Insight Gained from Genome-wide Interaction and Enrichment Analysis on Weight Gain During Citalopram Treatment

2017 ◽  
Vol 41 (S1) ◽  
pp. S163-S163
Author(s):  
H. Corfitsen ◽  
A. Drago
Keyword(s):  
Weight Gain ◽  
Myogenic Differentiation ◽  
Antidepressant Treatment ◽  
Enrichment Analysis ◽  
Molecular Pathways ◽  
Present Contribution ◽  
White Adipocyte ◽  
Antidepressant Treatments ◽  
Molecular Events ◽  
Genome Wide

IntroductionWeight gain is a side effect of pharmacological antidepressant treatments, causing a poorer compliance, increasing the risk of metabolic syndrome and periods of untreated disease.ObjectivesThe ability to precisely prescribe pharmacological treatments based on personal genetic makeups would increase the quality of the current antidepressant treatments.AimsThe molecular pathways enriched during citalopram induced weight gain are identified.Methods643 depressed citalopram treated individuals with available clinical and genome-wide genetic information were investigated in the present contribution in order to identify the molecular pathways that holds the key to weight gain. Statistics were conducted in R environment (Bioconductor and Reactome packages), ANOVA and MANCOVA served when appropriate. Plink was used for genetic analysis in a linux environment.ResultsOne hundred and eleven individuals had their weight increased after treatment with citalopram. The axon guidance (P. adjust = 0.005) and the developmental biology pathway (P. adjust = 0.01) were found to be enriched in genetic variations associated with weight gain.ConclusionsThe development biology pathway includes molecular cascades involved in the regulation of beta-cell development, and the transcriptional regulation of white adipocyte differentiation. A number of variations were harboured by genes whose products are involved in the synthesis of collagen (COL4A3, COL5A1 and ITGA1), activity of the thyroid-hormones (NCOR1 and NCOR2), energy metabolism (ADIPOQ, PPARGC1A) and myogenic differentiation (CDON). A molecular pathway analysis conducted in a sample of depressed patients identifies new candidate genes whose future investigation may grant relevant insights in the molecular events that drive weight gain during antidepressant treatment.

scholarly journals Suicide Related Phenotypes in a Bipolar Sample: Genetic Underpinnings

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1482
Author(s):  
Line K. M. Lybech ◽  
Marco Calabró ◽  
Silvana Briuglia ◽  
Antonio Drago ◽  
Concetta Crisafulli
Keyword(s):  
Pathway Analysis ◽  
Individual Risk ◽  
Worth Living ◽  
Present Contribution ◽  
Molecular Pathway ◽  
Molecular Events ◽  
Genome Wide ◽  
Significant Enrichment ◽  
The Individual ◽  
Suicide Behaviors

Suicide in Bipolar Disorder (BD) is a relevant clinical concern. Genetics may shape the individual risk for suicide behavior in BD, together with known clinical factors. The lack of consistent replication in BD may be associated with its multigenetic component. In the present contribution we analyzed a sample of BD individuals (from STEP-BD database) to identify the genetic variants potentially associated with three different suicide-related phenotypes: 1) a feeling that the life was not worth living; 2) fantasies about committing a violent suicide; 3) previous attempted suicide. The sample under analysis included 1115 BD individuals. None of the SNPs reached genome-wide significance. However, a trend of association was evidenced for rs2767403, an intron variant of AOPEP gene, in association with phenotype #1 (p = 5.977 × 10−6). The molecular pathway analysis showed a significant enrichment in all the investigated phenotypes on pathways related to post synaptic signaling, neurotransmission and neurodevelopment. Further, NOTCH signaling or the γ-aminobutyric acid (GABA) -ergic signaling were found to be associated with specific suicide-related phenotypes. The present investigation contributes to the hypothesis that the genetic architecture of suicide behaviors in BD is related to alteration of entire pathways rather than single genes. In particular, our molecular pathway analysis points on some specific molecular events that could be the focus of further research in this field.

scholarly journals Molecular pathways to depression

2013 ◽  
Vol 35 (3) ◽  
pp. 10-14
Author(s):  
Christoph Anacker
Keyword(s):  
Major Depression ◽  
Molecular Mechanisms ◽  
Antidepressant Treatment ◽  
Biological Pathways ◽  
Mental Illnesses ◽  
Molecular Pathways ◽  
First Line ◽  
Antidepressant Treatments ◽  
Multiple Origins ◽  
Basic Concepts

