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Assary E, Coleman J, Hemani G, van Der Veijer M, Howe L, Palviainen T, Grasby K, Ahlskog R, Nygaard M, Cheesman R, Lim K, Reynolds C, Ordoñana J, Colodro-Conde L, Gordon S, Madrid-Valero J, Thalamuthu A, Hottenga JJ, Mengel-From J, Armstrong NJ, Sachdev P, Lee T, Brodaty H, Trollor J, Wright M, Ames D, Catts V, Latvala A, Vuoksimaa E, Mallard T, Harden K, Tucker-Drob E, Oskarsson S, Hammond C, Christensen K, Taylor M, Lundström S, Larsson H, Karlsson R, Pedersen N, Mather K, Medland S, Boomsma D, Martin N, Plomin R, Bartels M, Lichtenstein P, Kaprio J, Eley T, Davies N, Munroe P, Keers R. Genetics of environmental sensitivity to psychiatric and neurodevelopmental phenotypes: evidence from GWAS of monozygotic twins. RESEARCH SQUARE 2024:rs.3.rs-4333635. [PMID: 38746362 PMCID: PMC11092831 DOI: 10.21203/rs.3.rs-4333635/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes. However, environmental sensitivity genetic variants have proven challenging to detect. GWAS of monozygotic twin differences is a family-based variance analysis method, which is more robust to systemic biases that impact population-based methods. We combined data from up to 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct the largest GWAS meta-analysis of monozygotic phenotypic differences in children and adolescents/adults for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder (ADHD) symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism, and wellbeing. The SNP-heritability of variance in these phenotypes were estimated (h2: 0% to 18%), but were imprecise. We identified a total of 13 genome-wide significant associations (SNP, gene, and gene-set), including genes related to stress-reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. Monozygotic twins are an important new source of evidence about the genetics of environmental sensitivity.
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Affiliation(s)
| | - Jonathan Coleman
- Institute of Psychiatry, Psychology, and Neuroscience, King's College London
| | | | | | | | - Teemu Palviainen
- Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Karen Mather
- Centre for Healthy Brain Ageing, Psychiatry, University of New South Wales (UNSW)
| | | | - D Boomsma
- Vrije Universiteit Amsterdam, The Netherlands
| | | | - Robert Plomin
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London
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2
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Boer LL, Winter E, Gorissen B, Oostra RJ. Phenotypically Discordant Anomalies in Conjoined Twins: Quirks of Nature Governed by Molecular Pathways? Diagnostics (Basel) 2023; 13:3427. [PMID: 37998563 PMCID: PMC10669976 DOI: 10.3390/diagnostics13223427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/24/2023] [Accepted: 11/07/2023] [Indexed: 11/25/2023] Open
Abstract
A multitude of additional anomalies can be observed in virtually all types of symmetrical conjoined twins. These concomitant defects can be divided into different dysmorphological patterns. Some of these patterns reveal their etiological origin through their topographical location. The so-called shared anomalies are traceable to embryological adjustments and directly linked to the conjoined-twinning mechanism itself, inherently located within the boundaries of the coalescence area. In contrast, discordant patterns are anomalies present in only one of the twin members, intrinsically distant from the area of union. These dysmorphological entities are much more difficult to place in a developmental perspective, as it is presumed that conjoined twins share identical intra-uterine environments and intra-embryonic molecular and genetic footprints. However, their existence testifies that certain developmental fields and their respective developmental pathways take different routes in members of conjoined twins. This observation remains a poorly understood phenomenon. This article describes 69 cases of external discordant patterns within different types of otherwise symmetrical mono-umbilical conjoined twins and places them in a developmental perspective and a molecular framework. Gaining insights into the phenotypes and underlying (biochemical) mechanisms could potentially pave the way and generate novel etiological visions in the formation of conjoined twins itself.
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Affiliation(s)
- Lucas L. Boer
- Department of Medical Imaging, Section Anatomy and Museum for Anatomy and Pathology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Eduard Winter
- Pathologisch-Anatomische Sammlung im Narrenturm-NHM, 1090 Vienna, Austria
| | - Ben Gorissen
- Department of Medical Imaging, Section Anatomy and Museum for Anatomy and Pathology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Roelof-Jan Oostra
- Department of Medical Biology, Sections Clinical Anatomy & Embryology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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da Rosa N, de Medeiros FD, de Oliveira J, Laurentino AOM, Peretti EM, Machado RS, Fortunato JJ, Petronilho F. 6-Shogaol improves behavior and memory in Wistar rats prenatally exposed to lipopolysaccharide. Int J Dev Neurosci 2021; 82:39-49. [PMID: 34755374 DOI: 10.1002/jdn.10157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 10/27/2021] [Accepted: 11/05/2021] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVE 6-Shogaol, bioactive compound of Zingiber officinale Roscoe, has anti-inflammatory, antioxidant, and neuroprotective properties. The objective of the present study was to verify the effect of 6-shogaol on behavioral parameters in a preclinical model based on a maternal immune activation (MIA) by lipopolysaccharide (LPS). METHODOLOGY Twelve pregnant Wistar rats received 100-μg/kg LPS or saline solution on gestational day (GD) 9.5. Male offspring participated in the study and in the postnatal day (PND) 30 and 55 were supplemented with 6-shogaol or saline solution, by gavage at a dose of 10 mg/kg/day, orally for 5 days. In the PND 35 and 60 was performed the behavioral tests: grooming, crossing, and rearing that evaluated repetitive movements, anxiety, and interest in the new, respectively, and the inhibitory avoidance test that evaluated short-term (STM) and long-term memory (LTM). RESULT Prenatal exposure to LPS increased the grooming and crossing episodes at different ages and reduced rearing episodes in PND 37. Treatment with 6-shogaol reversed these parameters. In the inhibitory avoidance test, an improvement of memory was identified with 6-shogaol in the STM and LTM at both ages comparing training and test session of treated groups and between groups. CONCLUSION Administration of 6-shogaol reverses the stereotypy, exploratory behavior, and memory impairment in prenatal LPS-exposed offspring, acting as a promising therapeutic component against brain disorders associated with the process of MIA.
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Affiliation(s)
- Naiana da Rosa
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNISUL), Tubarão, Brazil
| | - Fabiana Durante de Medeiros
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNISUL), Tubarão, Brazil
| | - Juliana de Oliveira
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNISUL), Tubarão, Brazil
| | - Ana Olívia Martins Laurentino
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNISUL), Tubarão, Brazil
| | - Eduardo Medeiros Peretti
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNISUL), Tubarão, Brazil
| | - Richard Simon Machado
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNISUL), Tubarão, Brazil
| | - Jucélia Jeremias Fortunato
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNISUL), Tubarão, Brazil
| | - Fabrícia Petronilho
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNISUL), Tubarão, Brazil
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Corroenne R, Al Ibrahim A, Stirnemann J, Zayed LH, Essaoui M, Russell NE, Chalouhi GE, Salomon LJ, Ville Y. Management of monochorionic twins discordant for structural fetal anomalies. Prenat Diagn 2020; 40:1375-1382. [PMID: 32394424 DOI: 10.1002/pd.5734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 04/28/2020] [Accepted: 05/06/2020] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To review the perinatal management and outcomes of monochorionic twin pregnancies (MC) discordant for congenital anomalies (DCA). METHODS Retrospective, study of all MC DCA cases referred to our tertiary referral center from 1997 to 2018. We excluded cases complicated with twin-to-twin transfusion syndrome, twin anemia-polycythemia sequence, twin reversed arterial perfusion sequence or selective intra-uterine growth restriction. Patients were counseled about the possibility of expectant (EM) or interventional management (selective feticide [SF] or termination of the entire pregnancy [TOP]). RESULTS One hundred eight of 4157 (2.6%) MC pregnancies were discordant for anomaly. Fifty two of 108 n(48.1%) underwent SF at a mean gestational age of 31.4 ± 5.9 weeks while 52/108(48.1%) opted for EM. Livebirth rate of the healthy co-twin was similar between the two groups (SF: 88.5% vs EM: 82.7%, P = .87). In the SF group, six healthy co-twins (6/52, 11.5%) died 5.3 ± 3.1 days after SF of the abnormal co-twin. In the EM group, in-utero demise of the abnormal twin occurred in 9 of 52 (17.3%) of the cases and was followed by the spontaneous demise of the healthy co-twin in 4 of 9 (44.4%) of these cases. CONCLUSION Selective feticide does not seem to significantly alter survival of the healthy co-twin compared to EM.
