Publications by authors named "Sian M J Hemmings"

41 Publications

TERT rs2736100 and TERC rs16847897 genotypes moderate the association between internalizing mental disorders and accelerated telomere length attrition among HIV+ children and adolescents in Uganda.

BMC Med Genomics 2021 Jan 6;14(1):15. Epub 2021 Jan 6.

Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.

Background: Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5-11 years) and adolescents (aged 12-17 years).

Results: We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p = 0.007) and TERC rs16847897 (p = 0.012), respectively, on TL at 12 months.

Conclusions: TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12 months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-020-00857-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789327PMC
January 2021

DNA methylation and psychotherapy response in trauma-exposed men with appetitive aggression.

Psychiatry Res 2021 Jan 27;295:113608. Epub 2020 Nov 27.

Department of Psychiatry, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa; South African Medical Research Council / Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address:

Exposure to violence can lead to appetitive aggression (AA), the positive feeling and fascination associated with violence, and posttraumatic stress disorder (PTSD), characterised by hyperarousal, reexperience and feelings of ongoing threat. Psychotherapeutic interventions may act via DNA methylation, an environmentally sensitive epigenetic mechanism that can influence gene expression. We investigated epigenetic signatures of psychotherapy for PTSD and AA symptoms in South African men with chronic trauma exposure. Participants were assigned to one of three groups: narrative exposure therapy for forensic offender rehabilitation (FORNET), cognitive behavioural therapy or waiting list control (n = 9-10/group). Participants provided saliva and completed the Appetitive Aggression Scale and PTSD Symptom Severity Index at baseline, 8-month and 16-month follow-up. The relationship, over time, between methylation in 22 gene promoter region sites, symptom scores, and treatment was assessed using linear mixed models. Compared to baseline, PTSD and AA symptom severity were significantly reduced at 8 and 16 months, respectively, in the FORNET group. Increased methylation of genes implicated in dopaminergic neurotransmission (NR4A2) and synaptic plasticity (AUTS2) was associated with reduced PTSD symptom severity in participants receiving FORNET. Analyses across participants revealed a proportional relationship between AA and methylation of TFAM, a gene involved in mitochondrial biosynthesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psychres.2020.113608DOI Listing
January 2021

Shedding Light on the Transcriptomic Dark Matter in Biological Psychiatry: Role of Long Noncoding RNAs in D-cycloserine-Induced Fear Extinction in Posttraumatic Stress Disorder.

OMICS 2020 06 21;24(6):352-369. Epub 2020 May 21.

Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Biological psychiatry scholarship on posttraumatic stress disorder (PTSD) is making strides with new omics technologies. In this context, there is growing recognition that noncoding RNAs are vital for the regulation of gene and protein expression. Long noncoding RNAs (lncRNAs) can modulate splicing, influence RNA editing, messenger RNA (mRNA) stability, translation activation, and microRNA-mRNA interactions, are highly abundant in the brain, and have been implicated in neurodevelopmental disorders. The largest subclass of lncRNAs is long intergenic noncoding RNAs (lincRNAs). We report on lincRNAs and their predicted mRNA targets associated with fear extinction induced by co-administration of D-cycloserine and behavioral fear extinction in a PTSD animal model. Forty-three differentially expressed lincRNAs and 190 differentially expressed mRNAs were found to be associated with fear extinction. Eight lincRNAs were predicted to interact with and regulate 108 of these mRNAs, while seven lincRNAs were predicted to interact with 22 of their pre-mRNA transcripts. Based on the functions of their target mRNAs, we inferred that these lincRNAs bind to nucleotides, ribonucleotides, and proteins; subsequently influence nervous system development, morphology, and immune system functioning; and could be associated with nervous system and mental health disorders. We found the quantitative trait loci that overlapped with fear extinction-related lincRNAs included traits such as serum corticosterone level, neuroinflammation, anxiety, stress, and despair-related responses. To the best of our knowledge, this is the first study to identify lincRNAs and their RNA targets with a putative role in transcriptional regulation during fear extinction in the context of an animal model of PTSD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/omi.2020.0031DOI Listing
June 2020

Dissecting the genetic association of C-reactive protein with PTSD, traumatic events, and social support.

Neuropsychopharmacology 2020 Mar 16. Epub 2020 Mar 16.

Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, 06516, USA.

Inflammatory markers like C-reactive protein (CRP) have been associated with post-traumatic stress disorder (PTSD) and traumatic experiences, but the underlying mechanisms are unclear. We investigated the relationship among serum CRP, PTSD, and traits related to traumatic events and social support using genetic association data from the Psychiatric Genomics Consortium (23,185 PTSD cases and 151,309 controls), the UK Biobank (UKB; up to 117,900 individuals), and the CHARGE study (Cohorts for Heart and Aging Research in Genomic Epidemiology, 148,164 individual). Linkage disequilibrium score regression, polygenic risk scoring, and two-sample Mendelian randomization (MR) analyses were used to investigate genetic overlap and causal relationships. Genetic correlations of CRP were observed with PTSD (rg = 0.16, p = 0.026) and traits related to traumatic events, and the presence of social support (-0.28 < rg < 0.20; p < 0.008). We observed a bidirectional association between CRP and PTSD (CRP → PTSD: β = 0.065, p = 0.015; PTSD → CRP: β = 0.008, p = 0.009). CRP also showed a negative association with the "felt loved as a child" trait (UKB, β = -0.017, p = 0.008). Owing to the known association of socioeconomic status (SES) on PTSD, a multivariable MR was performed to investigate SES as potential mediator. We found that household income (univariate MR: β = -0.22, p = 1.57 × 10; multivariate MR: β = -0.17, p = 0.005) and deprivation index (univariate MR: β = 0.38, p = 1.63 × 10; multivariate MR: β = 0.27, p = 0.016) were driving the causal estimates of "felt loved as a child" and CRP on PTSD. The present findings highlight a bidirectional genetic association between PTSD and CRP, also suggesting a potential role of SES in the interplay between childhood support and inflammatory processes with respect to PTSD risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-020-0655-6DOI Listing
March 2020

The effect of childhood trauma, ApoE genotype and HIV-1 viral protein R variants on change in cognitive performance.

BMC Res Notes 2019 Dec 27;12(1):828. Epub 2019 Dec 27.

Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Tygerberg, 7505, South Africa.

Objective: Gene-environment interactions contribute to the development of HIV-associated neurocognitive disorders. We examined whether childhood trauma, apolipoprotein E isoforms and viral protein R (Vpr) variants were associated with change in cognitive performance. Seventy-three seropositive women completed neuropsychological assessments at baseline and 1-year follow-up. We conducted genetic analyses using DNA obtained from blood and calculated risk scores based on Vpr amino acid 37, 41 and 55 variants that were previously associated with cognitive performance.

Results: Global cognitive scores declined significantly over the 1-year study period (p = 0.029). A reduction in global cognitive scores was associated with childhood trauma experience (p = 0.039).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13104-019-4869-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935155PMC
December 2019

Natural compulsive-like behaviour in the deer mouse (Peromyscus maniculatus bairdii) is associated with altered gut microbiota composition.

