The shared genetic basis of mood instability and psychiatric disorders: A cross‐trait genome‐wide association analysis

Hindley, Guy; O’Connell, Kevin; Rahman, Zillur; Frei, Oleksandr; Bahrami, Shahram; Shadrin, Alexey; Høegh, Margrethe Collier; Cheng, Weiqiu; Karadag, Naz; Lin, Aihua; Rødevand, Linn; Fan, Chun; Djurovic, Srdjan; Lagerberg, Trine Vik; Dale, Anders M.; Smeland, Olav B.; Andreassen, Ole A.

doi:10.1002/ajmg.b.32907

Cited by 15 publications

(6 citation statements)

References 58 publications

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“…A similar pattern of overlap has also been identified using MiXeR between mental disorders and sleep phenotypes, mood instability, risk-taking, and BMI. [280][281][282][283] Taken together, this suggests that trait-specific genetic variants associated with mental disorders and complex mental traits, such as cognitive functioning and neuroticism, represent small proportions of their total SNP-based heritability.…”

Section: Genome-wide Genetic Overlap and Its Implications For Concept...mentioning

confidence: 99%

Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation

Hindley

Frei

Shadrin

et al. 2022

AJP

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Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have typically treated these complex mental traits as distinct constructs. We applied the "pleiotropy-informed" multivariate omnibus statistical test to genome-wide association studies (GWAS) of 35 measures of neuroticism and cognitive function from the UK Biobank (n=336,993). We identified 431 significantly associated loci with evidence of abundant pleiotropy across personality and cognitive function domains. Functional characterisation implicated genes with significant tissue-specific expression in all tested brain tissues and brain-specific gene-sets. We conditioned independent GWASs of the Big 5 personality traits and cognitive function on our multivariate findings, boosting genetic discovery in other personality traits and improving polygenic prediction. These findings advance our understanding of the polygenic architecture of these complex mental traits, indicating a prominence of pleiotropic genetic effects across higher-order domains of mental function such as personality and cognitive function.

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Section: Genome-wide Genetic Overlap and Its Implications For Concept...mentioning

confidence: 99%

Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation

Hindley

Frei

Shadrin

et al. 2022

AJP

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“…Similarly, UBE2C, a key regulator of cell cycle progression, has been implicated in various brain tumors, including astrocyte tumors and malignant gliomas. Notably, UBE2C's high expression in the hippocampus of Alzheimer's patients, along with its genetic association with mental diseases [30,31,32], suggests its potential role in the development of MDD. Therefore, the differential expression of EN1 and UBE2C genes may be an important reason for the connection between MDD and GBM.…”

Section: Discussionmentioning

confidence: 99%

“…At the same time, UBE2C is also highly expressed in the hippocampus of patients with Alzheimer's disease, which is closely related to patients' cognitive decline, memory decline, and psychological and behavioral abnormalities [31]. At the same time, related genomic studies have proven that the UBE2C gene locus is also highly related to mental diseases [32]. Therefore, high expression of UBE2C may also be one of the potential causes of MDD (shown as in Table 1).…”

Section: Differentially Expression Analysis Identified a Set Of Share...mentioning

confidence: 99%

Decoding Shared Genetics: Unveiling the Link Between Major Depressive Disorder and Glioblastoma Multiforme

Tian

2024

BIO Web Conf.

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Major depressive disorder (MDD) is a common psychiatric disorder, and glioblastoma multiforme (GBM) is the most common primary central nervous system tumor. Patients with GBM have been shown to have a high incidence of MDD, but the pathogenesis of these two diseases remains unclear. This study utilized a high-throughput omics approach to explore the genetic link between MDD and GBM. First, five shared genes between MDD and GBM were identified using differential expression analysis, including EN1 and UBE2C. The result showed that the shared genes EN1 and UBE2C were both differentially expressed in the two diseases, respectively, and related to the development of glioma, dopamine regulation and Alzheimer's disease. Subsequently, weighted gene co-expression network analysis (WGCNA) revealed different functional enrichments in neural activity for GBM and MDD, respectively. The co-expression network results highlighted the common molecular mechanisms between MDD and GBM gene modules, emphasizing neuralrelated activities and gene expression regulation. Our study reveals a compelling genetic link between MDD and GBM, revealing potential co-pathogenesis. And EN1 and UBE2C emerged as key genes, indicating common signaling pathways and potential therapeutic targets. Further exploration of these genes and pathways could provide avenues for targeted therapeutic intervention in these devastating diseases.

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“…Numerous previous studies investigating personality traits using large-scale biobank data share this limitation (of relying on simple questionnaires) but have sufficient statistical power for genetic analyses due to the hundreds of thousands of participants; such studies have nonetheless yielded novel genetic discoveries and insights into human behavior 63 , 64 . For example, the GWASs of risk-taking behavior and mood instability, which were based on a single question, identified and replicated loci associated with the respective traits and revealed a shared genetic basis with other psychiatric traits 63 , 65 , 66 . In the future, studies incorporating more comprehensive questionnaires, such as the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto Questionnaire 2 , may be used to support our findings.…”

Section: Discussionmentioning

confidence: 99%

Leveraging genetic overlap between irritability and psychiatric disorders to identify genetic variants of major psychiatric disorders

et al. 2023

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Irritability is a heritable core mental trait associated with several psychiatric illnesses. However, the genomic basis of irritability is unclear. Therefore, this study aimed to 1) identify the genetic variants associated with irritability and investigate the associated biological pathways, genes, and tissues as well as single-nucleotide polymorphism (SNP)-based heritability; 2) explore the relationships between irritability and various traits, including psychiatric disorders; and 3) identify additional and shared genetic variants for irritability and psychiatric disorders. We conducted a genome-wide association study (GWAS) using 379,506 European samples (105,975 cases and 273,531 controls) from the UK Biobank. We utilized various post-GWAS analyses, including linkage disequilibrium score regression, the bivariate causal mixture model (MiXeR), and conditional and conjunctional false discovery rate approaches. This GWAS identified 15 independent loci associated with irritability; the total SNP heritability estimate was 4.19%. Genetic correlations with psychiatric disorders were most pronounced for major depressive disorder (MDD) and bipolar II disorder (BD II). MiXeR analysis revealed polygenic overlap with schizophrenia (SCZ), bipolar I disorder (BD I), and MDD. Conditional false discovery rate analyses identified additional loci associated with SCZ (number [n] of additional SNPs = 105), BD I (n = 54), MDD (n = 107), and irritability (n = 157). Conjunctional false discovery rate analyses identified 85, 41, and 198 shared loci between irritability and SCZ, BD I, and MDD, respectively. Multiple genetic loci were associated with irritability and three main psychiatric disorders. Given that irritability is a cross-disorder trait, these findings may help to elucidate the genomics of psychiatric disorders.

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The shared genetic basis of mood instability and psychiatric disorders: A cross‐trait genome‐wide association analysis

Cited by 15 publications

References 58 publications

Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation

Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation

Decoding Shared Genetics: Unveiling the Link Between Major Depressive Disorder and Glioblastoma Multiforme

Leveraging genetic overlap between irritability and psychiatric disorders to identify genetic variants of major psychiatric disorders

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