SUNScholar - Browsing by Author "Hemmings, Sian M. J."

Browsing by Author "Hemmings, Sian M. J."

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5-HT2A: Its role in frontally mediated executive function and related psychopathology
(2007) Stein D.J.; Hemmings, Sian M. J.; Moolman-Smook H.; Audenaert K.
Serotonin (5-HT)2A receptors are widely distributed, with high levels in the frontal cortex, where postsynaptic activation may increase activity in pyramidal glutamatergic neurons and mediate various executive functions. More specifically, reciprocal cortical-raphe pathways may allow the ventral prefrontal cortex to inhibit stress-induced neural activity in the brainstem when stressors are perceived as controllable. However, early adversity and negative attitudes may be associated with higher frontal 5-HT2A receptor levels and greater risk for stress-induced psychopathology, and certain 5-HT2A gene variants have been associated with increased risk for impulsive behavior. Conversely, many antidepressants result in decreased levels of 5-HT2A receptor levels, and blockade of 5-HT2A receptors has proven useful in the treatment of a number of psychiatric disorders.
Appetitive and reactive aggression are differentially associated with the STin2 genetic variant in the serotonin transporter gene
(Nature Research (part of Springer Nature), 2018-04) Hemmings, Sian M. J.; Xulu, Khethelo; Sommer, Jessica; Hinsberger, Martina; Malan-Muller, Stefanie; Tromp, Gerard; Elbert, Thomas; Weierstall, Roland; Seedat, Soraya
Appetitive aggression is a sub-category of instrumental aggression, characterised by the primary intrinsic enjoyment of aggressive activity. Aggression is heritable, and serotonergic and monoaminergic neurotransmitter systems have been found to contribute to the underlying molecular mechanisms. The aim of this study was to investigate the role that genetic variants in the serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) genes play in the aetiology of appetitive aggression in South African Xhosa males (n = 290). SLC6A4 5-HTTLPR, rs25531, and STin2 variants, as well as MAOA-uVNTR were investigated for their association with levels of appetitive aggression using Poisson regression analysis. The STin2 VNTR12 allele was found to be associated with increased levels of appetitive aggression (p = 0.003), but with decreased levels of reactive aggression (p = 7 × 10−5). This study is the first to investigate genetic underpinnings of appetitive aggression in a South African population, with preliminary evidence suggesting that SCL6A4 STin2 variants play a role in its aetiology, and may also be important in differentiating between appetitive and reactive aggression. Although the results require replication, they shed some preliminary light on the molecular dichotomy that may underlie the two forms of aggression.
Association between serotonin transporter gene polymorphisms and increased suicidal risk among HIV positive patients in Uganda
(BioMed Central, 2017-07-25) Kalungi, Allan; Seedat, Soraya; Hemmings, Sian M. J.; Van der Merwe, Lize; Joloba, Moses L.; Nanteza, Ann; Nakassujja, Noeline; Birabwa, Harriet; Serwanga, Jennifer; Kaleebu, Pontiano; Kinyanda, Eugene
Background: Persons living with HIV/AIDS (PLWHA) are at an increased risk of suicide. Increased suicidal risk is a predictor of future attempted and completed suicides and has been associated with poor quality of life and poor adherence with antiretroviral therapy. Clinical risk factors have low predictive value for suicide, hence the interest in potential neurobiological correlates and specific heritable markers of suicide vulnerability. The serotonin transporter gene has previously been implicated in the aetiology of increased suicidal risk in non-HIV infected study populations and its variations may provide a platform for identifying genetic risk for suicidality among PLWHA. The present cross-sectional study aimed at identifying two common genetic variants of the serotonin transporter gene and their association with increased suicidal risk among human immunodeficiency virus (HIV)-positive adults in Uganda. Results: The prevalence of increased suicidal risk (defined as moderate to high risk suicidality on the suicidality module of the Mini Neuropsychiatric Interview (M.I.N.I) was 3.3% (95% CI, 2.0–5.3). The 5-HTTLPR was found to be associated with increased suicidal risk before Bonferroni correction (p-value = 0.0174). A protective effect on increased suicidal risk was found for the 5-HTTLPR/rs25531 S A allele (p-value = 0.0046)- which directs reduced expression of the serotonin transporter gene (5-HTT). Conclusion: The S A allele at the 5-HTTLPR/rs25531 locus is associated with increased suicidal risk among Ugandan PLWHA. Further studies are needed to validate this finding in Ugandan and other sub-Saharan samples.
