Translational genomics and beyond in bipolar disorder

Zhang, Chen; Xiao, Xiao; Li, Tao; Li, Ming

doi:10.1038/s41380-020-0782-9

Cited by 32 publications

(25 citation statements)

References 201 publications

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“…In the present study, we report the results of the third GWAS meta-analysis of the PGC Bipolar Disorder Working Group, comprising 41,917 patients with BD and 371,549 controls. These results confirm and expand on many previously reported findings, identify novel therapeutic leads and prioritize genes for functional follow-up studies 28,29 . Thus, our results further illuminate the biological etiology of BD.…”

Section: Introductionsupporting

confidence: 91%

“…Both FURIN and DCLK3 also encode druggable proteins (although they are not targets for any current psychiatric medications) 73,78 . These eQTL results provide promising BD candidate genes for functional follow-up experiments 29 . While several of these are in genome-wide significant loci, many are not the closest gene to the index SNP, highlighting the value of probing underlying molecular mechanisms to prioritize the most likely causal genes in the loci.…”

Section: Discussionmentioning

confidence: 89%

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Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Mullins¹,

Aj²,

Ks³

et al. 2020

Preprint

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Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic and calcium signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers and antiepileptics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

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Section: Introductionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 89%

Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Mullins¹,

Aj²,

Ks³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Genome-wide association studies (GWAS) now have progressively larger sample sizes, such that more single nucleotide polymorphisms are detected, and this is helpful in elucidating the genetic architecture of bipolar disorder. 23 A well cited meta-analysis showed that amongst the 226 genes with noteworthy influence in BD, nine varied in manifestation in the patients' dorsolateral prefrontal cortex: CACNA1C (encoding calcium channel, voltage-dependent, L type, α1C subunit), DTNA (encoding dystrobrevin α), FOXP1 (encoding forkhead box protein P1), GNG2 (encoding guanine nucleotide-binding protein Gi/Gs/Go subunit γ-2), ITPR2 (encoding inositol 1,4,5-trisphosphate receptor, type 2), LSAMP (encoding limbic system-associated membrane protein), NPAS3 (encoding transcription factor neuronal PAS domain protein 3), NCOA2 (encoding nuclear receptor coactivator 2), and NTRK3 (encoding tropomyosin receptor kinase C). 24 Initial scrutiny of the entire genome/transcriptome/proteome sequence points to the involvement of calcium, CREB, and potassium channels signaling.…”

Section: Geneticsmentioning

confidence: 99%

Section: Candidate Biomarkersmentioning

confidence: 99%

The Discovery of Clinically Applicable Biomarkers for Bipolar Disorder: A Review of Candidate and Proteomic Approaches

Muneer

2020

Chonnam Med J

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Bipolar disorder (BD) is a severe psychiatric condition which affects innumerable people across the globe. The etiopathogenesis of BD is multi-faceted with genetic, environmental and psychosocial factors playing a role. Hitherto, the diagnosis and management of BD are purely on empirical grounds as we lack confirmed biomarkers for this condition. In this regard, hypothesis-driven investigations have been unable to identify clinically applicable biomarkers, steering the field towards newer technologies. Innovative, state-of-the-art techniques like multiplex immunoassays and mass spectrometry can potentially investigate the entire proteome. By detecting up or down regulated proteins, novel biomarkers are identified and new postulates about the etiopathogenesis of BD are specified. Hence, biological pathways are uncovered which are involved in the initiation and advancement of the disease and new therapeutic targets are identified. In this manuscript, the extant literature is thoroughly reviewed and the latest findings on candidate BD biomarkers are provided, followed by an overview of the proteomic approaches. It was found that due to the heterogeneous nature of BD no single biomarker is feasible, instead a panel of tests is more likely to be useful. With the application of latest technologies, it is expected that validated biomarkers will be discovered which will be useful as diagnostic tools and help in the delivery of individually tailored therapies to the patients.

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“…A number of BPD genes identified by genome-wide association study (GWAS) have been widely replicated and intensively studied (e.g., CACAN1C and ANK3 ) 24 , but these studies did not include early-onset BPD. Over the past two decades, a host of studies have investigated genetic loci responsible for early-onset BPD through linkage-analyses, candidate–gene association, analyses of copy number variants (CNVs), and GWAS, but findings are inconclusive.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study of early-onset bipolar I disorder in the Han Taiwanese population

Huang

Fann

et al. 2021

Transl Psychiatry

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The search for susceptibility genes underlying the heterogeneous bipolar disorder has been inconclusive, often with irreproducible results. There is a hope that narrowing the phenotypes will increase the power of genetic analysis. Early-onset bipolar disorder is thought to be a genetically homogeneous subtype with greater symptom severity. We conducted a genome-wide association study (GWAS) for this subtype in bipolar I (BPI) disorder. Study participants included 1779 patients of Han Chinese descent with BPI disorder recruited by the Taiwan Bipolar Consortium. We conducted phenotype assessment using the Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry and prepared a life chart with graphic depiction of lifetime clinical course for each of the BPI patient recruited. The assessment of onset age was based on this life chart with early onset defined as ≤20 years of age. We performed GWAS in a discovery group of 516 early-onset and 790 non-early-onset BPI patients, followed by a replication study in an independent group of 153 early-onset and 320 non-early-onset BPI patients and a meta-analysis with these two groups. The SNP rs11127876, located in the intron of CADM2, showed association with early-onset BPI in the discovery cohort (P = 7.04 × 10−8) and in the test of replication (P = 0.0354). After meta-analysis, this SNP was demonstrated to be a new genetic locus in CADM2 gene associated with early-onset BPI disorder (P = 5.19 × 10−8).

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Translational genomics and beyond in bipolar disorder

Cited by 32 publications

References 201 publications

Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

The Discovery of Clinically Applicable Biomarkers for Bipolar Disorder: A Review of Candidate and Proteomic Approaches

Genome-wide association study of early-onset bipolar I disorder in the Han Taiwanese population

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