Functional genetic variation in the Rev-Erbαpathway and lithium response in the treatment of bipolar disorder

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium’s therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium’s exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

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Involvement of microRNAs in Lithium Response in Patients With Bipolar Disorder and Related Phenotypes

Biological Psychiatry ◽

10.1016/j.biopsych.2021.02.053 ◽

2021 ◽

Vol 89 (9) ◽

pp. S13

Author(s):

Claudia Pisanu ◽

Donatella Congiu ◽

Giovanni Severino ◽

Paola Niola ◽

Juan Pablo Lopez ◽

...

Keyword(s):

Bipolar Disorder ◽

Lithium Response

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A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety

Translational Psychiatry ◽

10.1038/s41398-018-0278-4 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 5

Author(s):

L. G. Hommers ◽

J. Richter ◽

Y. Yang ◽

A. Raab ◽

C. Baumann ◽

...

Keyword(s):

Genetic Variation ◽

Functional Genetic Variation ◽

Fear And Anxiety

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Network-based integrative analysis of lithium response in bipolar disorder using transcriptomic and GWAS data

10.1101/2022.01.10.21268493 ◽

2022 ◽

Author(s):

Vipavee Niemsiri ◽

Sarah Brin Rosenthal ◽

Caroline M. Nievergelt ◽

Adam X. Maihofer ◽

Maria C. Marchetto ◽

...

Keyword(s):

Bipolar Disorder ◽

Focal Adhesion ◽

Gene Networks ◽

Gene List ◽

Integrative Analysis ◽

Functional Enrichment ◽

Network Propagation ◽

Lithium Response ◽

The Difference ◽

Effective Drugs

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric=1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

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The crucial role of genome-wide genetic variation in conservation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2104642118 ◽

2021 ◽

Vol 118 (48) ◽

pp. e2104642118

Author(s):

Marty Kardos ◽

Ellie E. Armstrong ◽

Sarah W. Fitzpatrick ◽

Samantha Hauser ◽

Philip W. Hedrick ◽

...

Keyword(s):

Genetic Variation ◽

Environmental Changes ◽

Population Viability ◽

Adaptive Potential ◽

Biodiversity Crisis ◽

Genome Wide ◽

Simulation Based ◽

Functional Genetic Variation

The unprecedented rate of extinction calls for efficient use of genetics to help conserve biodiversity. Several recent genomic and simulation-based studies have argued that the field of conservation biology has placed too much focus on conserving genome-wide genetic variation, and that the field should instead focus on managing the subset of functional genetic variation that is thought to affect fitness. Here, we critically evaluate the feasibility and likely benefits of this approach in conservation. We find that population genetics theory and empirical results show that conserving genome-wide genetic variation is generally the best approach to prevent inbreeding depression and loss of adaptive potential from driving populations toward extinction. Focusing conservation efforts on presumably functional genetic variation will only be feasible occasionally, often misleading, and counterproductive when prioritized over genome-wide genetic variation. Given the increasing rate of habitat loss and other environmental changes, failure to recognize the detrimental effects of lost genome-wide genetic variation on long-term population viability will only worsen the biodiversity crisis.

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