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Genetic Basis of Stress-Related Neuropsychiatric Disorders
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Genetic Basis of Stress-Related Neuropsychiatric Disorders

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Neurogenomics".

Deadline for manuscript submissions: closed (10 November 2023) | Viewed by 21793

Special Issue Editor

Dr. Dubravka Švob Štrac

E-Mail Website
Guest Editor
Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia
Interests: molecular genetics of psychiatric disorders; genetics in addiction research; pharmacogenetics; neurobiology; neuropharmacology; neurodegenerative diseases

Special Issue Information

Dear Colleagues,

Environmental stressful events in combination with genetic underpinnings might trigger the development of various stress-related neuropsychiatric disorders, including post-traumatic stress disorder, anxiety and mood disorders, substance use disorders, and many others. Acute or chronic exposure to stress can lead to numerous adaptive and maladaptive changes in different brain regions, affecting both neurotransmission and morphology, and represents one of the main risk factors in the etiopathogenesis of neuropsychiatric diseases. However, there are other social and biological factors, including genetic determinants, which differentiate between individuals who will develop neuropsychiatric disorders following stress exposure from those who will be resilient. Therefore, the identification of genetic and epigenetic mechanisms underlying resilience and vulnerability to stress is essential in order to better understand the pathophysiology of neuropsychiatric disorders, and for their prevention and treatment. The Special Issue of Genes, “Genetic Basis of Stress-Related Neuropsychiatric Disorders”, will present recent findings on the research targeting genetic background, stress-associated epigenetic changes, as well as gene–stress interactions in different stress-related neuropsychiatric disorders, and give a broad overview of new advances in the field, including pathophysiological mechanisms, model systems, diagnostic biomarkers, and therapeutic approaches.

Dr. Dubravka Švob Štrac
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • psychiatric disorders
  • genetics
  • epigenetics
  • environment
  • stress
  • GxE interaction
  • risk factors
  • polymorphisms
  • gene expression
  • molecular mechanisms
  • biomarkers
  • PTSD
  • mood disorders
  • anxiety disorders
  • substance use disorders
  • addiction
  • human genetics
  • animal models
  • therapeutic targets

Published Papers (9 papers)