Eur J Neurosci 2020 03 21;51(6):1419-1427. Epub 2019 Nov 21.

Centre of Excellence for Pharmaceutical Sciences, North West-University, Potchefstroom, South Africa.

Obsessive-compulsive disorder (OCD) is a psychiatric illness that significantly impacts affected patients and available treatments yield suboptimal therapeutic response. Recently, the role of the gut-brain axis (GBA) in psychiatric illness has emerged as a potential target for therapeutic exploration. However, studies concerning the role of the GBA in OCD are limited. To investigate whether a naturally occurring obsessive-compulsive-like phenotype in a rodent model, that is large nest building in deer mice, is associated with perturbations in the gut microbiome, we investigated and characterised the gut microbiota in specific-pathogen-free bred and housed large (LNB) and normal (NNB) nest-building deer mice of both sexes (n = 11 per group, including three males and eight females). Following baseline characterisation of nest-building behaviour, a single faecal sample was collected from each animal and the gut microbiota analysed. Our results reveal the overall microbial composition of LNB animals to be distinctly different compared to controls (PERMANOVA p < .05). While no genera were found to be significantly differentially abundant after correcting for multiple comparisons, the normal phenotype showed a higher loading of Prevotella and Anaeroplasma, while the OC phenotype demonstrated a higher loading of Desulfovermiculus, Aestuariispira, Peptococcus and Holdemanella (cut-off threshold for loading at 0.2 in either the first or second component of the PCA). These findings not only provide proof-of-concept for continued investigation of the GBA in OCD, but also highlight a potential underlying aetiological association between alterations in the gut microbiota and the natural development of obsessive-compulsive-like behaviours.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.14610DOI Listing
March 2020

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

Authors:
Caroline M Nievergelt Adam X Maihofer Torsten Klengel Elizabeth G Atkinson Chia-Yen Chen Karmel W Choi Jonathan R I Coleman Shareefa Dalvie Laramie E Duncan Joel Gelernter Daniel F Levey Mark W Logue Renato Polimanti Allison C Provost Andrew Ratanatharathorn Murray B Stein Katy Torres Allison E Aiello Lynn M Almli Ananda B Amstadter Søren B Andersen Ole A Andreassen Paul A Arbisi Allison E Ashley-Koch S Bryn Austin Esmina Avdibegovic Dragan Babić Marie Bækvad-Hansen Dewleen G Baker Jean C Beckham Laura J Bierut Jonathan I Bisson Marco P Boks Elizabeth A Bolger Anders D Børglum Bekh Bradley Megan Brashear Gerome Breen Richard A Bryant Angela C Bustamante Jonas Bybjerg-Grauholm Joseph R Calabrese José M Caldas-de-Almeida Anders M Dale Mark J Daly Nikolaos P Daskalakis Jürgen Deckert Douglas L Delahanty Michelle F Dennis Seth G Disner Katharina Domschke Alma Dzubur-Kulenovic Christopher R Erbes Alexandra Evans Lindsay A Farrer Norah C Feeny Janine D Flory David Forbes Carol E Franz Sandro Galea Melanie E Garrett Bizu Gelaye Elbert Geuze Charles Gillespie Aferdita Goci Uka Scott D Gordon Guia Guffanti Rasha Hammamieh Supriya Harnal Michael A Hauser Andrew C Heath Sian M J Hemmings David Michael Hougaard Miro Jakovljevic Marti Jett Eric Otto Johnson Ian Jones Tanja Jovanovic Xue-Jun Qin Angela G Junglen Karen-Inge Karstoft Milissa L Kaufman Ronald C Kessler Alaptagin Khan Nathan A Kimbrel Anthony P King Nastassja Koen Henry R Kranzler William S Kremen Bruce R Lawford Lauren A M Lebois Catrin E Lewis Sarah D Linnstaedt Adriana Lori Bozo Lugonja Jurjen J Luykx Michael J Lyons Jessica Maples-Keller Charles Marmar Alicia R Martin Nicholas G Martin Douglas Maurer Matig R Mavissakalian Alexander McFarlane Regina E McGlinchey Katie A McLaughlin Samuel A McLean Sarah McLeay Divya Mehta William P Milberg Mark W Miller Rajendra A Morey Charles Phillip Morris Ole Mors Preben B Mortensen Benjamin M Neale Elliot C Nelson Merete Nordentoft Sonya B Norman Meaghan O'Donnell Holly K Orcutt Matthew S Panizzon Edward S Peters Alan L Peterson Matthew Peverill Robert H Pietrzak Melissa A Polusny John P Rice Stephan Ripke Victoria B Risbrough Andrea L Roberts Alex O Rothbaum Barbara O Rothbaum Peter Roy-Byrne Ken Ruggiero Ariane Rung Bart P F Rutten Nancy L Saccone Sixto E Sanchez Dick Schijven Soraya Seedat Antonia V Seligowski Julia S Seng Christina M Sheerin Derrick Silove Alicia K Smith Jordan W Smoller Scott R Sponheim Dan J Stein Jennifer S Stevens Jennifer A Sumner Martin H Teicher Wesley K Thompson Edward Trapido Monica Uddin Robert J Ursano Leigh Luella van den Heuvel Miranda Van Hooff Eric Vermetten Christiaan H Vinkers Joanne Voisey Yunpeng Wang Zhewu Wang Thomas Werge Michelle A Williams Douglas E Williamson Sherry Winternitz Christiane Wolf Erika J Wolf Jonathan D Wolff Rachel Yehuda Ross McD Young Keith A Young Hongyu Zhao Lori A Zoellner Israel Liberzon Kerry J Ressler Magali Haas Karestan C Koenen

Nat Commun 2019 10 8;10(1):4558. Epub 2019 Oct 8.

Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12576-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783435PMC
October 2019

Internalizing Mental Disorders and Accelerated Cellular Aging Among Perinatally HIV-Infected Youth in Uganda.

Front Genet 2019 2;10:705. Epub 2019 Aug 2.

Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.

Internalizing mental disorders (IMDs) in HIV+ children and adolescents are associated with impaired quality of life and non-adherence to anti-retroviral treatment. Telomere length is a biomarker of cellular aging, and shorter telomere length has been associated with IMDs. However, the nature of this association has yet to be elucidated. We determined the longitudinal association between IMDs and relative telomere length (rTL) and the influence of chronic stress among Ugandan perinatally HIV-infected youth (PHIY). IMDs (depressive disorders, anxiety disorders, and post-traumatic stress disorder) and IMDs were assessed using the locally adapted Child and Adolescent Symptom Inventory-5. In 368 PHIY with any IMD and 368 age- and sex-matched PHIY controls without any psychiatric disorder, rTL was assessed using quantitative polymerase chain reaction. Hierarchical cluster analysis was used to generate the three chronic stress classes (mild, moderate, and severe). -tests were used to assess the difference between baseline and 12 month rTL and the mean difference in rTL between cases and controls both at baseline and at 12 months. Linear regression analysis was used to model the effects of chronic stress on the association between IMDs and rTL, controlling for age and sex. We observed longer rTL among cases of IMDs compared with controls ( < 0.001). We also observed a statistically significant reduction in rTL between baseline and 12 months in the combined sample of cases and controls ( < 0.001). The same statistical difference was observed when cases and controls were individually analyzed ( < 0.001). We found no significant difference in rTL between cases and controls at 12 months ( = 0.117). We found no significant influence of chronic stress on the association between IMDs and rTL at both baseline and 12 months. rTL is longer among cases of IMDs compared with age- and sex-matched controls. We observed a significant attrition in rTL over 12 months, which seems to be driven by the presence of any IMDs. There is a need for future longitudinal and experimental studies to understand the mechanisms driving our findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2019.00705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688656PMC
August 2019

Childhood trauma interacts with ApoE to influence neurocognitive function in women living with HIV.

