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Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

Published online by Cambridge University Press:  07 October 2019

Catharine E. Krebs Open the ORCID record for Catharine E. Krebs [Opens in a new window] ,
Anil P.S. Ori ,
Annabel Vreeker ,
Timothy Wu ,
Rita M. Cantor ,
Marco P. M. Boks ,
Rene S. Kahn ,
Loes M. Olde Loohuis  and
Roel A. Ophoff
Catharine E. Krebs
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA Department of Human Genetics, University California Los Angeles, Los Angeles, CA, USA
Anil P.S. Ori
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA
Annabel Vreeker
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
Timothy Wu
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA
Rita M. Cantor
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA Department of Human Genetics, University California Los Angeles, Los Angeles, CA, USA
Marco P. M. Boks
Affiliation:
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
Rene S. Kahn
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Loes M. Olde Loohuis
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA
Roel A. Ophoff*
Affiliation:
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA Department of Human Genetics, University California Los Angeles, Los Angeles, CA, USA Department of Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
*
Author for correspondence: Roel A. Ophoff, E-mail: [email protected]
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Abstract

Background

Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. Previous transcriptomic BD studies have had inconsistent findings due to issues such as small sample sizes and difficulty in adequately accounting for confounders like medication use.

Methods

We performed a differential expression analysis in a well-characterized BD case-control sample (Nsubjects = 480) by RNA sequencing of whole blood. We further performed co-expression network analysis, functional enrichment, and cell type decomposition, and integrated differentially expressed genes with genetic risk.

Results

While we observed widespread differential gene expression patterns between affected and unaffected individuals, these effects were largely linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell signaling and immune response functional annotations, among others, and were associated with neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression genetic risk based on information from genome-wide association studies, nor was gene expression associated with polygenic risk scores for BD.

Conclusions

These findings suggest that BD is associated with minimal changes in whole blood gene expression independent of medication use but emphasize the importance of accounting for medication use and cell type heterogeneity in psychiatric transcriptomic studies. The results of this study add to mounting evidence of lithium's cell signaling and immune-related mechanisms.

Keywords

Bipolar disordergenome-wide disease risklithiumneutrophilstranscriptomewhole blood
Type
Original Articles
Information
Psychological Medicine , Volume 50 , Issue 15 , November 2020 , pp. 2575 - 2586
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Copyright
Copyright © Cambridge University Press 2019

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Footnotes

*

Shared senior authorship.

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