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Affiliation(s)
- Romain Corroenne
- Department of Obstetrics and Fetal Therapy, AP-HP, Necker-Enfants Malades Hospital, Paris, France
| | - Abdullah Al Ibrahim
- Department of Obstetrics and Fetal Therapy, AP-HP, Necker-Enfants Malades Hospital, Paris, France
| | - Julien Stirnemann
- Department of Obstetrics and Fetal Therapy, AP-HP, Necker-Enfants Malades Hospital, Paris, France
| | - Louay Hassan Zayed
- Department of Obstetrics and Fetal Therapy, AP-HP, Necker-Enfants Malades Hospital, Paris, France
| | - Mohamed Essaoui
- Department of Obstetrics and Fetal Therapy, AP-HP, Necker-Enfants Malades Hospital, Paris, France
| | - Noirin E Russell
- Department of Obstetrics and Fetal Therapy, AP-HP, Necker-Enfants Malades Hospital, Paris, France
| | - Gihad E Chalouhi
- Department of Obstetrics and Fetal Therapy, AP-HP, Necker-Enfants Malades Hospital, Paris, France
| | - Laurent J Salomon
- Department of Obstetrics and Fetal Therapy, AP-HP, Necker-Enfants Malades Hospital, Paris, France
| | - Yves Ville
- Department of Obstetrics and Fetal Therapy, AP-HP, Necker-Enfants Malades Hospital, Paris, France
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Mehl-Madrona L, McFarlane P, Mainguy B. Epigenetics, Gender, and Sex in the Diagnosis of Depression. CURRENT PSYCHIATRY RESEARCH AND REVIEWS 2020. [DOI: 10.2174/2666082215666191029141418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background :
A marked sexual dimorphism exists in psychiatric diagnoses. Culture derived
gender bias in diagnostic criteria is one explanation. Adverse childhood events, including sexual
and physical abuse, are more reliable and consistent predictors of later psychiatric diagnoses,
including depression and post-traumatic stress disorder. Some interesting interactions between genes
and experience have been uncovered, but the primary effect appears to be epigenetic with life experience
altering gene expression and being transmitted to subsequent generations.
Objectives :
To determine if reconceptualizing depression as encompassing both internalizing and
externalizing strategies would eliminate gender differences in the diagnosis of depression
Methods :
We reviewed 74 life stories of patients, collected during a study of the effect of physicians’
knowing patients’ life stories on the quality of the doctor-patient relationship. Looking at
diagnoses, the prevalence of women to men was 2.9 to 1. We redefined depression as a response to
being in a seemingly hopeless situation accompanied by despair, either externalizing ((more often
diagnosed as substance use disorders, impulse control disorders, antisocial personality disorder, or
bipolar disorder) or internalizing (the more standard diagnosis of depression). Then we reviewed
these life stories from that perspective to determine how many would be diagnosed as depressed.
Results :
With this reconceptualization of depression, the sex ratio changed to 1.2 to 1.
Conclusions:
From this perspective, men and women are equally likely to respond to hopelessness,
though men are more socialized to externalize and women to internalize. Considering depression in
this way may help to better identify men at risk for suicide.
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Affiliation(s)
- Lewis Mehl-Madrona
- Eastern Maine Medical Center Family Medicine Residency, Bangor, ME 04401, United States
| | - Patrick McFarlane
- Eastern Maine Medical Center Family Medicine Residency, Bangor, ME 04401, United States
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Nusrat S, Harbig T, Gehlenborg N. Tasks, Techniques, and Tools for Genomic Data Visualization. COMPUTER GRAPHICS FORUM : JOURNAL OF THE EUROPEAN ASSOCIATION FOR COMPUTER GRAPHICS 2019; 38:781-805. [PMID: 31768085 PMCID: PMC6876635 DOI: 10.1111/cgf.13727] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Genomic data visualization is essential for interpretation and hypothesis generation as well as a valuable aid in communicating discoveries. Visual tools bridge the gap between algorithmic approaches and the cognitive skills of investigators. Addressing this need has become crucial in genomics, as biomedical research is increasingly data-driven and many studies lack well-defined hypotheses. A key challenge in data-driven research is to discover unexpected patterns and to formulate hypotheses in an unbiased manner in vast amounts of genomic and other associated data. Over the past two decades, this has driven the development of numerous data visualization techniques and tools for visualizing genomic data. Based on a comprehensive literature survey, we propose taxonomies for data, visualization, and tasks involved in genomic data visualization. Furthermore, we provide a comprehensive review of published genomic visualization tools in the context of the proposed taxonomies.
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Affiliation(s)
- S Nusrat
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - T Harbig
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - N Gehlenborg
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
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Barnes‐Davis ME, Cortezzo DE. Two cases of atypical twinning: Phenotypically discordant monozygotic and conjoined twins. Clin Case Rep 2019; 7:920-925. [PMID: 31110715 PMCID: PMC6509934 DOI: 10.1002/ccr3.2113] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 03/01/2019] [Accepted: 03/03/2019] [Indexed: 12/13/2022] Open
Abstract
Atypical twinning highlights that complex mechanisms responsible for twinning are not fully understood and may give further insight into the mechanisms involved. To assume that phenotypic difference is the result of dizygotic twinning would be erroneous and could have significant implications in the care and counseling provided to these patients.
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Affiliation(s)
- Maria E. Barnes‐Davis
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhio
- Division of Neonatal and Pulmonary BiologyCincinnati Children’s Hospital Medical CenterCincinnatiOhio
| | - DonnaMaria E. Cortezzo
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhio
- Division of Neonatal and Pulmonary BiologyCincinnati Children’s Hospital Medical CenterCincinnatiOhio
- Department of AnesthesiologyUniversity of Cincinnati College of MedicineCincinnatiOhio
- Division of Pain and Palliative MedicineCincinnati Children’s Hospital Medical CenterCincinnatiOhio
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8
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Editorial overview: Epigenetics, genomic imprinting and behaviour. Curr Opin Behav Sci 2019. [DOI: 10.1016/j.cobeha.2018.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Iris F, Beopoulos A, Gea M. How scientific literature analysis yields innovative therapeutic hypothesis through integrative iterations. Curr Opin Pharmacol 2018; 42:62-70. [PMID: 30092386 DOI: 10.1016/j.coph.2018.07.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 07/12/2018] [Indexed: 12/27/2022]
Abstract
It is becoming generally accepted that the current diagnostic system often guarantees, rather than diminishes, disease heterogeneity. In effects, syndrome-dominated conceptual thinking has become a barrier to understanding the biological causes of complex, multifactorial diseases characterized by clinical and therapeutic heterogeneity. Furthermore, not only is the flood of currently available medical and biological information highly heterogeneous, it is also often conflicting. Together with the entire absence of functional models of pathogenesis and pathological evolution of complex diseases, this leads to a situation where illness activity cannot be coherently approached and where therapeutic developments become highly problematic. Acquisition of the necessary knowledge can be obtained, in parts, using in silico models produced through analytical approaches and processes collectively known as `Systems Biology'. However, without analytical approaches that specifically incorporate the facts that all that is called `information' is not necessarily useful nor utilisable and that all information should be considered as a priori suspect, modelling attempts will fail because of the much too numerous conflicting and, although correct in molecular terms, physiologically invalid reports. In the present essay, we suggest means whereby this body of problems could be functionally attacked and describe new analytical approaches that have demonstrated their efficacy in alleviating these difficulties.
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Affiliation(s)
- Francois Iris
- Bio-Modeling Systems, Tour CIT, 3 Rue de l'Arrivée, 75015, Paris, France.
| | | | - Manuel Gea
- Bio-Modeling Systems, Tour CIT, 3 Rue de l'Arrivée, 75015, Paris, France
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10
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Epigenetic and Cellular Diversity in the Brain through Allele-Specific Effects. Trends Neurosci 2018; 41:925-937. [PMID: 30098802 DOI: 10.1016/j.tins.2018.07.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 06/29/2018] [Accepted: 07/10/2018] [Indexed: 01/18/2023]
Abstract
The benefits of diploidy are considered to involve masking partially recessive mutations and increasing genetic diversity. Here, we review new studies showing evidence for diverse allele-specific expression and epigenetic states in mammalian brain cells, which suggest that diploidy expands the landscape of gene regulatory and expression programs in cells. Allele-specific expression has been thought to be restricted to a few specific classes of genes. However, new studies show novel genomic imprinting effects that are brain-region-, cell-type- and age-dependent. In addition, novel forms of random monoallelic expression that impact many autosomal genes have been described in vitro and in vivo. We discuss the implications for understanding the benefits of diploidy, and the mechanisms shaping brain development, function, and disease.