J Neurovirol 2019 04 26;25(2):183-193. Epub 2018 Nov 26.

Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Tygerberg, 7505, South Africa.

HIV-associated neurocognitive disorder (HAND) describes a spectrum of behavioural, motor and cognitive disturbances that can occur secondary to HIV infection. Less severe forms of the disorder persist despite advances in antiretroviral medication efficacy and availability. Childhood trauma (CT) may predispose individuals to developing HAND. As genetic variation in human apolipoprotein E (ApoE) has been implicated in cognitive decline and may mediate the development of long-term health outcomes following CT, we investigated the influence of ApoE and CT on cognitive function in the context of HIV. One hundred twenty-eight HIV-positive Xhosa women completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF) as well as the HIV Neurobehavioural Research Center neurocognitive test battery. rs7412 and rs429358 were genotyped using KASP assays, and this data was used to determine the ApoE isoform. Baseline differences in demographic and clinical variables according to CT exposure were calculated. Analysis of covariance was used to assess the contributions of CT and ApoE variants, as well as their interaction, to cognitive function. Eighty-eight participants reported experiencing CT. The rs7412 C allele protected against the harmful effect of CT on motor scores using an additive model. The interaction of ApoE ε4 and CT was associated with worse attention/working memory scores. ApoE ε4, alone and in combination with CT, is associated with poorer cognitive function. Further research into this gene-environment interaction may assist in identifying at-risk individuals for targeted interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-018-0700-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010592PMC
April 2019

Hypothalamic-pituitary-adrenal axis variants and childhood trauma influence anxiety sensitivity in South African adolescents.

Metab Brain Dis 2018 04 4;33(2):601-613. Epub 2017 Nov 4.

Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Anxiety sensitivity (AS) is characterised by the fear of anxiety-related symptoms and is a risk factor for the development of anxiety-related disorders. We examined whether genetic variation in three stress response genes, CRHR1, NR3C1, and FKBP5, interact with childhood trauma (CT) to predict AS in South African adolescents. Xhosa (n = 634) and Coloured (n = 317) students completed self-report measures of AS and CT, and a total of eighteen polymorphisms within CRHR1, NR3C1, and FKBP5 were genotyped. Differences in AS based on genetic variation and CT were analysed within population and gender groups using multiple linear regression. Associations were found between AS and FKBP5 rs9296158 (p = 0.025) and rs737054 (p = 0.045) in Coloured males. Analysis of gene x CT interactions indicated that NR3C1 rs190488 CC-genotype, NR3C1 rs10482605 G-allele addition, and FKBP5 rs3800373 C-allele addition protect against AS with increasing CT in Xhosa females (p = 0.009), Xhosa males (p = 0.036) and Coloured males (p = 0.049), respectively. We identified two different protective single nucleotide polymorphism (SNP) combinations in a four-SNP CRHR1 haplotype in Coloured males. An analysis of the interaction between CT and a six-SNP FKBP5 haplotype in Coloured males revealed both protective and risk allelic combinations. Our results provide evidence for the influence of both genetic variation in CRHR1, NR3C1 and FKBP5, as well as CT x SNP interactions, on AS in South African adolescents. This study reinforces the importance of examining the influence of gene-environment (G X E) interactions within gender and population groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11011-017-0138-6DOI Listing
April 2018

The Gut Microbiome and Mental Health: Implications for Anxiety- and Trauma-Related Disorders.

OMICS 2018 02 2;22(2):90-107. Epub 2017 Aug 2.

1 Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University , Tygerberg, South Africa .

Biological psychiatry research has long focused on the brain in elucidating the neurobiological mechanisms of anxiety- and trauma-related disorders. This review challenges this assumption and suggests that the gut microbiome and its interactome also deserve attention to understand brain disorders and develop innovative treatments and diagnostics in the 21st century. The recent, in-depth characterization of the human microbiome spurred a paradigm shift in human health and disease. Animal models strongly suggest a role for the gut microbiome in anxiety- and trauma-related disorders. The microbiota-gut-brain (MGB) axis sits at the epicenter of this new approach to mental health. The microbiome plays an important role in the programming of the hypothalamic-pituitary-adrenal (HPA) axis early in life, and stress reactivity over the life span. In this review, we highlight emerging findings of microbiome research in psychiatric disorders, focusing on anxiety- and trauma-related disorders specifically, and discuss the gut microbiome as a potential therapeutic target. 16S rRNA sequencing has enabled researchers to investigate and compare microbial composition between individuals. The functional microbiome can be studied using methods involving metagenomics, metatranscriptomics, metaproteomics, and metabolomics, as discussed in the present review. Other factors that shape the gut microbiome should be considered to obtain a holistic view of the factors at play in the complex interactome linked to the MGB. In all, we underscore the importance of microbiome science, and gut microbiota in particular, as emerging critical players in mental illness and maintenance of mental health. This new frontier of biological psychiatry and postgenomic medicine should be embraced by the mental health community as it plays an ever-increasing transformative role in integrative and holistic health research in the next decade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/omi.2017.0077DOI Listing
February 2018

The Gut Microbiome and Mental Health: Implications for Anxiety- and Trauma-Related Disorders.

OMICS 2018 02 2;22(2):90-107. Epub 2017 Aug 2.

1 Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University , Tygerberg, South Africa .

Biological psychiatry research has long focused on the brain in elucidating the neurobiological mechanisms of anxiety- and trauma-related disorders. This review challenges this assumption and suggests that the gut microbiome and its interactome also deserve attention to understand brain disorders and develop innovative treatments and diagnostics in the 21st century. The recent, in-depth characterization of the human microbiome spurred a paradigm shift in human health and disease. Animal models strongly suggest a role for the gut microbiome in anxiety- and trauma-related disorders. The microbiota-gut-brain (MGB) axis sits at the epicenter of this new approach to mental health. The microbiome plays an important role in the programming of the hypothalamic-pituitary-adrenal (HPA) axis early in life, and stress reactivity over the life span. In this review, we highlight emerging findings of microbiome research in psychiatric disorders, focusing on anxiety- and trauma-related disorders specifically, and discuss the gut microbiome as a potential therapeutic target. 16S rRNA sequencing has enabled researchers to investigate and compare microbial composition between individuals. The functional microbiome can be studied using methods involving metagenomics, metatranscriptomics, metaproteomics, and metabolomics, as discussed in the present review. Other factors that shape the gut microbiome should be considered to obtain a holistic view of the factors at play in the complex interactome linked to the MGB. In all, we underscore the importance of microbiome science, and gut microbiota in particular, as emerging critical players in mental illness and maintenance of mental health. This new frontier of biological psychiatry and postgenomic medicine should be embraced by the mental health community as it plays an ever-increasing transformative role in integrative and holistic health research in the next decade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/omi.2017.0077DOI Listing
February 2018

The Microbiome in Posttraumatic Stress Disorder and Trauma-Exposed Controls: An Exploratory Study.