Big effects of small RNAs : a review of MicroRNAs in anxiety
(SpringerLink, 2012-11) Malan-Muller, Stephanie; Hemmings, Sian M. J.; Seedat, Soraya
Epigenetic and regulatory elements provide an additional layer of complexity to the heterogeneity of anxiety disorders. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that have recently drawn interest as epigenetic modulators of gene expression in psychiatric disorders. miRNAs elicit their effects by binding to target messenger RNAs (mRNAs) and hindering translation or accelerating degradation. Considering their role in neuronal differentiation and synaptic plasticity, miRNAs have opened up new investigative avenues in the aetiology and treatment of anxiety disorders. In this review, we provide a thorough analysis of miRNAs, their targets and their functions in the central nervous system (CNS), focusing on their role in anxiety disorders. The involvement of miRNAs in CNS functions (such as neurogenesis, neurite outgrowth, synaptogenesis and synaptic and neural plasticity) and their intricate regulatory role under stressful conditions strongly support their importance in the aetiology of anxiety disorders. Furthermore, miRNAs could provide new avenues for the development of therapeutic targets in anxiety disorders.
Brain-derived neurotrophic factor (BDNF) protein levels in anxiety disorders : systematic review and meta-regression analysis
(Frontiers, 2013-07) Suliman, Sharain; Hemmings, Sian M. J.; Seedat, Soraya
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.
Comorbid obsessive-compulsive personality disorder in obsessive-compulsive disorder (OCD): A marker of severity
(2011) Lochner C.; Serebro P.; Van der Merwe, L.; Hemmings, Sian M. J.; Kinnear C.; Seedat S.; Stein D.J.
Introduction: Comorbid obsessive-compulsive personality disorder (OCPD) is well-described in obsessive-compulsive disorder (OCD). It remains unclear, however, whether OCPD in OCD represents a distinct subtype of OCD or whether it is simply a marker of severity in OCD. Materials and methods: The aim of this study was to compare a large sample of OCD subjects (n = 403) with and without OCPD on a range of demographic, clinical and genetic characteristics to evaluate whether comorbid OCPD in OCD represents a distinct subtype of OCD, or is a marker of severity. Results: Our findings suggest that OCD with and without OCPD are similar in terms of gender distribution and age at onset of OC symptoms. Compared to OCD. -OCPD (n = 267, 66%), those with OCD. +. OCPD (n = 136, 34%) are more likely to present with the OC symptom dimensions which reflect the diagnostic criteria for OCPD (e.g. hoarding), and have significantly greater OCD severity, comorbidity, functional impairment, and poorer insight. Furthermore there are no differences in distribution of gene variants, or response to treatment in the two groups. Conclusion: The majority of our findings suggest that in OCD, patients with OCPD do not have a highly distinctive phenomenological or genetic profile, but rather that OCPD represents a marker of severity. © 2011 Elsevier Inc.
Dopamine transporter binding in social anxiety disorder: The effect of treatment with escitalopram
(2012) Warwick, James M.; Carey P.D.; Cassimjee N.; Lochner C.; Hemmings, Sian M. J.; Moolman-Smook H.; Beetge E.; Dupont P.; Stein D.J.