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Sobolewski M, Singh G, Schneider JS, Cory-Slechta DA. Different Behavioral Experiences Produce Distinctive Parallel Changes in, and Correlate With, Frontal Cortex and Hippocampal Global Post-translational Histone Levels. Front Integr Neurosci 2018; 12:29. [PMID: 30072878 PMCID: PMC6060276 DOI: 10.3389/fnint.2018.00029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 06/29/2018] [Indexed: 12/29/2022] Open
Abstract
While it is clear that behavioral experience modulates epigenetic profiles, it is less evident how the nature of that experience influences outcomes and whether epigenetic/genetic "biomarkers" could be extracted to classify different types of behavioral experience. To begin to address this question, male and female mice were subjected to either a Fixed Interval (FI) schedule of food reward, or a single episode of forced swim followed by restraint stress, or no explicit behavioral experience after which global expression levels of two activating (H3K9ac and H3K4me3) and two repressive (H3K9me2 and H3k27me3) post-translational histone modifications (PTHMs), were measured in hippocampus (HIPP) and frontal cortex (FC). The specific nature of the behavioral experience differentiated profiles of PTHMs in a sex- and brain region-dependent manner, with all 4 PTHMs changing in parallel in response to different behavioral experiences. These different behavioral experiences also modified the pattern of correlations of PTHMs both within and across FC and HIPP. Unexpectedly, highly robust correlations were found between global PTHM levels and behavioral performances, suggesting that global PTHMs may provide a higher-order pattern recognition function. Further efforts are needed to determine the generality of such findings and what characteristics of behavioral experience are critical for modulating PTHM responses.
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Affiliation(s)
- Marissa Sobolewski
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, United States
| | - Garima Singh
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Jay S. Schneider
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Deborah A. Cory-Slechta
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, United States
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12
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Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, Nordentoft M, Glenthøj B. Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register. Biol Psychiatry 2018; 83:492-498. [PMID: 28987712 DOI: 10.1016/j.biopsych.2017.08.017] [Citation(s) in RCA: 344] [Impact Index Per Article: 49.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 08/22/2017] [Accepted: 08/22/2017] [Indexed: 01/17/2023]
Abstract
BACKGROUND Twin studies have provided evidence that both genetic and environmental factors contribute to schizophrenia (SZ) risk. Heritability estimates of SZ in twin samples have varied methodologically. This study provides updated heritability estimates based on nationwide twin data and an improved statistical methodology. METHODS Combining two nationwide registers, the Danish Twin Register and the Danish Psychiatric Research Register, we identified a sample of twins born between 1951 and 2000 (N = 31,524 twin pairs). Twins were followed until June 1, 2011. Liability threshold models adjusting for censoring with inverse probability weighting were used to estimate probandwise concordance rates and heritability of the diagnoses of SZ and SZ spectrum disorders. RESULTS The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. We estimated the heritability of SZ to be 79%. When expanding illness outcome to include SZ spectrum disorders, the heritability estimate was almost similar (73%). CONCLUSIONS The key strength of this study is the application of a novel statistical method accounting for censoring in the follow-up period to a nationwide twin sample. The estimated 79% heritability of SZ is congruent with previous reports and indicates a substantial genetic risk. The high genetic risk also applies to a broader phenotype of SZ spectrum disorders. The low concordance rate of 33% in monozygotic twins demonstrates that illness vulnerability is not solely indicated by genetic factors.
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Affiliation(s)
- Rikke Hilker
- CINS-Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark; CNSR-Center for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, Mental Health Services, Capital Region of Denmark, Glostrup, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
| | - Dorte Helenius
- Mental Health Centre Sct Hans, Mental Health Services, Capital Region of Denmark, Roskilde, Denmark; iPSYCH-Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Birgitte Fagerlund
- CINS-Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark; CNSR-Center for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, Mental Health Services, Capital Region of Denmark, Glostrup, Denmark
| | - Axel Skytthe
- The Danish Twin Register, University of Southern Denmark, Odense, Denmark
| | - Kaare Christensen
- The Danish Twin Register, University of Southern Denmark, Odense, Denmark
| | - Thomas M Werge
- CINS-Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark; Mental Health Centre Sct Hans, Mental Health Services, Capital Region of Denmark, Roskilde, Denmark; iPSYCH-Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
| | - Merete Nordentoft
- CINS-Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; iPSYCH-Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark; Mental Health Centre Copenhagen, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
| | - Birte Glenthøj
- CINS-Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark; CNSR-Center for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, Mental Health Services, Capital Region of Denmark, Glostrup, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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13
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Même patrimoine génétique et pourtant différents : étude de cas comparative de jumeaux. Int Orthod 2017; 15:483-497. [DOI: 10.1016/j.ortho.2017.06.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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14
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Mas C, Frapier L. A genetic heritage; the same yet different: A comparative study in twins. Int Orthod 2017; 15:483-497. [PMID: 28838757 DOI: 10.1016/j.ortho.2017.06.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Since the 19th century, and in every field of medicine, monozygotic twins have been studied to assess the involvement of genetic and environmental factors in phenotypic expression. The phenotype/genotype relationship remains the leading problem in contemporary biology. In dentofacial orthopedics, this relationship is of relevance in the three-dimensional approach to the face, in both diagnosis and treatment. The present study of two monozygotic twins presenting skeletal class III malocclusions which were genetic yet different is a clear illustration of the interaction of genotype and epigenetic factors with environmental influences. We will demonstrate that treatment can reduce phenotypic differences.
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Affiliation(s)
- Catherine Mas
- Département d'ODF, UFR Odontologie de Montpellier, 545, avenue du Pr-Jean-Louis-Viala, 34080 Montpellier, France.
| | - Laure Frapier
- Département d'ODF, UFR Odontologie de Montpellier, 545, avenue du Pr-Jean-Louis-Viala, 34080 Montpellier, France
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Vink JM, Jansen R, Brooks A, Willemsen G, van Grootheest G, de Geus E, Smit JH, Penninx BW, Boomsma DI. Differential gene expression patterns between smokers and non-smokers: cause or consequence? Addict Biol 2017; 22:550-560. [PMID: 26594007 PMCID: PMC5347870 DOI: 10.1111/adb.12322] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 08/18/2015] [Accepted: 09/18/2015] [Indexed: 01/31/2023]
Abstract
The molecular mechanisms causing smoking‐induced health decline are largely unknown. To elucidate the molecular pathways involved in cause and consequences of smoking behavior, we conducted a genome‐wide gene expression study in peripheral blood samples targeting 18 238 genes. Data of 743 smokers, 1686 never smokers and 890 ex‐smokers were available from two population‐based cohorts from the Netherlands. In addition, data of 56 monozygotic twin pairs discordant for ever smoking were used. One hundred thirty‐two genes were differentially expressed between current smokers and never smokers (P < 1.2 × 10−6, Bonferroni correction). The most significant genes were G protein‐coupled receptor 15 (P < 1 × 10−150) and leucine‐rich repeat neuronal 3 (P < 1 × 10−44). The smoking‐related genes were enriched for immune system, blood coagulation, natural killer cell and cancer pathways. By taking the data of ex‐smokers into account, expression of these 132 genes was classified into reversible (94 genes), slowly reversible (31 genes), irreversible (6 genes) or inconclusive (1 gene). Expression of 6 of the 132 genes (three reversible and three slowly reversible) was confirmed to be reactive to smoking as they were differentially expressed in monozygotic pairs discordant for smoking. Cis‐expression quantitative trait loci for GPR56 and RARRES3 (downregulated in smokers) were associated with increased number of cigarettes smoked per day in a large genome‐wide association meta‐analysis, suggesting a causative effect of GPR56 and RARRES3 expression on smoking behavior. In conclusion, differential gene expression patterns in smokers are extensive and cluster in several underlying disease pathways. Gene expression differences seem mainly direct consequences of smoking, and largely reversible after smoking cessation. However, we also identified DNA variants that may influence smoking behavior via the mediating gene expression.