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Research

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11 pages, 519 KiB  
Article
Association of Functional Polymorphism in TPH2 Gene with Alcohol Dependence and Personality Traits: Study in Cloninger’s Type I and Type II Alcohol-Dependent Inpatients
by Marcela Konjevod, Mirta Rešetar, Ana Matošić, Lipa Čičin-Šain and Jasminka Štefulj
Genes 2023, 14(2), 413; https://doi.org/10.3390/genes14020413 - 4 Feb 2023
Cited by 1 | Viewed by 1506
Abstract
Alcohol dependence (AD) is a complex disorder with a poorly understood etiology. In this study, we investigated the relationship between genetic variation in the TPH2 gene, which encodes the enzyme responsible for serotonin synthesis in the brain, and both AD and personality traits, [...] Read more.
Alcohol dependence (AD) is a complex disorder with a poorly understood etiology. In this study, we investigated the relationship between genetic variation in the TPH2 gene, which encodes the enzyme responsible for serotonin synthesis in the brain, and both AD and personality traits, with attention to Cloninger’s types of AD. The study included 373 healthy control subjects, 206 inpatients with type I AD, and 110 inpatients with type II AD. All subjects were genotyped for the functional polymorphism rs4290270 in the TPH2 gene, and AD patients completed the Tridimensional Personality Questionnaire (TPQ). The AA genotype and the A allele of the rs4290270 polymorphism were more frequent in both patient groups compared with the control group. In addition, a negative association was found between the number of A alleles and TPQ scores for harm avoidance in patients with type II, but not type I, AD. These results support the involvement of genetic variations of the serotonergic system in the pathogenesis of AD, especially type II AD. They also suggest that in a subset of patients, genetic variation of TPH2 could potentially influence the development of AD by affecting the personality trait of harm avoidance. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)
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20 pages, 7884 KiB  
Article
Hippocampal Changes Elicited by Metabolic and Inflammatory Stressors following Prenatal Maternal Infection
by Sandra L. Rodriguez-Zas, Bruce R. Southey, Haley E. Rymut, Laurie A. Rund and Rodney W. Johnson
Genes 2023, 14(1), 77; https://doi.org/10.3390/genes14010077 - 26 Dec 2022
Cited by 5 | Viewed by 2150
Abstract
The hippocampus participates in spatial navigation and behavioral processes, displays molecular plasticity in response to environmental challenges, and can play a role in neuropsychiatric diseases. The combined effects of inflammatory prenatal and postnatal challenges can disrupt the hippocampal gene networks and regulatory mechanisms. [...] Read more.
The hippocampus participates in spatial navigation and behavioral processes, displays molecular plasticity in response to environmental challenges, and can play a role in neuropsychiatric diseases. The combined effects of inflammatory prenatal and postnatal challenges can disrupt the hippocampal gene networks and regulatory mechanisms. Using a proven pig model of viral maternal immune activation (MIA) matched to controls and an RNA-sequencing approach, the hippocampal transcriptome was profiled on two-month-old female and male offspring assigned to fasting, mimetic viral, or saline treatments. More than 2600 genes presented single or combined effects (FDR-adjusted p-value < 0.05) of MIA, postnatal stress, or sex. Biological processes and pathways encompassing messenger cyclic adenosine 3′,5′-monophosphate (cAMP) signaling were enriched with genes including gastric inhibitory polypeptide receptor (GIPR) predominantly over-expressed in the MIA-exposed fasting males relative to groups that differed in sex, prenatal or postnatal challenge. While this pattern was amplified in fasting offspring, the postnatal inflammatory challenge appeared to cancel out the effects of the prenatal challenge. The transcription factors C-terminal binding protein 2 (CTBP2), RE1 silencing transcription factor (REST), signal transducer and activator of transcription 1 (STAT1), and SUZ12 polycomb repressive complex 2 subunit were over-represented among the genes impacted by the prenatal and postnatal factors studied. Our results indicate that one environmental challenge can influence the effect of another challenge on the hippocampal transcriptome. These findings can assist in the identification of molecular targets to ameliorate the effects of pre-and post-natal stressors on hippocampal-associated physiology and behavior. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)
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20 pages, 1272 KiB  
Article
Analysis of CACNA1C and KCNH2 Risk Variants on Cardiac Autonomic Function in Patients with Schizophrenia
by Alexander Refisch, Shoko Komatsuzaki, Martin Ungelenk, Andy Schumann, Ha-Yeun Chung, Susann S. Schilling, Wibke Jantzen, Sabine Schröder, Markus M. Nöthen, Thomas W. Mühleisen, Christian A. Hübner and Karl-Jürgen Bär
Genes 2022, 13(11), 2132; https://doi.org/10.3390/genes13112132 - 16 Nov 2022
Viewed by 1733
Abstract
Background: Cardiac autonomic dysfunction (CADF) is a major contributor to increased cardiac mortality in schizophrenia patients. The aberrant function of voltage-gated ion channels, which are widely distributed in the brain and heart, may link schizophrenia and CADF. In search of channel-encoding genes that [...] Read more.