Psychosom Med 2017 Oct;79(8):936-946

From the Department of Psychiatry (Hemmings, Malan-Müller, van den Heuvel, Seedat), Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa; Departments of Molecular, Cellular and Developmental Biology (Demmitt, Krauter), Chemistry and Biochemistry (Smith), and Integrative Physiology (Bohr, Stamper, Siebler, McQueen, Lowry), Institute for Behavioral Genetics (Demmitt, Bohr, McQueen, Krauter), and Center for Neuroscience (Lowry), University of Colorado Boulder, Boulder; Departments of Epidemiology (Stanislawski), Psychiatry and Neurology (Brenner), and Physical Medicine and Rehabilitation (Brenner, Lowry), and Center for Neuroscience (Lowry), University of Colorado Anschutz Medical Campus, Aurora; US Department of Veterans Affairs (Stanislawski), Denver, CO; Departments of Pediatrics (Hyde, Marotz, Knight) and Computer Science & Engineering (Morton, Knight), and Center for Microbiome Innovation (Knight), University of California San Diego, La Jolla, CA; NXT-Dx (Braspenning); Department of Mathematical Modelling (Van Criekinge), Statistics and Bio-informatics, Ghent University, Gent, Belgium; Department of Civil and Environmental Engineering (Hoisington), United States Air Force Academy, Colorado Springs; Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE) (Hoisington, Brenner, Postolache, Lowry); VA Rocky Mountain Mental Illness Research, Education, and Clinical Center (MIRECC) (Brenner, Postolache, Lowry), Denver, CO; and Department of Psychiatry (Postolache), School of Medicine, University of Maryland, Baltimore, MD.

Objective: Inadequate immunoregulation and elevated inflammation may be risk factors for posttraumatic stress disorder (PTSD), and microbial inputs are important determinants of immunoregulation; however, the association between the gut microbiota and PTSD is unknown. This study investigated the gut microbiome in a South African sample of PTSD-affected individuals and trauma-exposed (TE) controls to identify potential differences in microbial diversity or microbial community structure.

Methods: The Clinician-Administered PTSD Scale for DSM-5 was used to diagnose PTSD according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Microbial DNA was extracted from stool samples obtained from 18 individuals with PTSD and 12 TE control participants. Bacterial 16S ribosomal RNA gene V3/V4 amplicons were generated and sequenced. Microbial community structure, α-diversity, and β-diversity were analyzed; random forest analysis was used to identify associations between bacterial taxa and PTSD.

Results: There were no differences between PTSD and TE control groups in α- or β-diversity measures (e.g., α-diversity: Shannon index, t = 0.386, p = .70; β-diversity, on the basis of analysis of similarities: Bray-Curtis test statistic = -0.033, p = .70); however, random forest analysis highlighted three phyla as important to distinguish PTSD status: Actinobacteria, Lentisphaerae, and Verrucomicrobia. Decreased total abundance of these taxa was associated with higher Clinician-Administered PTSD Scale scores (r = -0.387, p = .035).

Conclusions: In this exploratory study, measures of overall microbial diversity were similar among individuals with PTSD and TE controls; however, decreased total abundance of Actinobacteria, Lentisphaerae, and Verrucomicrobia was associated with PTSD status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PSY.0000000000000512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763914PMC
October 2017

Childhood maltreatment and HIV-associated neurocognitive disorders share similar pathophysiology: a potential sensitisation mechanism?

Metab Brain Dis 2017 10 5;32(5):1717-1733. Epub 2017 Jul 5.

Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Tygerberg, 7505, South Africa.

HIV-associated neurocognitive disorders (HAND) are increasingly prevalent despite the use of antiretroviral therapies. Previous research suggests that individual host factors play an important role in determining susceptibility to HAND. In this review, we propose that childhood trauma (CT) and HAND share several common aetiological mechanisms, namely hypothalamic-pituitary-adrenal axis dysregulation, neuroinflammation and oxidative stress. These convergent and consequent mechanisms may translate into an increased risk of developing HAND in individuals who have experienced early life stress. We provide an overview of basic and clinical research relating to these pathophysiological mechanisms and suggest that further research examine brain-derived neurotrophic factor and telomere length as common mediating factors and potential therapeutic targets for HAND and CT. Graphical abstract Both childhood trauma and HIV-associated neurocognitive disorders are associated with HPA axis dysregulation, inflammation and oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11011-017-0062-9DOI Listing
October 2017

The role of microRNAs in the therapeutic action of D-cycloserine in a post-traumatic stress disorder animal model: an exploratory study.

Psychiatr Genet 2017 08;27(4):139-151

aDepartment of Psychiatry bDivision of Molecular Biology and Human Genetics, Stellenbosch University cSouth African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Cape Town dSchool of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg eCentre for Statistical Consultation, Stellenbosch University, Stellenbosch, South Africa.

Objectives: Post-traumatic stress disorder is characterized by impaired fear extinction and excessive anxiety. D-Cycloserine (DCS) has previously been shown to facilitate fear extinction and decrease anxiety in animal and human studies. This study utilized a contextual fear-conditioning animal model to investigate the involvement of microRNAs (miRNAs) in fear extinction and the reduction of anxiety, as mediated by the co-administration of DCS and behavioural fear extinction.

Methods: Fear conditioning consisted of an electric foot shock; fear extinction consisted of behavioural fear extinction co-administered with either DCS or saline. The light/dark avoidance test was used to evaluate anxiety-related behaviour subsequent to fear conditioning and was used to evaluate anxiety-related behaviour following fear conditioning and to subsequently group animals into well-adapted and maladapted subgroups. These subgroups also showed significant differences in terms of fear extinction. Small RNAs extracted from the left dorsal hippocampus were sequenced using next-generation sequencing to identify differentially expressed miRNAs associated with DCS-induced fear extinction and reduction of anxiety. In-silico prediction analyses identified mRNA targets (from data of the same animals) of the differentially expressed miRNAs. Two of the predicted mRNA-miRNA interactions were functionally investigated.

Results: Overall, 32 miRNAs were differentially expressed between rats that were fear conditioned, received DCS and were well adapted and rats that were fear conditioned, received saline and were maladapted. Nineteen of these miRNAs were predicted to target and regulate the expression of 63 genes differentially expressed between fear-conditioned, DCS-administered, well-adapted and fear-conditioned, saline-administered, and maladapted groups (several of which are associated with neuronal inflammation, learning and memory). Functional luciferase assays indicated that rno-mir-31a-5p may have regulated the expression of interleukin 1 receptor antagonist (Il1rn) and metallothionein 1a (Mt1a).