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Affiliation(s)
- Jacqueline M. Vink
- Department of Biological Psychology; VU University; Amsterdam The Netherlands
- Neuroscience Campus Amsterdam; VU University Medical Center; Amsterdam The Netherlands
- EMGO Institute for Health and Care Research; Amsterdam The Netherlands
| | - Rick Jansen
- Neuroscience Campus Amsterdam; VU University Medical Center; Amsterdam The Netherlands
- Department of Psychiatry/GGZ in Geest; VU University Medical Center; Amsterdam The Netherlands
| | - Andy Brooks
- Department of Genetics; Rutgers University; New Brunswick New Jersey USA
| | - Gonneke Willemsen
- Department of Biological Psychology; VU University; Amsterdam The Netherlands
- EMGO Institute for Health and Care Research; Amsterdam The Netherlands
| | - Gerard van Grootheest
- Department of Psychiatry/GGZ in Geest; VU University Medical Center; Amsterdam The Netherlands
| | - Eco de Geus
- Department of Biological Psychology; VU University; Amsterdam The Netherlands
- EMGO Institute for Health and Care Research; Amsterdam The Netherlands
| | - Jan H. Smit
- Department of Psychiatry/GGZ in Geest; VU University Medical Center; Amsterdam The Netherlands
| | - Brenda W. Penninx
- Neuroscience Campus Amsterdam; VU University Medical Center; Amsterdam The Netherlands
- Department of Psychiatry/GGZ in Geest; VU University Medical Center; Amsterdam The Netherlands
- EMGO Institute for Health and Care Research; Amsterdam The Netherlands
| | - Dorret I. Boomsma
- Department of Biological Psychology; VU University; Amsterdam The Netherlands
- Neuroscience Campus Amsterdam; VU University Medical Center; Amsterdam The Netherlands
- EMGO Institute for Health and Care Research; Amsterdam The Netherlands
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Fortunato JJ, da Rosa N, Martins Laurentino AO, Goulart M, Michalak C, Borges LP, da Cruz Cittadin Soares E, Reis PA, de Castro Faria Neto HC, Petronilho F. Effects of ω-3 fatty acids on stereotypical behavior and social interactions in Wistar rats prenatally exposed to lipopolysaccarides. Nutrition 2017; 35:119-127. [DOI: 10.1016/j.nut.2016.10.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 10/21/2016] [Accepted: 10/29/2016] [Indexed: 02/07/2023]
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17
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Ahmadi M, Gharibi T, Dolati S, Rostamzadeh D, Aslani S, Baradaran B, Younesi V, Yousefi M. Epigenetic modifications and epigenetic based medication implementations of autoimmune diseases. Biomed Pharmacother 2017; 87:596-608. [DOI: 10.1016/j.biopha.2016.12.072] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Revised: 12/19/2016] [Accepted: 12/19/2016] [Indexed: 02/07/2023] Open
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Dissecting bipolar disorder complexity through epigenomic approach. Mol Psychiatry 2016; 21:1490-1498. [PMID: 27480490 PMCID: PMC5071130 DOI: 10.1038/mp.2016.123] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 06/09/2016] [Accepted: 06/13/2016] [Indexed: 01/16/2023]
Abstract
In recent years, numerous studies of gene regulation mechanisms have emerged in neuroscience. Epigenetic modifications, described as heritable but reversible changes, include DNA methylation, DNA hydroxymethylation, histone modifications and noncoding RNAs. The pathogenesis of psychiatric disorders, such as bipolar disorder, may be ascribed to a complex gene-environment interaction (G × E) model, linking the genome, environmental factors and epigenetic marks. Both the high complexity and the high heritability of bipolar disorder make it a compelling candidate for neurobiological analyses beyond DNA sequencing. Questions that are being raised in this review are the precise phenotype of the disorder in question, and also the trait versus state debate and how these concepts are being implemented in a variety of study designs.
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Prusator DK, Andrews A, Greenwood-Van Meerveld B. Neurobiology of early life stress and visceral pain: translational relevance from animal models to patient care. Neurogastroenterol Motil 2016; 28:1290-305. [PMID: 27251368 DOI: 10.1111/nmo.12862] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/22/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Epidemiological studies show that females are twice as likely to receive a diagnosis of irritable bowel syndrome (IBS) than their male counterparts. Despite evidence pointing to a role for sex hormones in the onset or exacerbation of IBS symptoms, the mechanism by which ovarian hormones may predispose women to develop IBS remains largely undefined. On the other hand, there is a growing body of research showing a correlation between reports of early life stress (ELS) and the diagnosis of IBS. Current treatments available for IBS patients target symptom relief including abdominal pain and alterations in bowel habits, but are not directed to the etiology of the disease. PURPOSE To better understand the mechanisms by which sex hormones and ELS contribute to IBS, animal models have been developed to mirror complex human experiences allowing for longitudinal studies that investigate the lifelong consequences of ELS. These preclinical models have been successful in recapitulating ELS-induced visceral pain. Moreover, in female rats the influence of cycling hormones on visceral hypersensitivity resembles that seen in women with IBS. Such studies suggest that rodent models of ELS may serve as pivotal tools in determining (i) the etiology of IBS, (ii) novel future treatments for IBS, and (iii) improving individualized patient care. The current review aims to shed light on the progress and the challenges observed by clinicians within the field of gastroenterology and the preclinical science aimed at addressing those challenges in an effort to understand and more efficiently treat functional gastrointestinal disorders (FGIDs) in both children and adults.
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Affiliation(s)
- D K Prusator
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - A Andrews
- Section of Pediatric Gastroenterology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - B Greenwood-Van Meerveld
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
- VA Medical Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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Saavedra K, Molina-Márquez AM, Saavedra N, Zambrano T, Salazar LA. Epigenetic Modifications of Major Depressive Disorder. Int J Mol Sci 2016; 17:ijms17081279. [PMID: 27527165 PMCID: PMC5000676 DOI: 10.3390/ijms17081279] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 07/24/2016] [Accepted: 07/29/2016] [Indexed: 12/17/2022] Open
Abstract
Major depressive disorder (MDD) is a chronic disease whose neurological basis and pathophysiology remain poorly understood. Initially, it was proposed that genetic variations were responsible for the development of this disease. Nevertheless, several studies within the last decade have provided evidence suggesting that environmental factors play an important role in MDD pathophysiology. Alterations in epigenetics mechanism, such as DNA methylation, histone modification and microRNA expression could favor MDD advance in response to stressful experiences and environmental factors. The aim of this review is to describe genetic alterations, and particularly altered epigenetic mechanisms, that could be determinants for MDD progress, and how these alterations may arise as useful screening, diagnosis and treatment monitoring biomarkers of depressive disorders.
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Affiliation(s)
- Kathleen Saavedra
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
| | - Ana María Molina-Márquez
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
| | - Nicolás Saavedra
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
| | - Tomás Zambrano
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
| | - Luis A Salazar
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile.
- Millennium Institute for Research in Depression and Personality (MIDAP), Universidad de La Frontera, Temuco 4811230, Chile.
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Abstract
Network perspectives, in their emphasis on components and their interactions, might afford the best approach to the complexities of the ASD realm. Categorical approaches are unlikely to be fruitful as one should not expect to find a single or even predominant underlying cause of autism behavior across individuals. It is possible that the complex, highly interactive, heterogeneous and individualistic nature of the autism realm is intractable in terms of identifying clinically useful biomarker tests. It is hopeful from an emergenic perspective that small corrective changes in a single component of a deleterious network/configuration might have large beneficial consequences on developmental trajectories and in later treatment. It is suggested that the relationship between ASD and intellectual disability might be fundamentally different in single-gene versus nonsyndromic ASD. It is strongly stated that available biomarker "tests" for autism/ASD will do more harm than good. Finally, the serotonin-melatonin-oxidative stress-placental intersection might be an especially fruitful area of biological investigation.
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Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins. Transl Psychiatry 2015; 5:e557. [PMID: 25918994 PMCID: PMC4462612 DOI: 10.1038/tp.2015.49] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 03/02/2015] [Accepted: 03/09/2015] [Indexed: 12/13/2022] Open
Abstract
Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling. These results expand on previous research to indicate that both differential methylation and differential variability have a role in the etiology and clinical manifestation of depression, and provide clues on specific genomic loci of potential interest in the epigenetics of depression.
