Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

Kao, Cheng−Yan; Chen, Hui-Wen; Chen, Hsi‐Chung; Yang, Jenn Hwai; Huang, Ming; Chiu, Yu‐Hui; Lin, Shih Ku; Lee, Ya Chin; Liu, Chih-Min; Chuang, Li Chung; Chen, Chien Hsiun; Wu, Jer Yuarn; Lu, Ru Band; Kuo, Po-Hsiu

doi:10.1093/ijnp/pyw064

Cited by 19 publications

(16 citation statements)

References 70 publications

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“…The pathway associated with substance dependence (morphine addiction signalling) has never been related to BD; however, because BD is a common comorbid condition with substance use disorder, common genetic underpinnings may be present. Our findings did not replicate the signalling pathways for BD-II identified by Kao et al 46 , probably because of the different approaches implemented. We used candidate miRNAs, whereas Kao et al used single nucleotide polymorphisms identified from genome-wide association scans.…”

Section: Discussioncontrasting

confidence: 99%

Serum miRNA as a possible biomarker in the diagnosis of bipolar II disorder

Lee

Wang

et al. 2020

Sci Rep

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The diagnosis of Bipolar II disorder (BD-II) is currently based on the patients' description of symptoms and clinical behavioral observations. This study explored the possibility of miRNA in peripheral blood (serum) as a specific biomarker for BD-II. We identified 6 candidate miRNAs to differentiate BD-II patients from controls using next-generation sequencing. We then examined these candidate miRNAs using real-time PCR in the first cohort (as training group) of 79 BD-II and 95 controls. A diagnostic model was built based on these candidate miRNAs and then tested on an individual testing group (BD-II: n = 20, controls: n = 20). We found that serum expression levels of miR-7-5p, miR-23b-3p, miR-142-3p, miR-221-5p, and miR-370-3p significantly increased in BD-II compared with controls in the first cohort, whereas that of miR-145-5p showed no significant difference. The diagnostic power of the identified miRNAs was further analyzed using receiver-operating characteristic (ROC). Support vector machine (SVM) measurements revealed that a combination of the significant miRNAs reached good diagnostic accuracy (AUC: 0.907). We further examined an independent testing group and the diagnostic power reached fair for BD-II (specificity = 90%, sensitivity = 85%). We constructed miRNA panels using SVM model, which may aid in the diagnosis for BD-II.Bipolar disorder (BD) has several subtypes. Bipolar I disorder (BD-I) and bipolar II disorder (BD-II) are two of the most commonly seen subtypes of BD. BD-I and BD-II differ in clinical presentation: BD-I involves one or more manic or mixed episodes in addition to one or more major depressive episodes. BD-II is characterised by at least one hypomanic episode with one or more major depressive episodes 1,2 . BD-II has become the focus of increasing attention and has been recognised as a unique disorder. Its prevalence rate ranges from 3% to 11% 3 . Nevertheless, because of the complex spectrum of symptoms, the diagnosis of BD remains subjective. Diagnosing BD is challenging because patients typically regard hypomanic episodes as a positive mood status or experience, and they only seek medical help during depressive episodes 4 . BD is initially misdiagnosed at a rate of approximately 40% and typically requires approximately 5-12 years to be correctly diagnosed and treated appropriately 5,6 . Delayed diagnosis and inefficacious treatment of BD-II may lead to a prolonged course, more affective episodes, and an increased suicide rate, adding further to its socioeconomic burden 5,7 .Accumulating evidence reveals that microribonucleic acids (miRNAs) are involved in many biological processes such as neurogenesis, neuroproliferation, and synaptic plasticity in the central nervous system 8,9 . Different expressions of peripheral miRNA have been reported in several mental disorders including schizophrenia, major depressive disorder, and Alzheimer disease [10][11][12] . Changes in peripheral miRNA may be correlated with changes in neuroendocrine or neuroimmune responses 13 . Because brain tissue ...

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Section: Discussioncontrasting

confidence: 99%

Serum miRNA as a possible biomarker in the diagnosis of bipolar II disorder

Lee

Wang

et al. 2020

Sci Rep

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“…Similar to CACNA1C and CACNAB2 , EFHD1 functions as a novel mitochondrial Ca2+ sensor underlying Ca2+-dependent activation of mitoflashes, and was identified as associated with risk to SCZ in a family-based GWAS strategy in an enlarged, ethnically homogeneous, Arab-Israeli family sample (Alkelai et al, 2011; Hou et al, 2016). The ETF1 gene, located in the 5q31, plays important roles in regulating the activity in the translational termination process and transcriptional regulation, and has been reported as a novel susceptible gene for pure BP-II in the latest research literature (Kao et al, 2016; Larkin et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Multivariate analysis of genome-wide data to identify potential pleiotropic genes for five major psychiatric disorders using MetaCCA

Jia

Yang

Chen

et al. 2019

Journal of Affective Disorders

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“… 41 PKP4 is involved in the regulation of cell adhesion and cytoskeletal organization. 42 In pathway analyses of PGC GWAS data, cell adhesion was associated with BIP, 43 and SCZ, 44 whereas cell junction was implicated in MDD, as well as in an integrative pathway analysis of all three disorders. 45 …”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia

Witt¹,

Streit²,

Jungkunz³

et al. 2017

Transl Psychiatry

160

109

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Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

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Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

Cited by 19 publications

References 70 publications

Serum miRNA as a possible biomarker in the diagnosis of bipolar II disorder

Serum miRNA as a possible biomarker in the diagnosis of bipolar II disorder

Multivariate analysis of genome-wide data to identify potential pleiotropic genes for five major psychiatric disorders using MetaCCA

Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia

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