Basic mechanisms of and treatment targets for bipolar disorder

2020 ◽  
pp. 721-734
Author(s):  
Grant C. Churchill ◽  
Nisha Singh ◽  
Michael J. Berridge
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Calcium Signalling ◽  
Cyclic Adenosine Monophosphate ◽  
Mood Stabilizer ◽  
Adenosine Monophosphate ◽  
Genome Wide Association Studies ◽  
Treatment Targets ◽  
Intracellular Signalling Pathways ◽  
Genome Wide

This chapter on basic mechanisms of, and treatment targets for, bipolar disorder examines the cause and treatment of bipolar disorder from the perspective of intracellular signalling pathways implicated by the convergence of evidence from efficacious drugs, pathophysiology, and genetics and concludes that the unifying concept is calcium signalling. It discusses the pathways for cyclic adenosine monophosphate and inositol trisphosphate/calcium in the context of the action of drugs, with emphasis on lithium, the most effective true mood stabilizer. It proposes that the calcium signalling pathway and its components, such as channels, pumps, messengers, and enzymes, can explain both how dysfunction can affect neural activity and how this can be remedied by drugs. It argues for the central role of calcium, based on new evidence for the inositol depletion hypothesis and evidence of calcium dysregulation in peripheral and inducible pluripotent stem cells, as well as genome-wide association studies and drugs implicating a plasma membrane calcium channel.

scholarly journals Pharmacogenomics of Lithium Response in Bipolar Disorder

2021 ◽  
Vol 14 (4) ◽  
pp. 287
Author(s):  
Courtney M. Vecera ◽  
Gabriel R. Fries ◽  
Lokesh R. Shahani ◽  
Jair C. Soares ◽  
Rodrigo Machado-Vieira
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Mood Stabilizer ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Lithium Response ◽  
Genetic Loading ◽  
Long Non Coding Rna

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.

scholarly journals Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans

2020 ◽  
Author(s):  
Tim B Bigdeli ◽  
Ayman H Fanous ◽  
Yuli Li ◽  
Nallakkandi Rajeevan ◽  
Frederick Sayward ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Susceptibility Loci ◽  
New Associations ◽  
Genome Wide ◽  
Us Veterans

Abstract Background Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world’s population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. Methods We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. Results Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10–30) and African American (P < .0005) participants in CSP #572. Conclusions We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

scholarly journals Epistasis analysis reveals associations between gene variants and bipolar disorder

2017 ◽  
Author(s):  
Carlo Maj ◽  
Elena Milanesi ◽  
Massimo Gennarelli ◽  
Luciano Milanesi ◽  
ivan Merelli
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Statistical Tests ◽  
Genome Wide Association Studies ◽  
Epistasis Analysis ◽  
Complex Phenotypes ◽  
Genome Wide ◽  
A Genome ◽  
Gene Associations ◽  
Wide Scale

In complex phenotypes (e.g., psychiatric diseases) single locus tests, commonly performed with Genome-Wide Association Studies, have proven to be limited in discovering strong gene associations. A growing body of evidence suggests that epistatic non-linear effects may be responsible for complex phenotypes arising from the interaction of different biological factors. A major issue in epistasis analysis is the computational burden due to the huge number of statistical tests to be performed when considering all the potential genotype combinations. In this work, we developed a computational efficient pipeline to investigate the presence of epistasis at a genome-wide scale in bipolar disorder, which is a typical example of complex phenotype with a relevant but unexplained genetic background. By running our pipeline we were able to identify 13 epistasis interactions between variants located in genes potentially involved in biological processes associated with the analyzed phenotype.

scholarly journals Transcriptome association studies of neuropsychiatric traits in African Americans implicate PRMT7 in schizophrenia

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7778 ◽  
Author(s):  
Peter N. Fiorica ◽  
Heather E. Wheeler
Keyword(s):  
Bipolar Disorder ◽  
African Americans ◽  
Complex Traits ◽  
Multiple Testing ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Potential Candidate ◽  
Candidate Locus ◽  
Genome Wide ◽  
Multiple Testing Adjustment

In the past 15 years, genome-wide association studies (GWAS) have provided novel insight into the genetic architecture of various complex traits; however, this insight has been primarily focused on populations of European descent. This emphasis on European populations has led to individuals of recent African descent being grossly underrepresented in the study of genetics. With African Americans making up less than 2% of participants in neuropsychiatric GWAS, this discrepancy is magnified in diseases such as schizophrenia and bipolar disorder. In this study, we performed GWAS and the gene-based association method PrediXcan for schizophrenia (n = 2,256) and bipolar disorder (n = 1,019) in African American cohorts. In our PrediXcan analyses, we identified PRMT7 (P = 5.5 × 10−6, local false sign rate = 0.12) as significantly associated with schizophrenia following an adaptive shrinkage multiple testing adjustment. This association with schizophrenia was confirmed in the much larger, predominantly European, Psychiatric Genomics Consortium. In addition to the PRMT7 association with schizophrenia, we identified rs10168049 (P = 1.0 × 10−6) as a potential candidate locus for bipolar disorder with highly divergent allele frequencies across populations, highlighting the need for diversity in genetic studies.