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23
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Kiser DP, Rivero O, Lesch KP. Annual research review: The (epi)genetics of neurodevelopmental disorders in the era of whole-genome sequencing--unveiling the dark matter. J Child Psychol Psychiatry 2015; 56:278-95. [PMID: 25677560 DOI: 10.1111/jcpp.12392] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/13/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND SCOPE Neurodevelopmental disorders (NDDs) are defined by a wide variety of behavioural phenotypes, psychopathology and clinically informed categorical classifications. Diagnostic entities include intellectual disability (ID), the autism spectrum (ASD) and attention-deficit/hyperactivity disorder (ADHD). The aetiopathogenesis of these conditions and disorders involves an interaction between both genetic and environmental risk factors on the developmental trajectory. Despite their remarkable genetic heterogeneity and complexity of pathophysiological mechanisms, NDDs display an overlap in their phenotypic features, a considerable degree of comorbidity as well as sharing of genetic and environmental risk factors. This review aims to provide an overview of the genetics and epigenetic of NDDs. FINDINGS Recent evidence suggests a critical role of defined and tightly regulated neurodevelopmental programs running out of control in NDDs, most notably neuronal proliferation and migration, synapse formation and remodelling, as well as neural network configuration resulting in compromised systems connectivity and function. Moreover, the machinery of epigenetic programming, interacting with genetic liability, impacts many of those processes and pathways, thus modifying vulnerability of, and resilience to, NDDs. Consequently, the categorically defined entities of ID, ADHD and ASD are increasingly viewed as disorders on a multidimensional continuum of molecular and cellular deficiencies in neurodevelopment. As such, this range of NDDs displays a broad phenotypic diversity, which may be explained by a combination and interplay of underlying loss- and potential gain-of-function traits. CONCLUSION In this overview, we discuss a backbone continuum concept of NDDs by summarizing pertinent findings in genetics and epigenetics. We also provide an appraisal of the genetic overlap versus differences, with a focus on genome-wide screening approaches for (epi)genetic variation. Finally, we conclude with insights from evolutionary psychobiology suggesting positive selection for discrete NDD-associated traits.
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Affiliation(s)
- Dominik P Kiser
- Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany
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Affiliation(s)
- David Roofeh
- a Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Divya Tumuluru
- b Department of Psychiatry, University of Pittsburgh School of Medicine
| | - Sona Shilpakar
- b Department of Psychiatry, University of Pittsburgh School of Medicine
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25
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House SH. Transgenerational healing: Educating children in genesis of healthy children, with focus on nutrition, emotion, and epigenetic effects on brain development. Nutr Health 2014; 22:9-45. [PMID: 25005446 DOI: 10.1177/0260106013506666] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Although our continuing evolution can never achieve our perfection, we long for our children's birth and health to be near-perfect. Many children are born healthy, though fewer than is possible. Birthing and health rapidly improved generally due to modern housing, sanitation and medicine, as well as birth interventions. Arguably interventions have exceeded the optimal level, without enough regard for natural physical and intuitive resources. Conception, often too easy, receives too little personal preparation unless a couple has problems. Nurturing the health of sperm and ovum seems hard to focus on, yet is needed by both parents - and even by the four grandparents. What are the key factors? Positive: The fields of hormones/emotions and of nutrition/metabolism. Negative: stress, poor nutrition, toxins, diseases; much being due to poverty. Positive and negative both have structural and also epigenetic effects. Interventions, essential or inessential, are seldom without negative side effects. Health can best, and most economically, be generated at the beginning of life, through healthy conception, gestation and birth. Understanding prime needs improves initial health. It also informs therapy of any early-life problems. Healing is therefore more efficient when transgenerational, and much more powerful than individual healing. My vision of healing is safeguarding our evolution in progress. Children's choices - eating, exercise, emotional attitudes and relationships - are already profoundly affecting any children they may have, their mental and physical health. The most practical starting point seems to be educating boys as well as girls. Childhood is therefore the time to educate them in choices. The correction of often unnoticed problems- nutrient deficits, toxins, uro-genital disease - has enabled nearly nine out of ten couples to bear fully healthy babies, even following severe problems - infertility, miscarriages, stillbirths and malformations. Correcting problems before conception prevents both structural faults and wrong setting of gene-switches. Children's habits set. Once courting most are preoccupied and many pregnant unintentionally. Childhood is the time to be adopting a healthy lifestyle, the way to healthy babies The mother's nutritional and emotional status throughout pregnancy continues to affect her child's future physical and mental health, behaviour and ability. Before conception a woman needs to build her appropriate body stores - vitamins and minerals, proteins, docosahexaenoic acid. Before bearing another child, a replenishment time of 3 years is desirable. A return to childbearing in the 20s and early 30s could reduce risks that have risen with the recent shift towards conception by school children and by women in their late 30s or more. Governments, schoolteachers, health professionals, need to adopt this policy of transgenerational health. Empowerment with knowledge is the one way to fend off the growing pandemic of mental ill health and related disorders and to make the most of a nation's genetic potential. Financially there could be no better investment, let alone in enhancing people's lives. Childhood is the most appropriate time for education in this way to generating a healthy, able and peaceful human race. Essential to our amazing genetic systems are the resources of land, sea and air. We are one with our biosphere. We need urgently to follow up the vital work of Developmental Origins of Health and Disease, and of Far East initiatives in sea-bed and sea husbandry.
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Affiliation(s)
- Simon H House
- The McCarrison Society for Nutrition & Health; International Society of Prenatal & Perinatal Psychology & Medicine; Association for Prenatal & Perinatal Psychology & Health; Royal Society of Medicine; Food & Health Council
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26
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Matias A, Silva S, Martins Y, Blickstein I. Monozygotic twins: Ten reasons to be different. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.diapre.2013.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Williams SD, Hughes TE, Adler CJ, Brook AH, Townsend GC. Epigenetics: a new frontier in dentistry. Aust Dent J 2014; 59 Suppl 1:23-33. [DOI: 10.1111/adj.12155] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- SD Williams
- School of Dentistry; The University of Adelaide; South Australia Australia
| | - TE Hughes
- School of Dentistry; The University of Adelaide; South Australia Australia
| | - CJ Adler
- Institute of Dental Research; Westmead Millennium Institute; Faculty of Dentistry; The University of Sydney; New South Wales Australia
| | - AH Brook
- School of Dentistry; The University of Adelaide; South Australia Australia
- Institute of Dentistry; Queen Mary University of London; United Kingdom
| | - GC Townsend
- School of Dentistry; The University of Adelaide; South Australia Australia
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28
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Andreazza TS, Costa AB, Massuda R, Salvador J, Silveira EM, Piccon F, Carvalho R, Fontanari AMV, Koff W, Belmonte-de-Abreu P, Lobato MIR. Discordant transsexualism in male monozygotic twins: neuroanatomical and psychological differences. ARCHIVES OF SEXUAL BEHAVIOR 2014; 43:399-405. [PMID: 23857518 DOI: 10.1007/s10508-013-0151-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Revised: 06/06/2013] [Accepted: 06/15/2013] [Indexed: 06/02/2023]
Abstract
One monozygotic male twin pair discordant for transsexualism is described. Both twins were interviewed and tested with the Wechsler Adult Intelligence Scale battery for cognitive functions and they underwent magnetic resonance imaging to measure the volumes of specific cerebral structures. Interviews with the twins and their mother indicated no unusual medical or life history events that could have had a causal role in the emergence of the disorder. Both cognitive function testing and neuroimaging detected differences between the twins that could be related to unexplained epigenetic effects and exogenous hormone usage.
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Affiliation(s)
- Tahiana Signorini Andreazza
- Gender Identity Disorder Program, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil,
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Dalton VS, Kolshus E, McLoughlin DM. Epigenetics and depression: return of the repressed. J Affect Disord 2014; 155:1-12. [PMID: 24238955 DOI: 10.1016/j.jad.2013.10.028] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 10/15/2013] [Accepted: 10/16/2013] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Epigenetics has recently emerged as a potential mechanism by which adverse environmental stimuli can result in persistent changes in gene expression. Epigenetic mechanisms function alongside the DNA sequence to modulate gene expression and ultimately influence protein production. The current review provides an introduction and overview of epigenetics with a particular focus on preclinical and clinical studies relevant to major depressive disorder (MDD). METHODS PubMed and Web of Science databases were interrogated from January 1995 up to December 2012 using combinations of search terms, including "epigenetic", "microRNA" and "DNA methylation" cross referenced with "depression", "early life stress" and "antidepressant". RESULTS There is an association between adverse environmental stimuli, such as early life stress, and epigenetic modification of gene expression. Epigenetic changes have been reported in humans with MDD and may serve as biomarkers to improve diagnosis. Antidepressant treatments appear to reverse or initiate compensatory epigenetic alterations that may be relevant to their mechanism of action. LIMITATIONS As a narrative review, the current report was interpretive and qualitative in nature. CONCLUSION Epigenetic modification of gene expression provides a mechanism for understanding the link between long-term effects of adverse life events and the changes in gene expression that are associated with depression. Although still a developing field, in the future, epigenetic modifications of gene expression may provide novel biomarkers to predict future susceptibility and/or onset of MDD, improve diagnosis, and aid in the development of epigenetics-based therapies for depression.