Background: Cardiac autonomic dysfunction (CADF) is a major contributor to increased cardiac mortality in schizophrenia patients. The aberrant function of voltage-gated ion channels, which are widely distributed in the brain and heart, may link schizophrenia and CADF. In search of channel-encoding genes that are associated with both CADF and schizophrenia, CACNA1C and KCNH2 are promising candidates. In this study, we tested for associations between genetic findings in both genes and CADF parameters in schizophrenia patients whose heart functions were not influenced by psychopharmaceuticals. Methods: First, we searched the literature for single-nucleotide polymorphisms (SNPs) in CACNA1C and KCNH2 that showed genome-wide significant association with schizophrenia. Subsequently, we looked for such robust associations with CADF traits at these loci. A total of 5 CACNA1C SNPs and 9 KCNH2 SNPs were found and genotyped in 77 unmedicated schizophrenia patients and 144 healthy controls. Genotype-related impacts on heart rate (HR) dynamics and QT variability indices (QTvi) were analyzed separately in patients and healthy controls. Results: We observed significantly increased QTvi in unmedicated patients with CADF-associated risk in CACNA1C rs2283274 C and schizophrenia-associated risk in rs2239061 G compared to the non-risk allele in these patients. Moreover, unmedicated patients with previously identified schizophrenia risk alleles in KCNH2 rs11763131 A, rs3807373 A, rs3800779 C, rs748693 G, and 1036145 T showed increased mean HR and QTvi as compared to non-risk alleles. Conclusions: We propose a potential pleiotropic role for common variation in CACNA1C and KCNH2 associated with CADF in schizophrenia patients, independent of antipsychotic medication, that predisposes them to cardiac arrhythmias and premature death. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)
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13 pages, 291 KiB  
Article
Brain Proteome-Wide Association Study Identifies Candidate Genes that Regulate Protein Abundance Associated with Post-Traumatic Stress Disorder
by Zhen Zhang, Peilin Meng, Huijie Zhang, Yumeng Jia, Yan Wen, Jingxi Zhang, Yujing Chen, Chun’e Li, Chuyu Pan, Shiqiang Cheng, Xuena Yang, Yao Yao, Li Liu and Feng Zhang
Genes 2022, 13(8), 1341; https://doi.org/10.3390/genes13081341 - 27 Jul 2022
Cited by 6 | Viewed by 2091
Abstract
Although previous genome-wide association studies (GWASs) on post-traumatic stress disorder (PTSD) have identified multiple risk loci, how these loci confer risk of PTSD remains unclear. Through the FUSION pipeline, we integrated two human brain proteome reference datasets (ROS/MAP and Banner) with the PTSD [...] Read more.
Although previous genome-wide association studies (GWASs) on post-traumatic stress disorder (PTSD) have identified multiple risk loci, how these loci confer risk of PTSD remains unclear. Through the FUSION pipeline, we integrated two human brain proteome reference datasets (ROS/MAP and Banner) with the PTSD GWAS dataset, respectively, to conduct a proteome-wide association study (PWAS) analysis. Then two transcriptome reference weights (Rnaseq and Splicing) were applied to a transcriptome-wide association study (TWAS) analysis. Finally, the PWAS and TWAS results were investigated through brain imaging analysis. In the PWAS analysis, 8 and 13 candidate genes were identified in the ROS/MAP and Banner reference weight groups, respectively. Examples included ADK (pPWAS-ROS/MAP = 3.00 × 10−5) and C3orf18 (pPWAS-Banner = 7.07 × 10−31). Moreover, the TWAS also detected multiple candidate genes associated with PTSD in two different reference weight groups, including RIMS2 (pTWAS-Splicing = 3.84 × 10−2), CHMP1A (pTWAS-Rnaseq = 5.09 × 10−4), and SIRT5 (pTWAS-Splicing = 4.81 × 10−3). Further comparison of the PWAS and TWAS results in different populations detected the overlapping genes: MADD (pPWAS-Banner = 4.90 × 10−2, pTWAS-Splicing = 1.23 × 10−2) in the total population and GLO1(pPWAS-Banner = 4.89 × 10−3, pTWAS-Rnaseq = 1.41 × 10−3) in females. Brain imaging analysis revealed several different brain imaging phenotypes associated with MADD and GLO1 genes. Our study identified multiple candidate genes associated with PTSD in the proteome and transcriptome levels, which may provide new clues to the pathogenesis of PTSD. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)
20 pages, 2010 KiB  
Article
Genetic and Epigenetic Association of Hepatocyte Nuclear Factor-1α with Glycosylation in Post-Traumatic Stress Disorder
by Lucija Tudor, Marcela Konjevod, Gordana Nedic Erjavec, Matea Nikolac Perkovic, Suzana Uzun, Oliver Kozumplik, Vlatka Zoldos, Gordan Lauc, Dubravka Svob Strac and Nela Pivac
Genes 2022, 13(6), 1063; https://doi.org/10.3390/genes13061063 - 14 Jun 2022
Cited by 1 | Viewed by 1996
Abstract
Post-traumatic stress disorder (PTSD) is a complex trauma-related disorder, the etiology and underlying molecular mechanisms of which are still unclear and probably involve different (epi)genetic and environmental factors. Protein N-glycosylation is a common post-translational modification that has been associated with several pathophysiological states, [...] Read more.
Post-traumatic stress disorder (PTSD) is a complex trauma-related disorder, the etiology and underlying molecular mechanisms of which are still unclear and probably involve different (epi)genetic and environmental factors. Protein N-glycosylation is a common post-translational modification that has been associated with several pathophysiological states, including inflammation and PTSD. Hepatocyte nuclear factor-1α (HNF1A) is a transcriptional regulator of many genes involved in the inflammatory processes, and it has been identified as master regulator of plasma protein glycosylation. The aim of this study was to determine the association between N-glycan levels in plasma and immunoglobulin G, methylation at four CpG positions in the HNF1A gene, HNF1A antisense RNA 1 (HNF1A-AS1), rs7953249 and HNF1A rs735396 polymorphisms in a total of 555 PTSD and control subjects. We found significant association of rs7953249 and rs735396 polymorphisms, as well as HNF1A gene methylation at the CpG3 site, with highly branched, galactosylated and sialyated plasma N-glycans, mostly in patients with PTSD. HNF1A-AS1 rs7953249 polymorphism was also associated with PTSD; however, none of the polymorphisms were associated with HNF1A gene methylation. These results indicate a possible regulatory role of the investigated HNF1A polymorphisms with respect to the abundance of complex plasma N-glycans previously associated with proinflammatory response, which could contribute to the clinical manifestation of PTSD and its comorbidities. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)
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Review