Major depression is one of the most debilitating mental illnesses of our time, and, after more than 60 years of research, we have only just begun to understand some of the basic concepts of this illness with multiple origins and manifestations. Approximately one-third of all depressed patients do not respond to any first line of antidepressant therapy, demonstrating dramatically how little we still understand about the neurobiological and molecular mechanisms underlying depression and antidepressant treatment response. Our discoveries to date are likely to be just the tip of the iceberg, and much research is thus needed to identify biological pathways to depression in order to develop more effective antidepressant treatments in the future.

scholarly journals Genome-wide translating mRNA analysis following ketamine reveals novel targets for antidepressant treatment

2018 ◽  
Author(s):  
Oliver H. Miller ◽  
Nils Grabole ◽  
Isabelle Wells ◽  
Benjamin J. Hall
Keyword(s):  
Protein Synthesis ◽  
Low Dose ◽  
Antidepressant Treatment ◽  
Enrichment Analysis ◽  
Protein Product ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Antidepressant Effects ◽  
Novel Target

AbstractLow-dose ketamine is an efficacious antidepressant for treatment-resistant unipolar and bipolar depressed patients. Major Depression Disorder patients receiving a single infusion report elevated mood within two hours, and ketamine’s antidepressant effects have been observed as long as seven days post-treatment. In light of this remarkable observation, efforts have been undertaken to “reverse-translate” ketamine’s effects to understand its mechanism of action. Major advances have been achieved in understanding the molecular, cellular, and circuit level changes that are initiated by low-dose ketamine. Although enhancement of protein synthesis clearly plays a role, the field lacks a comprehensive understanding of the protein synthesis program initiated after ketamine treatment. Here, using ribosome-bound mRNA footprinting and deep sequencing (RiboSeq), we uncover a genome-wide set of actively translated mRNAs (the translatome) in medial prefrontal cortex after an acute antidepressant-like dose of ketamine. Gene Ontology analysis confirmed that initiation of protein synthesis is a defining feature of antidepressant-dose ketamine in mice and Gene Set Enrichment Analysis points to a role for GPCR signaling, metabolism, vascularization, and structural plasticity in ketamine’s effects. One gene, VIPR2, whose protein product VPAC2 acts as a GPCR for the neuropeptide vasoactive intestinal peptide, was characterized in cortex and identified as a potential novel target for antidepressant action.

scholarly journals Gene set enrichment analysis for genome-wide DNA methylation data

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jovana Maksimovic ◽  
Alicia Oshlack ◽  
Belinda Phipson
Keyword(s):  
Dna Methylation ◽  
Enrichment Analysis ◽  
R Package ◽  
Gene Set Enrichment Analysis ◽  
Methylation Array ◽  
Gene Set ◽  
Genome Wide ◽  
Genome Methylation ◽  
Unbiased Gene ◽  
Gene Set Testing

AbstractDNA methylation is one of the most commonly studied epigenetic marks, due to its role in disease and development. Illumina methylation arrays have been extensively used to measure methylation across the human genome. Methylation array analysis has primarily focused on preprocessing, normalization, and identification of differentially methylated CpGs and regions. GOmeth and GOregion are new methods for performing unbiased gene set testing following differential methylation analysis. Benchmarking analyses demonstrate GOmeth outperforms other approaches, and GOregion is the first method for gene set testing of differentially methylated regions. Both methods are publicly available in the missMethyl Bioconductor R package.

Abstract 62: Molecular Basis of Regulatory Variation at Coronary Heart Disease-Associated Loci

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Clint L Miller ◽  
Milos Pjanic ◽  
Jonathan D Lee ◽  
Boxiang Liu ◽  
William J Greenleaf ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Chromatin Immunoprecipitation ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Regulatory Mechanisms ◽  
Tgf Beta ◽  
Genome Wide ◽  
Context Specific ◽  
Accessible Chromatin