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Affiliation(s)
- Victoria S Dalton
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry, Trinity College Dublin, St. Patrick's University Hospital, James's Street, Dublin 8, Ireland
| | - Erik Kolshus
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry, Trinity College Dublin, St. Patrick's University Hospital, James's Street, Dublin 8, Ireland
| | - Declan M McLoughlin
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry, Trinity College Dublin, St. Patrick's University Hospital, James's Street, Dublin 8, Ireland.
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Vaiopoulou A, Karamanolis G, Psaltopoulou T, Karatzias G, Gazouli M. Molecular basis of the irritable bowel syndrome. World J Gastroenterol 2014; 20:376-383. [PMID: 24574707 PMCID: PMC3923013 DOI: 10.3748/wjg.v20.i2.376] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 10/24/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional disorder characterized by abdominal pain, discomfort and bloating. The pathophysiology of IBS is poorly understood, but the presence of psychosocial basis is now known. There is an increasing number of publications supporting the role of genetics in IBS. Most of the variations are found in genes associated with the brain-gut axis, revealing the strong correlation of brain-gut axis and IBS. miRNAs, which play critical roles in physiological processes, are not well studied in IBS. However, so far there is found an involvement of alterations in miRNA expression or sequence, in IBS symptoms. IBS phenotype is affected by epigenetic alteration and environment. Changes in DNA and histone methylation are observed in patients who suffered childhood trauma or abuse, resulting in altered gene expression, such as the glucocorticoid receptor gene. Finally, diet is another factor associated with IBS, which may contribute to symptom onset. Certain foods may affect on bacterial metabolism and epigenetic modifications, predisposing to IBS.
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31
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Jackson FLC, Niculescu MD, Jackson RT. Conceptual shifts needed to understand the dynamic interactions of genes, environment, epigenetics, social processes, and behavioral choices. Am J Public Health 2013; 103 Suppl 1:S33-42. [PMID: 23927503 DOI: 10.2105/ajph.2013.301221] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Social and behavioral research in public health is often intimately tied to profound, but frequently neglected, biological influences from underlying genetic, environmental, and epigenetic events. The dynamic interplay between the life, social, and behavioral sciences often remains underappreciated and underutilized in addressing complex diseases and disorders and in developing effective remediation strategies. Using a case-study format, we present examples as to how the inclusion of genetic, environmental, and epigenetic data can augment social and behavioral health research by expanding the parameters of such studies, adding specificity to phenotypic assessments, and providing additional internal control in comparative studies. We highlight the important roles of gene-environment interactions and epigenetics as sources of phenotypic change and as a bridge between the life and social and behavioral sciences in the development of robust interdisciplinary analyses.
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Affiliation(s)
- Fatimah L C Jackson
- Fatimah L. C. Jackson, and Mihai D. Niculescu are with the University of North Carolina at Chapel Hill. Robert T. Jackson is with the University of Maryland at College Park
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32
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Keverne EB. Importance of the matriline for genomic imprinting, brain development and behaviour. Philos Trans R Soc Lond B Biol Sci 2013; 368:20110327. [PMID: 23166391 PMCID: PMC3539356 DOI: 10.1098/rstb.2011.0327] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Mammalian brain development commences during foeto-placental development and is strongly influenced by the epigenetic regulation of imprinted genes. The foetal placenta exerts considerable influence over the functioning of the adult maternal hypothalamus, and this occurs at the same time as the foetus itself is developing a hypothalamus. Thus, the action and interaction of two genomes in one individual, the mother, has provided a template for co-adaptive functions across generations that are important for maternal care and resource transfer, while co-adaptively shaping the mothering capabilities of each subsequent generation. The neocortex is complex, enabling behavioural diversity and cultural learning such that human individuals are behaviourally unique. Retrotransposons may, in part, be epigenetic mediators of such brain diversity. Interestingly some imprinted genes are themselves retrotransposon-derived, and retrotransposon silencing by DNA methylation is thought to have contributed to the evolutionary origins of imprint control regions. The neocortex has evolved to be adaptable and sustain both short-term and long-term synaptic connections that underpin learning and memory. The adapted changes are not themselves inherited, but the predisposing mechanisms for such epigenetic changes are heritable. This provides each generation with the same ability to make new adaptations while constrained by a transgenerational knowledge-based predisposition to preserve others.
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Affiliation(s)
- E B Keverne
- Sub-Department of Animal Behaviour, University of Cambridge, Madingley, Cambridge CB23 8AA, UK.
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Abstract
Two major environmental developments have occurred in mammalian evolution which have impacted on the genetic and epigenetic regulation of brain development. The first of these was viviparity and development of the placenta which placed a considerable burden of time and energy investment on the matriline, and which resulted in essential hypothalamic modifications. Maternal feeding, maternal care, parturition, milk letdown and the suspension of fertility and sexual behaviour are all determined by the maternal hypothalamus and have evolved to meet foetal needs under the influence of placental hormones. Viviparity itself provided a new environmental variable for selection pressures to operate via the co-existence over three generations of matrilineal genomes (mother, developing offspring and developing oocytes) in one individual. Also of importance for the matriline has been the evolution of epigenetic marks (imprint control regions) which are heritable and undergo reprogramming primarily in the oocyte to regulate imprinted gene expression according to parent of origin. Imprinting of autosomal genes has played a significant role in mammalian evolutionary development, particularly that of the hypothalamus and placenta. Indeed, many imprinted genes that are co-expressed in the placenta and hypothalamus play an important role in the co-adapted functioning of these organs. Thus the action and interaction of two genomes (maternal and foetal) have provided a template for transgenerational selection pressures to operate in shaping the mothering capabilities of each subsequent generation. The advanced aspects of neocortical brain evolution in primates have emancipated much of behaviour from the determining effects of hormonal action. Thus in large brain primates, most of the sexual behaviour is not reproductive hormone dependent and maternal care can and does occur outside the context of pregnancy and parturition. The neocortex has evolved to be adaptable and while the adapted changes are not inherited, the epigenetic predisposing processes can be. This provides each generation with the same ability to generate new adaptations while retaining a "cultural" predisposition to retain others. A significant evolutionary contribution to this epigenetic dimension has again been the matriline. The extensive neocortical development which takes place post-natally does so in an environment which is predominantly that of the caring guidance of the mother. Evidence for the epigenetic regulation of neocortical development is best illustrated by the GABA-ergic neurons and their long tangential migratory pathway from the ganglionic eminence, in contrast to the radial migration of principle neurons. GABA-ergic neurons play an integral role both in the developmental formation of canonical localised circuits and in synchronising widespread functional activity by the regulation of network oscillations. Such synchronisation enables distributed regions of the neocortex to coordinate firing. GABA-ergic dysfunction contributes to a broad spectrum of neurological and psychiatric disorders which can differ even across identical monozygotic twins. Moreover, major treatments for schizophrenia over the past 40 years have included the drugs lithium and valproate, both of which we now know are histone deacetylases. It is rarely the heritable dysfunctioning of these epigenetic mechanisms that is at fault, but the timing, duration and place where they are deployed. The timing and complexity in the development of the neocortex makes this region of the brain more vulnerable to perturbations.
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Affiliation(s)
- E B Keverne
- Sub-Department of Animal Behaviour, University of Cambridge, Madingley, Cambridge CB23 8AA, UK.
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Czyz W, Morahan JM, Ebers GC, Ramagopalan SV. Genetic, environmental and stochastic factors in monozygotic twin discordance with a focus on epigenetic differences. BMC Med 2012; 10:93. [PMID: 22898292 PMCID: PMC3566971 DOI: 10.1186/1741-7015-10-93] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Accepted: 08/17/2012] [Indexed: 03/16/2023] Open
Abstract
Genetic-epidemiological studies on monozygotic (MZ) twins have been used for decades to tease out the relative contributions of genes and the environment to a trait. Phenotypic discordance in MZ twins has traditionally been ascribed to non-shared environmental factors acting after birth, however recent data indicate that this explanation is far too simple. In this paper, we review other reasons for discordance, including differences in the in utero environment, genetic mosaicism, and stochastic factors, focusing particularly on epigenetic discordance. Epigenetic differences are gaining increasing recognition. Although it is clear that in specific cases epigenetic alterations provide a causal factor in disease etiology, the overall significance of epigenetics in twin discordance remains unclear. It is also challenging to determine the causality and relative contributions of environmental, genetic, and stochastic factors to epigenetic variability. Epigenomic profiling studies have recently shed more light on the dynamics of temporal methylation change and methylome heritability, yet have not given a definite answer regarding their relevance to disease, because of limitations in establishing causality. Here, we explore the subject of epigenetics as another component in human phenotypic variability and its links to disease focusing particularly on evidence from MZ twin studies.
