Genetic Variations of Ionotropic Glutamate Receptor Pathways on Interferon-α-induced Depression in Patients with Hepatitis C Viral Infection

Cheng, Szu-Wei; Li, Jing Xing; Chien, Yu Chuan; Chang, Jane Pei-Chen; Shityakov, Sergey; Huang, Shih Yi; Gałecki, Piotr; Su, Kuan‐Pin

doi:10.1016/j.bbi.2020.11.006

Cited by 13 publications

(10 citation statements)

References 69 publications

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“…TAOK3 is a serine/threonine protein kinase that regulates the p38/MAPK14 stress-activated MAPK cascade and the MAPK8/JNK cascade [ 84 , 85 ]. Interestingly, previous studies have reported the crucial role of MAPK signaling in depression [ 86 – 89 ]. These lines of evidence support that TAOK3 and MAPK signaling pathway may be a promising target for depression treatment.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders

Liu

Cheng

et al. 2022

Neuropsychopharmacol.

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Psychiatric disorders impose tremendous economic burden on society and are leading causes of disability worldwide. However, only limited drugs are available for psychiatric disorders and the efficacy of most currently used drugs is poor for many patients. To identify novel therapeutic targets for psychiatric disorders, we performed genome-wide Mendelian randomization analyses by integrating brain-derived molecular quantitative trait loci (mRNA expression and protein abundance quantitative trait loci) of 1263 actionable proteins (targeted by approved drugs or drugs in clinical phase of development) and genetic findings from large-scale genome-wide association studies (GWASs). Using transcriptome data, we identified 25 potential drug targets for psychiatric disorders, including 12 genes for schizophrenia, 7 for bipolar disorder, 7 for depression, and 1 ( TIE1 ) for attention deficit and hyperactivity. We also identified 10 actionable drug targets by using brain proteome data, including 4 (HLA-DRB1, CAMKK2, P2RX7, and MAPK3) for schizophrenia, 1 (PRKCB) for bipolar disorder, 6 (PSMB4, IMPDH2, SERPINC1, GRIA1, P2RX7 and TAOK3) for depression. Of note, MAPK3 and HLA-DRB1 were supported by both transcriptome and proteome-wide MR analyses, suggesting that these two proteins are promising therapeutic targets for schizophrenia. Our study shows the power of integrating large-scale GWAS findings and transcriptomic and proteomic data in identifying actionable drug targets. Besides, our findings prioritize actionable novel drug targets for development of new therapeutics and provide critical drug-repurposing opportunities for psychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders

Liu

Cheng

et al. 2022

Neuropsychopharmacol.

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“…The genome-wide permutations process powered by an accelerated expectation-maximization algorithm [34] or SNPs and haplotypes has been recognized as a valid predictor for the effects of multiple genes and linkage disequilibrium [35,36]. For instance, previous studies provided evidence suggesting the possible pathology of the kynurenine pathway [10] and the ionotropic glutamate receptor pathways [11] in MDD. Furthermore, to evaluate the combination effect of each SNP in the same gene, we carried out the haplotype association tests with Haploview 4.2.…”

Section: Discussionmentioning

confidence: 99%

“…Genome-wide association studies (GWAS) provide insights for the exploration of potential pathological genes in MDD. For instance, based on GWAS, genes such as Kynureninase (KYNU), Sirtuin (SIRT), glutamate ionotropic receptor AMPA type subunit 2 (GluR2), Neuronal Growth Regulator 1 (NEGR1), and High Mobility Group Box 1 (HMGB1) may relate to depressive symptoms [6][7][8][9][10][11]. Some of these aforementioned genes, including KYNU and SIRT, are also associated with NAD.…”

Section: Introductionmentioning

confidence: 99%

Identification of Genetic Variations in the NAD-Related Pathways for Patients with Major Depressive Disorder: A Case-Control Study in Taiwan

Chen

Cheng

Chen

et al. 2022

JCM

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Background and Objectives: Nicotinamide adenine dinucleotide (NAD) is an important coenzyme in various physiological processes, including sirtuins (SIRTs) and kynurenine pathway (KP). Previous studies have shown that lower NAD levels can be indicative of increased risks of cancer and psychiatric disorders. However, there has been no prior study exploring the link between NAD homeostasis and psychiatric disorders from a genetic perspective. Therefore, we aimed to investigate the association of genetic polymorphism in the pathways of NAD biosynthesis with major depressive disorder (MDD). Methods: A total of 317 patients were included in the case group and were compared with sex-matched control group of 1268 participants (1:4 ratio) from Taiwan Biobank (TWB). All subjects in the control group were over 65 years old, which is well past the average age of onset of MDD. Genomic DNA extracted from patients’ blood buffy coat was analyzed using the Affymetrix TWB array. Full-model tests were conducted for the analysis of single nucleotide polymorphism (SNPs) in all candidate genes. We focused on genes within the NAD-related candidate pathways, including 15 in KP, 12 in nicotinate metabolism, 7 in SIRTs, and 19 in aldehyde dehydrogenases (ALDHs). A total of 508 SNPs were analyzed in this study. After significant SNPs were determined, 5000 genome-wide max(T) permutations were performed in Plink. Finally, we built a predictive model with logistic regression and assessed the interactions of SNPs with the haplotype association tests. Results: We found three SNPs that were significantly associated with MDD in our NAD-related candidate pathways, one within the KP (rs12622574 in ACMSD) and two within the nicotinate metabolism (rs28532698 in BST1 and rs3733593 in CD38). The observed association with MDD was significant in the dominant model of inheritance with marital status, education level, and body mass index (BMI) adjusted as covariates. Lastly, in haplotype analysis, the three associated SNPs consisted of one haploblock in ACMSD, four haploblocks in BST1, and two haploblocks in CD38. Conclusions: This study provides the first evidence that genetic variations involved in NAD homeostasis in the KP and nicotinate metabolism may be associated with the occurrence of MDD.

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“…In follow-ups these individuals have shown to be prone to relapse into new depressive episodes ( 101) -hypothetically triggered by major stressful events or major infections. Genetic studies have also suggested that patients that develop depression under IFN-α have higher frequencies of certain genetic variations, single nucleotide polymorphisms (SNPs), associated to glutamate receptor pathways and kynurenine pathways (102,103). This could support the theory that individuals genetically predisposed may react to inflammation with changes in 5-HT levels or glutamate levels in the brain.…”

Section: Study IImentioning

confidence: 92%

Different Aspects of Psoriasis : Comorbidity, Comedication and Disease Biomarkers

Duvetorp

2021

Linköping University Medical Dissertations

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Genetic Variations of Ionotropic Glutamate Receptor Pathways on Interferon-α-induced Depression in Patients with Hepatitis C Viral Infection

Cited by 13 publications

References 69 publications

Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders

Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders

Identification of Genetic Variations in the NAD-Related Pathways for Patients with Major Depressive Disorder: A Case-Control Study in Taiwan

Different Aspects of Psoriasis : Comorbidity, Comedication and Disease Biomarkers

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