Genome-wide association studies have identified 46 replicated genetic loci for coronary heart disease (CHD), and 104 loci associated at a 5% false discovery rate. However, the regulatory mechanisms of these associations largely remain elusive. Given that the majority of these CHD-associated loci reside in non-coding regions, they are predicted to function via context-specific gene regulation. Recent high-throughput assays of regulatory function include the assay for transposase-accessible chromatin using sequencing (ATAC-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq). ATAC-seq utilizes a Tn5 transposase to fragment and tag accessible DNA sequences, which are often coupled to transcription factor occupancy identified by ChIP-seq. Importantly, this assay may reveal the spatio-temporal regulatory profiles in limited numbers of primary cells. Using ATAC-seq in human coronary artery smooth muscle cells (HCASMC) we identified 147,173 accessible chromatin peaks in control versus 198,976 peaks in TGF-beta-stimulated cells (136,446 shared peaks). Using de novo motif enrichment analysis we identified significant enrichment of specific AP-1 family members (29.2% vs. 5.1% background), chromatin remodeling, and SMC differentiation transcription factors. Using functional enrichment analysis of ChIP-seq and CHD-overlapping regions we observed enrichment of the hypoxia inducible factor 1 (HIF-1) and TGF-beta signaling pathways (1.5x10 -22 and 5.6x10 -18 , respectively) and relevant phenotypes, including cell migration and blood vessel morphology. Finally, we utilized these regulatory maps to explore the causal mechanisms underlying CHD-associated variants at four loci using haplotype-specific chromatin immunoprecipitation (haploChIP) and luciferase reporter assays. Taken together, these results suggest that genome-wide approaches such as ATAC-seq can be leveraged to map context-specific regulatory mechanisms of non-coding variants associated with complex diseases such as CHD, and reveal new biological and molecular insights into targeting heritable disease risk.

scholarly journals Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples

2018 ◽  
Vol 214 (1) ◽  
pp. 36-41 ◽  
Author(s):  
Chiara Fabbri ◽  
Siegfried Kasper ◽  
Alexander Kautzky ◽  
Lucie Bartova ◽  
Markus Dold ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Adenosine Monophosphate ◽  
Research Support ◽  
Antidepressant Treatments ◽  
Advisory Boards ◽  
Gene Sets ◽  
Genome Wide ◽  
A Genome ◽  
Resistant Depression

BackgroundTreatment-resistant depression (TRD) is the most problematic outcome of depression in terms of functional impairment, suicidal thoughts and decline in physical health.AimsTo investigate the genetic predictors of TRD using a genome-wide approach to contribute to the development of precision medicine.MethodA sample recruited by the European Group for the Study of Resistant Depression (GSRD) including 1148 patients with major depressive disorder (MDD) was characterised for the occurrence of TRD (lack of response to at least two adequate antidepressant treatments) and genotyped using the Infinium PsychArray. Three clinically relevant patient groups were considered: TRD, responders and non-responders to the first antidepressant trial, thus outcomes were based on comparisons of these groups. Genetic analyses were performed at the variant, gene and gene-set (i.e. functionally related genes) level. Additive regression models of the outcomes and relevant covariates were used in the GSRD participants and in a fixed-effect meta-analysis performed between GSRD, STAR*D (n = 1316) and GENDEP (n = 761) participants.ResultsNo individual polymorphism or gene was associated with TRD, although some suggestive signals showed enrichment in cytoskeleton regulation, transcription modulation and calcium signalling. Two gene sets (GO:0043949 and GO:0000183) were associated with TRD versus response and TRD versus response and non-response to the first treatment in the GSRD participants and in the meta-analysis, respectively (corrected P = 0.030 and P = 0.027).ConclusionsThe identified gene sets are involved in cyclic adenosine monophosphate mediated signal and chromatin silencing, two processes previously implicated in antidepressant action. They represent possible biomarkers to implement personalised antidepressant treatments and targets for new antidepressants.Declaration of interestD.S. has received grant/research support from GlaxoSmithKline and Lundbeck; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck. S.M. has been a consultant or served on advisory boards for: AstraZeneca, Bristol-Myers Squibb, Forest, Johnson & Johnson, Leo, Lundbeck, Medelink, Neurim, Pierre Fabre, Richter. S.K. has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen and Novartis; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, Pierre Fabre, Janssen and Neuraxpharm. J.Z. has received grant/research support from Lundbeck, Servier, Brainsway and Pfizer, has served as a consultant or on advisory boards for Servier, Pfizer, Abbott, Lilly, Actelion, AstraZeneca and Roche and has served on speakers' bureaus for Lundbeck, Roch, Lilly, Servier, Pfizer and Abbott. J.M. is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. A.S. is or has been consultant/speaker for: Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. C.M.L. receives research support from RGA UK Services Limited.

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