What is the impact of genome-wide supported risk variants for schizophrenia and bipolar disorder on brain structure and function? A systematic review

2015 ◽  
Vol 45 (12) ◽  
pp. 2461-2480 ◽  
Author(s):  
R. Gurung ◽  
D. P. Prata
Keyword(s):  
Bipolar Disorder ◽  
Brain Structure ◽  
Association Studies ◽  
Structure And Function ◽  
Future Research ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Brain Structure And Function ◽  
And Function ◽  
The Impact

The powerful genome-wide association studies (GWAS) revealed common mutations that increase susceptibility for schizophrenia (SZ) and bipolar disorder (BD), but the vast majority were not known to be functional or associated with these illnesses. To help fill this gap, their impact on human brain structure and function has been examined. We systematically discuss this output to facilitate its timely integration in the psychosis research field; and encourage reflection for future research. Irrespective of imaging modality, studies addressing the effect of SZ/BD GWAS risk genes (ANK3, CACNA1C, MHC, TCF4, NRGN, DGKH, PBRM1, NCANandZNF804A) were included. Most GWAS risk variations were reported to affect neuroimaging phenotypes implicated in SZ/BD: white-matter integrity (ANK3andZNF804A), volume (CACNA1CandZNF804A) and density (ZNF804A); grey-matter (CACNA1C, NRGN, TCF4andZNF804A) and ventricular (TCF4) volume; cortical folding (NCAN) and thickness (ZNF804A); regional activation during executive tasks (ANK3, CACNA1C, DGKH, NRGNandZNF804A) and functional connectivity during executive tasks (CACNA1CandZNF804A), facial affect recognition (CACNA1CandZNF804A) and theory-of-mind (ZNF804A); but inconsistencies and non-replications also exist. Further efforts such as standardizing reporting and exploring complementary designs, are warranted to test the reproducibility of these early findings.

scholarly journals Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

2016 ◽  
Author(s):  
Liping Hou ◽  
Sarah E. Bergen ◽  
Nirmala Akula ◽  
Jie Song ◽  
Christina M. Hultman ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
X Chromosome ◽  
Odds Ratio ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Chromosome Associations

ABSTRACTBipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10−9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10−9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

scholarly journals Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e1570 ◽  
Author(s):  
Emma-Jane Mallas ◽  
Francesco Carletti ◽  
Christopher A. Chaddock ◽  
James Woolley ◽  
Marco M. Picchioni ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
White Matter ◽  
Diffusion Tensor ◽  
Clinical Sample ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Risk Variant ◽  
White Matter Microstructure ◽  
Genome Wide ◽  
The Impact

Background.Schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls.Methods.230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA.Results.As predicted, statistically significant reductions in FA across a widely distributed brain network (p< 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d= 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d= 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found.Discussion.We provide the first evidence in a predominantly Caucasian clinical sample, of an association betweenZNF804Ars1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure.

Lithium pharmacogenetics. Two decades of studies

2020 ◽  
Vol 36 (1) ◽  
pp. 67-82
Author(s):  
Maciej D. Sobczak ◽  
Joanna M. Pawlak
Keyword(s):  
Bipolar Disorder ◽  
Reference Lists ◽  
Clock Genes ◽  
Association Studies ◽  
Lithium Treatment ◽  
Second Messengers ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Genome Wide

Pharmacogenetic research aims to elucidate associations of genetic variants and individual effects of pharmacotherapy. Personalised expected response to medications might be useful in prognosis for polygenetically determined disorders. In bipolar disorder (BP), that is partly hereditary polygenic disorder, a subgroup of patients excellently responding to lithium prophylaxis was described. During the last 20 years molecular technology allowed to investigate genome of patients treated with lithium and candidate association studies characterised them more precisely than clinical features. The role of several neurotransmitters’ pathways, second messengers, neuroprotection involved genes and clock genes associations were discovered. Further laboratory technics development enables us to perform genome-wide association studies (GWAS) and polygenic risk score (PRS) analyses. We aimed to review research on genes involved in lithium treatment efficacy and safety. PubMed for English papers, articles published in Polish and reference lists from full-text available papers were searched. Pharmacogenetic findings for lithium treatment effects might help develop new personalised strategies and consequently better symptom reduction. So far, chronicity and recurrent course of bipolar disorder impair the functioning of numerous patients and strongly increase the risk of suicide.

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