Conclusion: These differentially expressed miRNAs may be mediators of gene expression changes that facilitated decreased neuronal inflammation, optimum learning and memory and contributed towards effective fear extinction and reduction of anxiety following the co-administration of DCS and behavioural fear extinction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/YPG.0000000000000176DOI Listing
August 2017

Neuroinflammatory genes associated with post-traumatic stress disorder: implications for comorbidity.

Psychiatr Genet 2017 02;27(1):1-16

aDepartment of Molecular Biology and Human Genetics, SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics bDepartment of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Post-traumatic stress disorder (PTSD) is a debilitating condition that only occurs in the aftermath of traumatic event exposure and is characterized by an impaired stress response and chronic, low-grade inflammation. Dysregulation of the immune system may contribute towards central nervous system tissue damage and exacerbation of fear memories following trauma. Patients with PTSD often have comorbid psychiatric and somatic disorders that are of themselves associated with heightened inflammation. Several immune-related genes have been associated with PTSD and other co-occurring disorders. In this review, we propose that chronic inflammation, particularly neuroinflammation, is an important contributory factor towards PTSD comorbidity. Thus, novel treatments that target dysregulated inflammatory processes could provide symptomatic relief from PTSD and its comorbid disorders. This review investigates the intricate links between chronic stress, anxiety and neuroinflammation and the potential impact of increased neuroinflammation on PTSD pathology and comorbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/YPG.0000000000000143DOI Listing
February 2017

The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health.

Curr Environ Health Rep 2016 09;3(3):270-86

Center for Clinical Microbiology, UCL (University College London), WC1E 6BT, London, UK.

The hygiene or "Old Friends" hypothesis proposes that the epidemic of inflammatory disease in modern urban societies stems at least in part from reduced exposure to microbes that normally prime mammalian immunoregulatory circuits and suppress inappropriate inflammation. Such diseases include but are not limited to allergies and asthma; we and others have proposed that the markedly reduced exposure to these Old Friends in modern urban societies may also increase vulnerability to neurodevelopmental disorders and stress-related psychiatric disorders, such as anxiety and affective disorders, where data are emerging in support of inflammation as a risk factor. Here, we review recent advances in our understanding of the potential for Old Friends, including environmental microbial inputs, to modify risk for inflammatory disease, with a focus on neurodevelopmental and psychiatric conditions. We highlight potential mechanisms, involving bacterially derived metabolites, bacterial antigens, and helminthic antigens, through which these inputs promote immunoregulation. Though findings are encouraging, significant human subjects' research is required to evaluate the potential impact of Old Friends, including environmental microbial inputs, on biological signatures and clinically meaningful mental health prevention and intervention outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40572-016-0100-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763918PMC
September 2016

Posttraumatic Stress Disorder, Overweight, and Obesity: A Systematic Review and Meta-analysis.

Harv Rev Psychiatry 2016 Jul-Aug;24(4):271-93

From the Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.

Previous reports have suggested a high prevalence of overweight and obesity among individuals with posttraumatic stress disorder (PTSD). Few studies, however, systematically analyze the relationship between PTSD and body mass index (BMI). We conducted a systematic review and meta-analysis aimed at estimating the association between PTSD and BMI. Fifty-four articles were reviewed, 30 of which (with 191,948 individuals with PTSD and 418,690 trauma-exposed individuals or healthy controls) were eligible for inclusion in the meta-analysis. The pooled standard mean difference, based on a random-effects model, was 0.41 (95% confidence interval, 0.28-0.54; z = 6.26; p < .001). Statistical heterogeneity between the included studies was high (p < .001; I = 99%). Despite limitations, the findings of this systematic review and meta-analysis suggest an association between PTSD and BMI. Furthermore, longitudinal studies tentatively indicate that PTSD may lead to an increase in BMI and, as such, to the development of overweight/obesity, particularly in women. Further prospective studies and research elaborating the nature and etiology of the association are required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HRP.0000000000000106DOI Listing
January 2018

Pathologic grooming (acne excoriee, trichotillomania, and nail biting) in 4 generations of a single family.

JAAD Case Rep 2016 Jan 30;2(1):51-3. Epub 2016 Jan 30.

Division of Psychiatry, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdcr.2015.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809443PMC
January 2016

Serotonin transporter variants play a role in anxiety sensitivity in South African adolescents.

World J Biol Psychiatry 2016 3;17(1):66-75. Epub 2015 Dec 3.

a Department of Psychiatry, Faculty of Medicine and Health Sciences , Stellenbosch University , Tygerberg , South Africa ;

Objectives: Anxiety sensitivity (AS) has predictive potential for the development of anxiety disorders. We investigated the role that gene-environment (G × E) interactions, focussing on childhood trauma (CT) and selected SLC6A4 variants, play in modulating levels of AS in a South African adolescent population.

Methods: All adolescents (n = 951) completed measures for AS and CT. Six SLC6A4 polymorphisms were genotyped. G × E influences on AS levels were assessed using multiple linear regression models. Relevant confounders were included in all analyses.

Results: Xhosa (n = 634) and Coloured (n = 317) participants were analysed independently of one another. The 5-HTTLPR-rs25531 L-G haplotype associated with reduced AS among Xhosa adolescents (P = 0.010). In addition, the rs1042173 CC-genotype protected against increased levels of AS in Xhosa participants who had experienced increased levels of CT (P = 0.038). Coloured males homozygous for the S-allele had significantly increased levels of AS compared to Coloured males with at least one L-allele (P = 0.016).

Conclusions: This is the first study to be conducted on AS in adolescents from two ethnically diverse populations. Results indicate that the L-G haplotype confers protection against high AS levels in a Xhosa population. Furthermore, increased CT was found to protect against high levels of AS in Xhosa rs1042173 CC-carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/15622975.2015.1102324DOI Listing
October 2016

A systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia.

Schizophr Res 2016 Jan 25;170(1):1-17. Epub 2015 Nov 25.

Stellenbosch University, Department of Psychiatry, Cape Town, South Africa.

