRA are involved in immune response, SLC7A8 is associated with thyroid hormone transporter activity, and ZDHHC3 regulates synaptic clustering of GABA and glutamate receptors. These results implicate uncommon, functional alleles in TRD and suggest promising novel targets for future research.

Trial registration: ClinicalTrials.gov NCT00021528.

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Conflict of interest statement

Dr. Carlos A. Zarate, Jr. is a full-time U.S government employee. He is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation. Dr. Zarate is listed as a coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. Dr. Zarate is listed as co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders. Dr. Zarate has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors declare no competing interests.

Figures

**Figure 1**
Gene level results. The red lines denote FDR 5% significance threshold. Top: Quantile–Quantile Plots of Uncommon (A) Functional, (B) Damaging, and (C) Nonsense Variants. Middle: Manhattan Plots of uncommon (D) Functional, (E) Damaging, and (F) Nonsense Variants. Bottom: Bubble Plots of uncommon (G) Functional, (H) Damaging, and (I) Nonsense Variants. The number inside of each circle denotes the number of variants scored in each gene.

**Figure 2**
Gene set level results. The number adjacent to each bar denotes the number of genes contained within that gene set. (A) Bar Chart of Gene Set Analysis based on (A). Uncommon Functional and (B) Uncommon Damaging Variants. * denotes FDR q < 0.05.

See this image and copyright information in PMC

References

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Exome-wide association study of treatment-resistant depression suggests novel treatment targets

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Exome-wide association study of treatment-resistant depression suggests novel treatment targets

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