Social anxiety disorder (SAD) is characterised by fear of social or performance situations where the individual is exposed to unfamiliar people or to possible scrutiny by others. The literature on dopamine ligands and dopamine genotypes in SAD is however inconsistent. In this study we measured the effects of SSRI pharmacotherapy on dopamine transporter (DAT) binding in patients with SAD, also addressing variability in DAT genotype. Adult subjects meeting DSM-IV criteria for generalised SAD were studied before and after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor (SSRI) escitalopram. DAT single photon emission computed tomography (SPECT) using 123I-FP-CIT was performed at baseline, and repeated at 12 weeks. Striatal DAT binding was analysed for changes following therapy, and for correlations with clinical efficacy, in the whole group as well as for a subgroup with the A10/A10 DAT genotype. The study included 14 subjects (9 male, 5 female) with a mean (SD) age of 41 (±13) years. The subjects' Liebowitz Social Anxiety Scale (LSAS) score was significantly decreased following pharmacotherapy. In the combined group the left caudate and left putamen showed clusters of increased DAT binding after therapy. The left caudate changes were also observed in the subgroup of 9 A10/A10 homozygotes. However no correlation was found between improved symptoms and DAT binding. The changes found in DAT binding in the caudate and putamen may be due to serotonergic activation of dopamine function by SSRI therapy. This is consistent with previous work indicating decreased DAT binding in SAD, and increased DAT binding after SSRI administration. © Springer Science+Business Media, LLC 2012.
The effect of childhood trauma, ApoE genotype and HIV-1 viral protein R variants on change in cognitive performance
(BMC (part of Springer Nature), 2019-12-27) Womersley, Jacqueline S.; Clauss, Lara B.; Varathan, Olivette; Engelbrecht, Susan; Hemmings, Sian M. J.; Seedat, Soraya; Spies, Georgina
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).
Hoarding in obsessive-compulsive disorder: Clinical and genetic correlates
(2005) Lochner C.; Kinnear C.J.; Hemmings, Sian M. J.; Seller C.; Niehaus D.J.H.; Knowles J.A.; Daniels W.; Moolman-Smook J.C.; Seedat S.; Stein D.J.
Objective: Hoarding may be an important symptom dimension in obsessive-compulsive disorder (OCD). Hoarding in OCD has been associated with poor insight, poorer response to selective serotonin reuptake inhibitors than other OCD symptom dimensions, and a distinctive psychobiological profile. The clinical and genetic correlates of hoarding in OCD therefore deserve additional investigation. Method: Adult OCD patients (N = 315) underwent a comprehensive clinical assessment that included the Structured Clinical Interview for DSM-IV Axis I Disorders (Patient Edition) and for Diagnosis of Obsessive-Compulsive Spectrum Disorders. DNA extracted from venous blood (10-30 mL) in a Caucasian subset of the interviewed OCD patients (N = 204) and Caucasian controls (N = 169), including patients (N = 94) and controls (N = 138) of Afrikaner descent, was genotyped to investigate polymorphisms in genes involved in monoamine function and previously hypothesized to be relevant to OCD. Data were collected from 1998 through 2004. Results: OCD patients with hoarding made up 18.1% of the total sample. Compared with nonhoarding OCD, OCD with hoarding was associated with a number of comorbid Axis I disorders, obsessive-compulsive personality disorder, significantly higher OCD severity scores, and more functional impairment. In subjects of Afrikaner descent, the L/L genotype of the COMT Val158Met polymorphism was significantly more common in the OCD hoarding group, with a preponderance of low activity alleles, compared with nonhoarding patients and controls. Conclusions: These data are consistent with the hypothesis that hoarding represents a unique symptom subtype in OCD with a distinctive clinical and psychobiological profile. Further work is needed to determine the psychobiological mechanisms responsible for hoarding and to replicate the genetic findings noted here.
Host and microbiome genome-wide association studies : current state and challenges
(Frontiers Media, 2019) Awany, Denis; Allali, Imane; Dalvie, Shareefa; Hemmings, Sian M. J.; Mwaikono, Kilaza S.; Thomford, Nicholas E.; Gomez, Andres; Mulder, Nicola; Chimusa, Emile R.