Metabolic syndrome (MetS) is a cluster of factors that increases the risk of cardiovascular disease (CVD), one of the leading causes of mortality in patients with schizophrenia. Incidence rates of MetS are significantly higher in patients with schizophrenia compared to the general population. Several factors contribute to this high comorbidity. This systematic review focuses on genetic factors and interrogates data from association studies of genes implicated in the development of MetS in patients with schizophrenia. We aimed to identify variants that potentially contribute to the high comorbidity between these disorders. PubMed, Web of Science and Scopus databases were accessed and a systematic review of published studies was conducted. Several genes showed strong evidence for an association with MetS in patients with schizophrenia, including the fat mass and obesity associated gene (FTO), leptin and leptin receptor genes (LEP, LEPR), methylenetetrahydrofolate reductase (MTHFR) gene and the serotonin receptor 2C gene (HTR2C). Genetic association studies in complex disorders are convoluted by the multifactorial nature of these disorders, further complicating investigations of comorbidity. Recommendations for future studies include assessment of larger samples, inclusion of healthy controls, longitudinal rather than cross-sectional study designs, detailed capturing of data on confounding variables for both disorders and verification of significant findings in other populations. In future, big genomic datasets may allow for the calculation of polygenic risk scores in risk prediction of MetS in patients with schizophrenia. This could ultimately facilitate early, precise, and patient-specific pharmacological and non-pharmacological interventions to minimise CVD associated morbidity and mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.schres.2015.11.011DOI Listing
January 2016

Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

Authors:
Dongmei Yu Carol A Mathews Jeremiah M Scharf Benjamin M Neale Lea K Davis Eric R Gamazon Eske M Derks Patrick Evans Christopher K Edlund Jacquelyn Crane Jesen A Fagerness Lisa Osiecki Patience Gallagher Gloria Gerber Stephen Haddad Cornelia Illmann Lauren M McGrath Catherine Mayerfeld Sampath Arepalli Cristina Barlassina Cathy L Barr Laura Bellodi Fortu Benarroch Gabriel Bedoya Berrió O Joseph Bienvenu Donald W Black Michael H Bloch Helena Brentani Ruth D Bruun Cathy L Budman Beatriz Camarena Desmond D Campbell Carolina Cappi Julio C Cardona Silgado Maria C Cavallini Denise A Chavira Sylvain Chouinard Edwin H Cook M R Cookson Vladimir Coric Bernadette Cullen Daniele Cusi Richard Delorme Damiaan Denys Yves Dion Valsama Eapen Karin Egberts Peter Falkai Thomas Fernandez Eduardo Fournier Helena Garrido Daniel Geller Donald L Gilbert Simon L Girard Hans J Grabe Marco A Grados Benjamin D Greenberg Varda Gross-Tsur Edna Grünblatt John Hardy Gary A Heiman Sian M J Hemmings Luis D Herrera Dianne M Hezel Pieter J Hoekstra Joseph Jankovic James L Kennedy Robert A King Anuar I Konkashbaev Barbara Kremeyer Roger Kurlan Nuria Lanzagorta Marion Leboyer James F Leckman Leonhard Lennertz Chunyu Liu Christine Lochner Thomas L Lowe Sara Lupoli Fabio Macciardi Wolfgang Maier Paolo Manunta Maurizio Marconi James T McCracken Sandra C Mesa Restrepo Rainald Moessner Priya Moorjani Jubel Morgan Heike Muller Dennis L Murphy Allan L Naarden Erika Nurmi William Cornejo Ochoa Roel A Ophoff Andrew J Pakstis Michele T Pato Carlos N Pato John Piacentini Christopher Pittenger Yehuda Pollak Scott L Rauch Tobias Renner Victor I Reus Margaret A Richter Mark A Riddle Mary M Robertson Roxana Romero Maria C Rosário David Rosenberg Stephan Ruhrmann Chiara Sabatti Erika Salvi Aline S Sampaio Jack Samuels Paul Sandor Susan K Service Brooke Sheppard Harvey S Singer Jan H Smit Dan J Stein Eric Strengman Jay A Tischfield Maurizio Turiel Ana V Valencia Duarte Homero Vallada Jeremy Veenstra-VanderWeele Susanne Walitza Ying Wang Mike Weale Robert Weiss Jens R Wendland Herman G M Westenberg Yin Yao Shugart Ana G Hounie Euripedes C Miguel Humberto Nicolini Michael Wagner Andres Ruiz-Linares Danielle C Cath William McMahon Danielle Posthuma Ben A Oostra Gerald Nestadt Guy A Rouleau Shaun Purcell Michael A Jenike Peter Heutink Gregory L Hanna David V Conti Paul D Arnold Nelson B Freimer S Evelyn Stewart James A Knowles Nancy J Cox David L Pauls

Am J Psychiatry 2015 Jan 31;172(1):82-93. Epub 2014 Oct 31.

From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston; the Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass.; the Department of Psychiatry, University of California, San Francisco; the Department of Neurology, Massachusetts General Hospital, Boston; the Division of Cognitive and Behavioral Neurology, Brigham and Women's Hospital, Boston; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago; the Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam; the Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles; the Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Md.; the Genomic and Bioinformatic Unit, Filarete Foundation, Milan, Italy; the Department of Health Sciences, Graduate School of Nephrology, University of Milan, Milan; the Toronto Western Research Institute, University Health Network, Toronto; Hospital for Sick Children, Toronto; Università Vita-Salute San Raffaele, Milan; the Herman Dana Division of Child and Adolescent Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem; Universidad de Antioquia, Universidad Pontificia Bolivariana, Medellín, Colombia; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; the Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.; the Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil; North Shore-Long Island Jewish Medical Center and North Shore-Lo

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.

Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.

Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).

Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1176/appi.ajp.2014.13101306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282594PMC
January 2015

Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study.

Authors:
Lauren M McGrath Dongmei Yu Christian Marshall Lea K Davis Bhooma Thiruvahindrapuram Bingbin Li Carolina Cappi Gloria Gerber Aaron Wolf Frederick A Schroeder Lisa Osiecki Colm O'Dushlaine Andrew Kirby Cornelia Illmann Stephen Haddad Patience Gallagher Jesen A Fagerness Cathy L Barr Laura Bellodi Fortu Benarroch O Joseph Bienvenu Donald W Black Michael H Bloch Ruth D Bruun Cathy L Budman Beatriz Camarena Danielle C Cath Maria C Cavallini Sylvain Chouinard Vladimir Coric Bernadette Cullen Richard Delorme Damiaan Denys Eske M Derks Yves Dion Maria C Rosário Valsama Eapen Patrick Evans Peter Falkai Thomas V Fernandez Helena Garrido Daniel Geller Hans J Grabe Marco A Grados Benjamin D Greenberg Varda Gross-Tsur Edna Grünblatt Gary A Heiman Sian M J Hemmings Luis D Herrera Ana G Hounie Joseph Jankovic James L Kennedy Robert A King Roger Kurlan Nuria Lanzagorta Marion Leboyer James F Leckman Leonhard Lennertz Christine Lochner Thomas L Lowe Gholson J Lyon Fabio Macciardi Wolfgang Maier James T McCracken William McMahon Dennis L Murphy Allan L Naarden Benjamin M Neale Erika Nurmi Andrew J Pakstis Michele T Pato Carlos N Pato John Piacentini Christopher Pittenger Yehuda Pollak Victor I Reus Margaret A Richter Mark Riddle Mary M Robertson David Rosenberg Guy A Rouleau Stephan Ruhrmann Aline S Sampaio Jack Samuels Paul Sandor Brooke Sheppard Harvey S Singer Jan H Smit Dan J Stein Jay A Tischfield Homero Vallada Jeremy Veenstra-VanderWeele Susanne Walitza Ying Wang Jens R Wendland Yin Yao Shugart Euripedes C Miguel Humberto Nicolini Ben A Oostra Rainald Moessner Michael Wagner Andres Ruiz-Linares Peter Heutink Gerald Nestadt Nelson Freimer Tracey Petryshen Danielle Posthuma Michael A Jenike Nancy J Cox Gregory L Hanna Helena Brentani Stephen W Scherer Paul D Arnold S Evelyn Stewart Carol A Mathews James A Knowles Edwin H Cook David L Pauls Kai Wang Jeremiah M Scharf

J Am Acad Child Adolesc Psychiatry 2014 Aug 24;53(8):910-9. Epub 2014 Jun 24.

