Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing

Chiara Fabbri; Oliver Pain; Saskia P. Hagenaars; Cathryn M. Lewis; Alessandro Serretti

doi:10.1038/s41386-021-01059-6

Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing

Chiara Fabbri^*, Oliver Pain, Saskia P. Hagenaars, Cathryn M. Lewis, Alessandro Serretti

^*Corresponding author for this work

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

29 Citations (Scopus)

Abstract

Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20–30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.

Original language	English
Pages (from-to)	1821-1829
Number of pages	9
Journal	Neuropsychopharmacology
Volume	46
Issue number	10
DOIs	https://doi.org/10.1038/s41386-021-01059-6
Publication status	Published - Sept 2021

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title = "Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing",

abstract = "Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20–30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.",

author = "Chiara Fabbri and Oliver Pain and Hagenaars, {Saskia P.} and Lewis, {Cathryn M.} and Alessandro Serretti",

note = "Funding Information: The authors acknowledge use of the research computing facility at King{\textquoteright}s College London, Rosalind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the NIHR Biomedical Research Centres at South London & Maudsley and Guy{\textquoteright}s & St. Thomas{\textquoteright} NHS Foundation Trusts, and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy{\textquoteright}s & St. Thomas{\textquoteright} Charity (TR130505). This research has been conducted using the UK Biobank Resource under Application Number 56514 “Stratification of health outcomes in mood disorders”. UK Biobank is an open access resource for bona fide researchers (https://www.ukbiobank.ac.uk/ enable-your-research). Funding Information: This research was supported by the UK Medical Research Council (Saskia Hagenaars: MR/S0151132) and by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Chiara Fabbri was supported by Fondazione Umberto Veronesi (https://www.fondazioneveronesi.it). Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

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AU - Serretti, Alessandro

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N2 - Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20–30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.

AB - Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20–30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.

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Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing

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