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Affiliation(s)
- Witold Czyz
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, UK
| | - Julia M Morahan
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, UK
| | - George C Ebers
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, UK
| | - Sreeram V Ramagopalan
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, Oxford, UK
- Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK
- London School of Hygiene and Tropical Medicine, London, UK
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Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses. Mol Psychiatry 2012; 17:474-85. [PMID: 21670730 DOI: 10.1038/mp.2011.65] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
In this article, we review some of the data that contribute to our understanding of the genetic architecture of psychiatric disorders. These include results from evolutionary modelling (hence no data), the observed recurrence risk to relatives and data from molecular markers. We briefly discuss the common-disease common-variant hypothesis, the success (or otherwise) of genome-wide association studies, the evidence for polygenic variance and the likely success of exome and whole-genome sequencing studies. We conclude that the perceived dichotomy between 'common' and 'rare' variants is not only false, but unhelpful in making progress towards increasing our understanding of the genetic basis of psychiatric disorders. Strong evidence has been accumulated that is consistent with the contribution of many genes to risk of disease, across a wide range of allele frequencies and with a substantial proportion of genetic variation in the population in linkage disequilibrium with single-nucleotide polymorphisms (SNPs) on commercial genotyping arrays. At the same time, most causal variants that segregate in the population are likely to be rare and in total these variants also explain a significant proportion of genetic variation. It is the combination of allele frequency, effect size and functional characteristics that will determine the success of new experimental paradigms such as whole exome/genome sequencing to detect such loci. Empirical results suggest that roughly half the genetic variance is tagged by SNPs on commercial genome-wide chips, but that individual causal variants have a small effect size, on average. We conclude that larger experimental sample sizes are essential to further our understanding of the biology underlying psychiatric disorders.
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Abstract
Fundamental aspects of mammalian brain evolution occurred in the context of viviparity and placentation brought about by the epigenetic regulation of imprinted genes. Since the fetal placenta hormonally primes the maternal brain, two genomes in one individual are transgenerationally co-adapted to ensure maternal care and nurturing. Advanced aspects of neocortical brain evolution has shown very few genetic changes between monkeys and humans. Although these lineages diverged at approximately the same time as the rat and mouse (20 million years ago), synonymous sequence divergence between the rat and mouse is double that when comparing monkey with human sequences. Paradoxically, encephalization of rat and mouse are remarkably similar, while comparison of the human and monkey shows the human cortex to be three times the size of the monkey. This suggests an element of genetic stability between the brains of monkey and man with a greater emphasis on epigenetics providing adaptable variability.
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Affiliation(s)
- Eric B Keverne
- Sub-Department of Animal Behavior, University of Cambridge, Madingley, Cambridge CB23 8AA, UK.
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Gao Y, He Z, Wang Z, Luo Y, Sun H, Zhou Y, Huang L, Li M, Fang Q, Jiang S. Increased expression and altered methylation of HERVWE1 in the human placentas of smaller fetuses from monozygotic, dichorionic, discordant twins. PLoS One 2012; 7:e33503. [PMID: 22457770 PMCID: PMC3310130 DOI: 10.1371/journal.pone.0033503] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Accepted: 02/10/2012] [Indexed: 12/22/2022] Open
Abstract
Background The human endogenous retroviral family W, Env(C7), member 1 gene (HERVWE1) is thought to participate in trophoblast cell fusion, and its expression is diminished in the placentas of singleton intrauterine growth-retarded pregnancies. However, there is limited information about the role of HERVWE1 in discordant fetal growth in twins. This study was to compare HERVWE1 gene expression between the placentas of discordant monozygotic twins and to identify its regulation by methylation. Methodology/Principal Findings Fetuses from twenty-one pairs of monozygotic, dichorionic, discordant twins were marked as “smaller” or “larger” according to birth weight. Placental HERVWE1 mRNA and protein expression profiles were analyzed using quantitative RT-PCR and immunohistochemistry (IHC) staining. Methylation profiles of the HERVWE1 promoter region were analyzed using a pyrosequencing assay. DNA methyltransferase (DNMT) transcript levels were analyzed by RT-PCR. 5-methyl cytosine (5-MC) was stained using an immunohistochemical assay. There was a significant negative correlation between HERVWE1 mRNA levels and birth weight in twins (P<0.01). Whereas the mean methylation level of the HERVWE1 promoter region was diminished in the smaller group in discordant twins(P<0.01), increased mRNA and protein levels of HERVWE1 were found in smaller fetuses compared with larger fetuses in discordant twins(P<0.01). There was no significant difference in 5-MC staining intensity between discordant twins (P>0.05). The DNMT3b3 mRNA levels in the smaller group were significantly downregulated compared with the larger group in discordant twins(P<0.05), whereas the DNMT3b7 mRNA levels in the smaller group were significantly upregulated compared with the larger group in discordant twins(P<0.05). Conclusions/Significance In discordant, monozygotic, dichorionic twins, HERVWE1 expression was higher in smaller fetuses and lower in larger fetuses. Methylation of the HERVWE1 gene promoter region may participate in the regulation of HERVWE1 gene expression in discordant twin pregnancies.
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Affiliation(s)
- Yu Gao
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong Province, People's Republic of China
- Hoskins Center, Department of Biological Science, Mercer University School of Medicine, Savannah, Georgia, United States of America
| | - Zhiming He
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong Province, People's Republic of China
- Hoskins Center, Department of Biological Science, Mercer University School of Medicine, Savannah, Georgia, United States of America
| | - Zilian Wang
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong Province, People's Republic of China
| | - Yanmin Luo
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong Province, People's Republic of China
| | - Hongyu Sun
- Department of Forensic Medicine, Sun Yat-Sen University, Guangzhou, Guang Dong Province, People's Republic of China
| | - Yi Zhou
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong Province, People's Republic of China
| | - Linhuan Huang
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong Province, People's Republic of China
| | - Manchao Li
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong Province, People's Republic of China
| | - Qun Fang
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong Province, People's Republic of China
- * E-mail: (QF); (SJ)
| | - Shiwen Jiang
- Hoskins Center, Department of Biological Science, Mercer University School of Medicine, Savannah, Georgia, United States of America
- Department of Obstetrics and Gynecology, Mayo College of Medicine, Rochester, Minnesota, United States of America
- * E-mail: (QF); (SJ)
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Wopereis S, Radonjic M, Rubingh C, Erk MV, Smilde A, Duyvenvoorde WV, Cnubben N, Kooistra T, Ommen BV, Kleemann R. Identification of prognostic and diagnostic biomarkers of glucose intolerance in ApoE3Leiden mice. Physiol Genomics 2012; 44:293-304. [PMID: 22234995 DOI: 10.1152/physiolgenomics.00072.2011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
The prevalence of diabetes mellitus Type 2 could be significantly reduced by early identification of subjects at risk, allowing for better prevention and earlier treatment. Glucose intolerance (GI) is a hallmark of the prediabetic stage. This study aims at identifying 1) prognostic biomarkers predicting the risk of developing GI later in life and 2) diagnostic biomarkers reflecting the degree of already manifest GI. To this end, disease development was followed over time in mice, and biomarkers were identified using lipidomics and transcriptomics. Young adult ApoE3Leiden mice were treated a high-fat diet for 12 wk to induce GI. Blood was collected before and during disease development. The individual extent of GI was determined with a glucose tolerance test and the area under the curve (AUC) was calculated for each animal. Subject-specific AUC values were correlated to the plasma lipidome (t = 0) and the white blood cell (WBC) transcriptome (t = 0, 6, and 12 wk) to identify prognostic and diagnostic biomarkers, respectively. The plasma ratio of specific free fatty acids prior to high-fat feeding (C16:1/C16:0, C18:1/C18:0 and C18:2/C22:6) was significantly correlated with the AUC and predictive for future GI. Subsequently, the expression level of specific WBC genes (Acss2, Arfgap1, Tfrc, Cox6b2, Barhl2, Abcb4, Cyp4b1, Sars2, Fgf16, and Tceal8) reflected the individual degree of GI during disease progression. Specific plasma free fatty acids as well as their ratio can be used to predict future GI. The expression levels of specific WBC genes can serve as easy accessible markers to diagnose and monitor already existing GI.
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Affiliation(s)
- Suzan Wopereis
- TNO, Research Group Microbiology and Systems Biology, P.O. Box 360, 3700 AJ Zeist, the Netherlands.