Massachusetts General Hospital, Boston; Brigham and Womens Hospital, Boston; Harvard-MIT Broad Institute, Boston. Electronic address:

Objective: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date.

Method: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios.

Results: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%).

Conclusion: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaac.2014.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218748PMC
August 2014

Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.

Authors:
Lea K Davis Dongmei Yu Clare L Keenan Eric R Gamazon Anuar I Konkashbaev Eske M Derks Benjamin M Neale Jian Yang S Hong Lee Patrick Evans Cathy L Barr Laura Bellodi Fortu Benarroch Gabriel Bedoya Berrio Oscar J Bienvenu Michael H Bloch Rianne M Blom Ruth D Bruun Cathy L Budman Beatriz Camarena Desmond Campbell Carolina Cappi Julio C Cardona Silgado Danielle C Cath Maria C Cavallini Denise A Chavira Sylvain Chouinard David V Conti Edwin H Cook Vladimir Coric Bernadette A Cullen Dieter Deforce Richard Delorme Yves Dion Christopher K Edlund Karin Egberts Peter Falkai Thomas V Fernandez Patience J Gallagher Helena Garrido Daniel Geller Simon L Girard Hans J Grabe Marco A Grados Benjamin D Greenberg Varda Gross-Tsur Stephen Haddad Gary A Heiman Sian M J Hemmings Ana G Hounie Cornelia Illmann Joseph Jankovic Michael A Jenike James L Kennedy Robert A King Barbara Kremeyer Roger Kurlan Nuria Lanzagorta Marion Leboyer James F Leckman Leonhard Lennertz Chunyu Liu Christine Lochner Thomas L Lowe Fabio Macciardi James T McCracken Lauren M McGrath Sandra C Mesa Restrepo Rainald Moessner Jubel Morgan Heike Muller Dennis L Murphy Allan L Naarden William Cornejo Ochoa Roel A Ophoff Lisa Osiecki Andrew J Pakstis Michele T Pato Carlos N Pato John Piacentini Christopher Pittenger Yehuda Pollak Scott L Rauch Tobias J Renner Victor I Reus Margaret A Richter Mark A Riddle Mary M Robertson Roxana Romero Maria C Rosàrio David Rosenberg Guy A Rouleau Stephan Ruhrmann Andres Ruiz-Linares Aline S Sampaio Jack Samuels Paul Sandor Brooke Sheppard Harvey S Singer Jan H Smit Dan J Stein E Strengman Jay A Tischfield Ana V Valencia Duarte Homero Vallada Filip Van Nieuwerburgh Jeremy Veenstra-Vanderweele Susanne Walitza Ying Wang Jens R Wendland Herman G M Westenberg Yin Yao Shugart Euripedes C Miguel William McMahon Michael Wagner Humberto Nicolini Danielle Posthuma Gregory L Hanna Peter Heutink Damiaan Denys Paul D Arnold Ben A Oostra Gerald Nestadt Nelson B Freimer David L Pauls Naomi R Wray S Evelyn Stewart Carol A Mathews James A Knowles Nancy J Cox Jeremiah M Scharf

PLoS Genet 2013 Oct 24;9(10):e1003864. Epub 2013 Oct 24.

Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1003864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812053PMC
October 2013

Brain-Derived Neurotrophic Factor (BDNF) protein levels in anxiety disorders: systematic review and meta-regression analysis.

Front Integr Neurosci 2013 29;7:55. Epub 2013 Jul 29.

MRC Anxiety Disorders Unit, Department of Psychiatry, Faculty of Medicine and Health Sciences, University of Stellenbosch Cape Town, South Africa.

Background: Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that is involved in the synaptic plasticity and survival of neurons. BDNF is believed to be involved in the pathogenesis of several neuropsychiatric disorders. As findings of BDNF levels in anxiety disorders have been inconsistent, we undertook to conduct a systematic review and meta-analysis of studies that assessed BDNF protein levels in these disorders.

Methods: We conducted the review using electronic databases and searched reference lists of relevant articles for any further studies. Studies that measured BDNF protein levels in any anxiety disorder and compared these to a control group were included. Effect sizes of the differences in BDNF levels between anxiety disorder and control groups were calculated.

Results: Eight studies with a total of 1179 participants were included. Initial findings suggested that BDNF levels were lower in individuals with any anxiety disorder compared to those without [Standard Mean Difference (SMD) = -0.94 (-1.75, -0.12), p ≤ 0.05]. This was, however, dependent on source of BDNF protein [plasma: SMD = -1.31 (-1.69, -0.92), p ≤ 0.01; serum: SMD = -1.06 (-2.27, 0.16), p ≥ 0.01] and type of anxiety disorder [PTSD: SMD = -0.05 (-1.66, 1.75), p ≥ 0.01; OCD: SMD = -2.33 (-4.21, -0.45), p ≤ 0.01].

Conclusion: Although BDNF levels appear to be reduced in individuals with an anxiety disorder, this is not consistent across the various anxiety disorders and may largely be explained by the significantly lowered BDNF levels found in OCD. RESULTS further appear to be mediated by differences in sampling methods. Findings are, however, limited by the lack of research in this area, and given the potential for BDNF as a biomarker of anxiety disorders, it would be useful to clarify the relationship further.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnint.2013.00055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725410PMC
August 2013

The impact of voluntary exercise on relative telomere length in a rat model of developmental stress.

BMC Res Notes 2012 Dec 27;5:697. Epub 2012 Dec 27.

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Background: Exposure to early adverse events can result in the development of later psychopathology, and is often associated with cognitive impairment. This may be due to accelerated cell aging, which can be catalogued by attritioned telomeres. Exercise enhances neurogenesis and has been proposed to buffer the effect of psychological stress on telomere length. This study aimed to investigate the impact of early developmental stress and voluntary exercise on telomere length in the ventral hippocampus (VH) and prefrontal cortex (PFC) of the rat. Forty-five male Sprague-Dawley rats were categorised into four groups: maternally separated runners (MSR), maternally separated non-runners (MSnR), non-maternally separated runners (nMSR) and non-maternally separated non-runners (nMSnR). Behavioural analyses were conducted to assess anxiety-like behaviour and memory performance in the rats, after which relative telomere length was measured using qPCR.

Results: Maternally separated (MS) rats exhibited no significant differences in either anxiety levels or memory performance on the elevated-plus maze and the open field compared to non-maternally separated rats at 49 days of age. Exercised rats displayed increased levels of anxiety on the day that they were removed from the cages with attached running wheels, as well as improved spatial learning and temporal recognition memory compared to non-exercised rats. Exploratory post-hoc analyses revealed that maternally separated non-exercised rats exhibited significantly longer telomere length in the VH compared to those who were not maternally separated; however, exercise appeared to cancel this effect since there was no difference in VH telomere length between maternally separated and non-maternally separated runners.