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18 pages, 524 KiB  
Review
Epigenetic Regulation in Schizophrenia: Focus on Methylation and Histone Modifications in Human Studies
by Natasha Delphin, Caitlin Aust, Lyn Griffiths and Francesca Fernandez
Genes 2024, 15(3), 272; https://doi.org/10.3390/genes15030272 - 21 Feb 2024
Cited by 1 | Viewed by 2078
Abstract
Despite extensive research over the last few decades, the etiology of schizophrenia (SZ) remains unclear. SZ is a pathological disorder that is highly debilitating and deeply affects the lifestyle and minds of those affected. Several factors (one or in combination) have been reported [...] Read more.
Despite extensive research over the last few decades, the etiology of schizophrenia (SZ) remains unclear. SZ is a pathological disorder that is highly debilitating and deeply affects the lifestyle and minds of those affected. Several factors (one or in combination) have been reported as contributors to SZ pathogenesis, including neurodevelopmental, environmental, genetic and epigenetic factors. Deoxyribonucleic acid (DNA) methylation and post-translational modification (PTM) of histone proteins are potentially contributing epigenetic processes involved in transcriptional activity, chromatin folding, cell division and apoptotic processes, and DNA damage and repair. After establishing a summary of epigenetic processes in the context of schizophrenia, this review aims to highlight the current understanding of the role of DNA methylation and histone PTMs in this disorder and their potential roles in schizophrenia pathophysiology and pathogenesis. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)
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23 pages, 1399 KiB  
Review
The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy
by Milica Radosavljevic, Dubravka Svob Strac, Jasna Jancic and Janko Samardzic
Genes 2023, 14(5), 1095; https://doi.org/10.3390/genes14051095 - 16 May 2023
Cited by 8 | Viewed by 4797
Abstract
Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and the development of side effects. Pharmacogenetics, as a key part of personalized medicine, aims to optimize therapy according to a patient’s individual genetic [...] Read more.
Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and the development of side effects. Pharmacogenetics, as a key part of personalized medicine, aims to optimize therapy according to a patient’s individual genetic signature by targeting genetic variations involved in pharmacokinetic or pharmacodynamic processes. Pharmacokinetic variability refers to variations in a drug’s absorption, distribution, metabolism, and elimination, whereas pharmacodynamic variability results from variable interactions of an active drug with its target molecules. Pharmacogenetic research on depression and anxiety has focused on genetic polymorphisms affecting metabolizing cytochrome P450 (CYP) and uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, P-glycoprotein ATP-binding cassette (ABC) transporters, and monoamine and γ-aminobutyric acid (GABA) metabolic enzymes, transporters, and receptors. Recent pharmacogenetic studies have revealed that more efficient and safer treatments with antidepressants and anxiolytics could be achieved through genotype-guided decisions. However, because pharmacogenetics cannot explain all observed heritable variations in drug response, an emerging field of pharmacoepigenetics investigates how epigenetic mechanisms, which modify gene expression without altering the genetic code, might influence individual responses to drugs. By understanding the epi(genetic) variability of a patient’s response to pharmacotherapy, clinicians could select more effective drugs while minimizing the likelihood of adverse reactions and therefore improve the quality of treatment. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)
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12 pages, 307 KiB  
Review
Physiological Genomics Plays a Crucial Role in Response to Stressful Life Events, the Development of Aggressive Behaviours, and Post-Traumatic Stress Disorder (PTSD)
by Thabo Magwai and Khethelo Richman Xulu
Genes 2022, 13(2), 300; https://doi.org/10.3390/genes13020300 - 4 Feb 2022
Cited by 5 | Viewed by 2700
Abstract
Physiological genomics plays a crucial role in responding to stressful life events, such as violence and traumatic stress. This exposure to traumatic stress can trigger several physiological pathways, which are associated with genetic variability. Exposure to traumatic stress can result in the development [...] Read more.
Physiological genomics plays a crucial role in responding to stressful life events, such as violence and traumatic stress. This exposure to traumatic stress can trigger several physiological pathways, which are associated with genetic variability. Exposure to traumatic stress can result in the development of behavioural and psychiatric disorders, such as aggressive behaviour and anxiety disorders. Several genes play a crucial role in the neurophysiological response to chronic stress and trauma. These essential genes include monoamine oxidase A (MAOA), solute carrier family 6 member 4 (SLC6A4), brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), dopamine receptor 2 and 4 (DRD2 and DRD4), and FK506 binding protein 5 (FKBP5). Genetic variations in several genes have been found to have altered physiological response, which associates with the development of several behavioural traits. Interestingly, previous studies show that there is an interplay between aggressive behaviour and anxiety disorders, which may be associated with physiological genomics structure. The physiological responses are based on genetic architecture and its molecular reaction. Understanding physiological genomics may show underpinnings related to the development of aggressive behaviours and their interaction with anxiety disorders. This review aims to discuss the association between different physiological genes and the development of psychiatric disorders related to aggressive behaviours and anxiety disorders, such as post-traumatic stress disorder. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)