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39
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Genes, Environment and Inheritance. Mol Med 2012. [DOI: 10.1016/b978-0-12-381451-7.00002-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] Open
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40
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Ketelaar ME, Hofstra RMW, Hayden MR. What monozygotic twins discordant for phenotype illustrate about mechanisms influencing genetic forms of neurodegeneration. Clin Genet 2011; 81:325-33. [DOI: 10.1111/j.1399-0004.2011.01795.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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41
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Li X, McGue M, Gottesman II. Two Sources of Genetic Liability to Depression: Interpreting the Relationship Between Stress Sensitivity and Depression Under a Multifactorial Polygenic Model. Behav Genet 2011; 42:268-77. [DOI: 10.1007/s10519-011-9506-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Accepted: 09/12/2011] [Indexed: 12/20/2022]
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42
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Franklin TB, Mansuy IM. The involvement of epigenetic defects in mental retardation. Neurobiol Learn Mem 2011; 96:61-7. [PMID: 21549207 DOI: 10.1016/j.nlm.2011.04.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Revised: 01/17/2011] [Accepted: 04/08/2011] [Indexed: 01/22/2023]
Abstract
Mental retardation is a group of cognitive disorders with a significant worldwide prevalence rate. This high rate, together with the considerable familial and societal burden resulting from these disorders, makes it an important focus for prevention and intervention. While the diseases associated with mental retardation are diverse, a significant number are linked with disruptions in epigenetic mechanisms, mainly due to loss-of-function mutations in genes that are key components of the epigenetic machinery. Additionally, several disorders classed as imprinting syndromes are associated with mental retardation. This review will discuss the epigenetic abnormalities associated with mental retardation, and will highlight their importance for diagnosis, treatment, and prevention of these disorders.
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Affiliation(s)
- Tamara B Franklin
- Brain Research Institute, Swiss Federal Institute of Technology, Zurich, Switzerland.
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43
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Rosenthal R. Of schizophrenia, pruning, and epigenetics: a hypothesis and suggestion. Med Hypotheses 2011; 77:106-8. [PMID: 21477930 DOI: 10.1016/j.mehy.2011.03.038] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2010] [Revised: 03/01/2011] [Accepted: 03/17/2011] [Indexed: 01/07/2023]
Abstract
One area of relative agreement in schizophrenic research is that there is grey matter volume deficit in various cortical areas associated with this illness. One theory attempting to explain this involves an exaggerated action of the normal CNS pruning process. Various aspects of this process were discussed along with indirect supporting evidence for this hypothesis. A test of this hypothesis was proposed involving whole genome epigenetic scanning of discordant monozygotic twins to see if differences were present associated with transcription sites of proteins involved in the pruning process.
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Affiliation(s)
- Randall Rosenthal
- Southern Nevada Adult Mental Health, 6161 W Charleston, Las Vegas, NV, USA.
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Dias FMV, Kummer A, Doyle FCP, Harsányi E, Cardoso F, Fontenelle LF, Teixeira AL. Psychiatric disorders in primary focal dystonia and in Parkinson's disease. Neuropsychiatr Dis Treat 2011; 7:111-6. [PMID: 21552313 PMCID: PMC3083984 DOI: 10.2147/ndt.s17507] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Primary focal dystonia and Parkinson's disease are movement disorders that have contrasting motor phenotypes. The aim of this study was to compare the frequency and the severity of psychiatric disorders in primary focal dystonia and Parkinson's disease. METHODS Two groups of 30 patients matched by gender and age underwent a neurological and psychiatric assessment. RESULTS Parkinson's disease patients were diagnosed with higher rates of major depression (P = 0.02) and generalized anxiety disorder (P = 0.02), and greater severity of depressive symptoms (P = 0.04), while patients with primary focal dystonia exhibited increased severity of obsessive-compulsive symptoms (P = 0.02). DISCUSSION The difference in pathophysiology of primary focal dystonia and Parkinson's disease may explain the different psychiatric profiles of these two diseases. The increased frequency of affective symptoms in Parkinson's disease may be related to the fact that Parkinson's disease is a neurodegenerative disease marked by the loss of monoaminergic neurons which does not happen in primary focal dystonia. CONCLUSION The psychiatric profile differs in movement disorders with distinct neurobiological bases.
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Affiliation(s)
| | | | - Flávia CP Doyle
- Movement Disorders Clinic, Neurology Unit, University Hospital, Federal University of Minas Gerais, Belo Horizonte
| | | | - Francisco Cardoso
- Movement Disorders Clinic, Neurology Unit, University Hospital, Federal University of Minas Gerais, Belo Horizonte
| | - Leonardo F Fontenelle
- Department of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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45
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Abstract
Although popularly designated as "identical", monozygotic (MZ) twins are rarely identical. Much has been speculated on the origin of MZ twins and several theories have been proposed. Post-fertilization events, such as chromosomal mosaicism, skewed X-inactivation and imprinting mechanisms, as well as other epigenetic mechanisms are responsible for the differences between MZ twins. Numerous discordant MZ twins have been reported including discordance for lateral asymmetry, major malformation, growth and intrauterine death of the co-twin. This discrepancy may have long-term implications on complex diseases and their predisposition, organ transplantation and interpretation of twin-based studies. We reviewed the genotypic and phenotypic differences between MZ twins and discuss their main causes.
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Affiliation(s)
- Sara Silva
- Department of Obstetrics and Gynecology, University Hospital of S. Jo;atao, Medical Faculty of Porto, Porto, Portugal
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46
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Hjelmeland LM. Dark matters in AMD genetics: epigenetics and stochasticity. Invest Ophthalmol Vis Sci 2011; 52:1622-31. [PMID: 21429863 DOI: 10.1167/iovs.10-6765] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Leonard M Hjelmeland
- Department of Ophthalmology and Vision Science, School of Medicine, University of California, Davis, California, USA.
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47
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Mattick JS. RNA as the substrate for epigenome-environment interactions: RNA guidance of epigenetic processes and the expansion of RNA editing in animals underpins development, phenotypic plasticity, learning, and cognition. Bioessays 2011; 32:548-52. [PMID: 20544741 DOI: 10.1002/bies.201000028] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- John S Mattick
- Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
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48
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Striano P, Bianchi A, Pezzella M, Zara F. Similar but not identical: clinical implications for molecular studies in monozygotic discordant twins with epilepsy. Epilepsy Behav 2011; 20:419. [PMID: 21236736 DOI: 10.1016/j.yebeh.2010.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 12/07/2010] [Indexed: 10/18/2022]
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Abstract
The etiology of autoimmune diseases remains largely unknown. Concordance rates in monozygotic twins are lower than 50% while genome-wide association studies propose numerous significant associations representing only a minority of patients. These lines of evidence strongly support other complementary mechanisms involved in the regulation of genes expression ultimately causing overt autoimmunity. Alterations in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune diseases. In recent years, several studies both in clinical settings and experimental models proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and other autoimmune diseases, in some cases based on mechanistical observations. We herein discuss what we currently know and what we expect will come in the next future. Ultimately, epigenetic treatments already being used in oncology may soon prove beneficial also in autoimmune diseases.
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Affiliation(s)
- Francesca Meda
- Department of Medicine and Hepatobiliary Immunopathology Unit, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
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50
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Rosch RE, Ronan L, Cherkas L, Gurd JM. Cerebellar asymmetry in a pair of monozygotic handedness-discordant twins. J Anat 2011; 217:38-47. [PMID: 20579177 DOI: 10.1111/j.1469-7580.2010.01244.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Increasing evidence for a cerebellar role in human cognition has accrued with respect to anatomically and functionally distinct lobules. Questions of laterality, however, have been largely overlooked. This study therefore introduced and applied a novel measurement protocol for comparatively bias-free analysis of cerebellar asymmetries. Volumetric measurements were performed on magnetic resonance images from a single pair of monozygotic handedness-discordant twins. Against a background of functional cortical asymmetry for verbal and visuo-spatial functional magnetic resonance imaging activation, which was mirrored in the left-handed twin (Lux et al. 2008), between-twin differences in cerebellar asymmetry are described. Interestingly, asymmetry measures for the whole cerebellum did not correspond to either the direction of hand preference or to the weaker (functional magnetic resonance imaging) lateralization of the left-handed twin. The twins both showed clockwise cerebellar torques. This mirrored a counter-clockwise cerebral torque in the right-handed twin only. Selected single cerebellar lobules V and VII displayed between-twin laterality differences that partially reflected their discrepant handedness. Whole cerebellum anatomical measures appeared to be unrelated to single functional cortical asymmetries. These analyses contribute further anatomical evidence pertaining to the existence of multiple structurally and functionally distinct cortico-cerebellar networks of the healthy human brain in vivo.
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