Conclusions: The increased telomere length in the VH of maternally separated non-exercised rats may be indicative of reduced cellular proliferation, which could, in turn, indicate hippocampal dysfunction. This effect on telomere length was not observed in exercised rats, indicating that voluntary exercise may buffer against the progressive changes in telomere length caused by alterations in maternal care early in life. In future, larger sample sizes will be needed to validate results obtained in the present study and obtain a more accurate representation of the effect that psychological stress and voluntary exercise have on telomere length.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1756-0500-5-697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543200PMC
December 2012

BDNF Val66Met and DRD2 Taq1A polymorphisms interact to influence PTSD symptom severity: a preliminary investigation in a South African population.

Prog Neuropsychopharmacol Biol Psychiatry 2013 Jan 26;40:273-80. Epub 2012 Oct 26.

Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Background: We evaluated the role that selected variants in serotonin transporter (5-HTT), dopamine receptor 2 (DRD2) and brain-derived neurotrophic factor (BDNF) genes play in PTSD symptom severity in an at-risk population. We also investigated the interaction between the genetic variants to determine whether these variables and the interactions between the variables influenced the severity of PTSD symptoms.

Methods: PTSD symptoms were quantitatively assessed using the Davidson Trauma Scale (DTS) in 150 participants from an at-risk South African population. All participants were genotyped for the 5-HTTLPR, DRD2 Taq1A and BDNF Val66Met polymorphisms. Gene-gene interactions were investigated using various linear models. All analyses were adjusted for age, gender, major depressive disorder diagnosis, level of resilience, level of social support and alcohol dependence.

Results: A significant interaction effect between DRD2 Taq1A and BDNF Val66Met variants on DTS score was observed. On the background of the BDNF Val66Val genotype, DTS score increased significantly with the addition of a DRD2 Taq1A A1 allele. However, on the BDNF Met66 allele background, the addition of an A1 allele was found to reduce total DTS score.

Conclusions: This study provides preliminary evidence for an epistatic interaction between BDNF Val66Met and DRD2 Taq1A polymorphisms on the severity of PTSD symptoms, where both too little and too much dopamine can result in increased PTSD symptom severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2012.10.011DOI Listing
January 2013

Investigating SAPAP3 variants in the etiology of obsessive-compulsive disorder and trichotillomania in the South African white population.

Compr Psychiatry 2011 Mar-Apr;52(2):181-7. Epub 2010 Jul 1.

Division of Molecular Biology and Human Genetics, Department Biomedical Sciences, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.

Background: Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by repeated obsessions and compulsions. Trichotillomania (TTM), a psychiatric disorder characterized by repetitive hairpulling, is presently classified as an impulse control disorder, but has also been viewed as an obsessive-compulsive spectrum disorder. Both conditions are complex disorders, with evidence from family and twin studies indicating that their etiology includes a genetic component. Results from a recent knockout animal model suggest that SAP90/PSD95-associated protein 3 (SAPAP3) may be involved in the pathophysiology of both disorders.

Methods: Seven polymorphic variants distributed across the gene encoding SAPAP3 were genotyped in South African white OCD (n = 172), TTM (n = 45), and control (n = 153) subjects. Single-locus and haplotype analyses were conducted to determine association between genetic variants and subjects with OCD, TTM, and controls.

Results: Although single-locus analysis revealed a significant association between rs11583978 in SAPAP3 and TTM, this association was nonsignificant after correction for multiple testing. In the OCD group, a significant association was observed between earlier age at onset and the A-T-A-T (rs11583978-rs7541937-rs6662980-rs4652867) haplotype compared with the C-G-G-G haplotype.

Conclusions: This study generated preliminary evidence to link SAPAP3 variants to the development of earlier onset OCD. Future studies should concentrate on locating the susceptibility variant(s) by focusing on functional polymorphisms within SAPAP3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.comppsych.2010.05.007DOI Listing
June 2011

The role of the brain-derived neurotrophic factor (BDNF) val66met variant in the phenotypic expression of obsessive-compulsive disorder (OCD).

Am J Med Genet B Neuropsychiatr Genet 2009 Dec;150B(8):1050-62

Department of Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands.

Evidence suggests that the Val66Met variant of the brain-derived neurotrophic factor (BDNF) gene may play a role in the etiology of Obsessive-Compulsive Disorder (OCD). In this study, the role of the BDNF Val66Met variant in the etiology and the phenotypic expression of OCD is investigated. Associations between the BDNF Val66Met variant and OCD, obsessive-compulsive symptom dimensions, Yale-Brown Obsessive Compulsive Scale (YBOCS) severity scores, age of onset and family history of obsessive-compulsive symptoms were assessed. The BDNF Val66Met variant was genotyped in 419 patients with sub-/clinical OCD and 650 controls. No differences in allele or genotype frequency were observed between cases and controls. In females with OCD, the Met66Met genotype was associated with later age of onset and a trend for a negative family history, whereas the Val66Val genotype was associated with a trend for lower YBOCS severity scores. Item-level factor analysis revealed six factors: 1) Contamination/cleaning; 2) Aggressive obsessions/checking; 3) Symmetry obsessions, counting, ordering and repeating; 4) Sexual/religious obsessions; 5) Hoarding and 6) Somatic obsessions/checking. A trend was found for a positive association between Factor 4 (Sexual/religious obsessions) and the BDNF Val66Val genotype. The results suggest that BDNF function may be implicated in the mediation of OCD. We found that for the BDNF Met66Met genotype may be associated with a milder phenotype in females and a possible role for the BDNF Val66Val genotype and the BDNF Val66 allele in the sexual/religious obsessions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.30930DOI Listing
December 2009

Cluster analysis of obsessive-compulsive symptomatology: identifying obsessive-compulsive disorder subtypes.

Isr J Psychiatry Relat Sci 2008 ;45(3):164-76

MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, University of Stellenbosch, South Africa.

Background: There is increasing evidence that obsessive-compulsive disorder (OCD) is a heterogeneous disorder. Different clinical subtypes may be characterized by differing pathophysiological mechanisms and treatment outcomes.

Methods: A cluster analysis was performed on 45 items of the Yale-Brown Obsessive-Compulsive Symptoms Checklist (YBOCS-CL) for 261 patients with OCD. Cluster solutions emerging at different linkage distance levels, and the associations of identified clusters with demographic, clinical and relevant genetic variables, were investigated.

Results: A 6-cluster solution emerged at a linkage distance level of 1.5, and a 3-cluster solution emerged at a linkage distance level of 2.1. The 3 clusters in the latter solution were labeled I) Contamination / washing, II) Hoarding / symmetry / ordering, and III) Obsessional / checking. Increased Cluster III scores were associated with earlier age of OCD onset and the Met/Met (L/L) genotype of the COMT Val158Met polymorphism.

Conclusion: The data here are consistent with previous work delineating the different symptom subtypes of OCD, also with previous work suggesting that the Met/Met (L/L) genotype of the COMT Val158Met polymorphism may be associated with anxiety symptoms, as well as with previous work suggesting that dopaminergic genes may be particularly important in early-onset OCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2009