Other

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10 pages, 1476 KiB  
Hypothesis
How Can CpG Methylations, and Pair-to-Pair Correlations between the Main (Gene) and the Opposite Strands, Suggest a Bending DNA Loop: Insights into the 5′-UTR of DAT1
by Vincenza Di Paola, Martina Morrone, Valentina Poli, Andrea Fuso, Esterina Pascale and Walter Adriani
Genes 2023, 14(1), 190; https://doi.org/10.3390/genes14010190 - 11 Jan 2023
Viewed by 1314
Abstract
A working hypothesis issues from patterns of methylation in the 5′-UTR of the DAT1 gene. We considered relationships between pairs of CpGs, of which one on the main-gene strand and another on the complementary opposite strand (COS). We elaborated on data from ADHD [...] Read more.
A working hypothesis issues from patterns of methylation in the 5′-UTR of the DAT1 gene. We considered relationships between pairs of CpGs, of which one on the main-gene strand and another on the complementary opposite strand (COS). We elaborated on data from ADHD children: we calculated all possible combinations of probabilities (estimated by multiplying two raw values of methylation) in pairs of CpGs from either strand. We analyzed all correlations between any given pair and all other pairs. For pairs correlating with M6-M6COS, some pairs had cytosines positioning to the reciprocal right (e.g., M3-M2COS and M6-M5COS), other pairs had cytosines positioning to the reciprocal left (e.g., M2-M3COS; M5-M6COS). Significant pair-to-pair correlations emerged between main-strand and COS CpG pairs. Through graphic representations, we hypothesized that DNA folded to looping conformations: the C1GG C2GG C3GG and C5G C6G motifs would become close enough to allow cytosines 1-2-3 to interact with cytosines 5-6 (on both strands). Data further suggest a sliding, with left- and right-ward oscillations of DNA strands. While thorough empirical verification is needed, we hypothesize simultaneous methylation of main-strand and COS DNA (“methylation dynamics”) to serve as a promising biomarker. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)
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