The involvement of the microbiome in health and disease is well established. Microbiome genome-wide association studies (mGWAS) are used to elucidate the interaction of host genetic variation with the microbiome. The emergence of this relatively new field has been facilitated by the advent of next generation sequencing technologies that enable the investigation of the complex interaction between host genetics and microbial communities. In this paper, we review recent studies investigating host–microbiome interactions using mGWAS. Additionally, we highlight the marked disparity in the sampling population of mGWAS carried out to date and draw attention to the critical need for inclusion of diverse populations.
HPA-axis genes as potential risk variants for neurocognitive decline in trauma-exposed, HIV-positive females
(Dove Medical Press, 2018) Jacobs, Sean; Moxley, Karis; Womersley, Jacqueline S.; Spies, Georgina; Hemmings, Sian M. J.; Seedat, Soraya
Purpose: Previous studies have independently provided evidence for the effects of HIV infection, hypothalamic–pituitary–adrenal (HPA) axis dysfunction and early life trauma on neurocognitive impairment (NCI). This study examined the interaction between single-nucleotide polymorphisms (SNPs) of two HPA axis genes, corticotrophin-releasing hormone receptor 1 (CRHR1; rs110402, rs242924, rs7209436, and rs4792888) and corticotrophin-releasing hormone-binding protein (CRHBP; rs32897, rs10062367, and rs1053989), childhood trauma, and HIV-associated NCI. Patients and methods: The sample comprised 128 HIV-positive Xhosa females of whom 88 (69%) had a history of childhood trauma. NCI was assessed using a battery of 17 measures sensitive to the effects of HIV, and the history of childhood trauma was assessed using the validated retrospective Childhood Trauma Questionnaire-Short Form. Generalized linear regression models were used to compare allelic distribution by trauma status and global NCI. The association between genotype, childhood trauma, and cognitive scores was also evaluated using generalized linear regression models, assuming additive models for the SNPs, and ANOVA. Results: Of the seven polymorphisms assessed, only the rs10062367 variant of CRHBP was significantly associated with global NCI (P=0.034), independent of childhood trauma. This polymorphism was not significantly associated with z-scores on any specific cognitive domain. The interaction of childhood trauma and variants of CRHR1 was associated with poorer learning (rs110402) and/or recall (rs110402 and rs4792888). Conclusion: These findings suggest that CRHBP rs10062367 A allele is a possible risk variant for NCI in HIV, independent of childhood trauma. Furthermore, results show that the interaction of childhood trauma with variants of CRHR1, rs110402 and rs4792888, confer added vulnerability to NCI in HIV-infected individuals in cognitive domains that are known to be impacted by HIV. While these findings need independent replication in larger samples, it adds CRHBP and CRHR1 to the list of known genes linked to HIV- and childhood trauma-associated neurocognitive phenotypes.
The impact of voluntary exercise on relative telomere length in a rat model of developmental stress
(BioMed Central, 2012-12) Botha, Martmari; Grace, Laurian; Bugarith, Kishor; Russell, Vivienne A.; Kidd, Martin; Seedat, Soraya; Hemmings, Sian M. J.
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.
Internalizing mental disorders and accelerated cellular aging among perinatally HIV-infected youth in Uganda
(Frontiers Media, 2019) Kalungi, Allan; Womersley, Jacqueline S.; Kinyanda, Eugene; Joloba, Moses L.; Ssembajjwe, Wilber; Nsubuga, Rebecca N.; Levin, Jonathan; Kaleebu, Pontiano; Kidd, Martin; Seedat, Soraya, 1966-; Hemmings, Sian M. J.
Introduction: 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. Objective: 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). Methods: 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). t-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. Results: We observed longer rTL among cases of IMDs compared with controls (p < 0.001). We also observed a statistically significant reduction in rTL between baseline and 12 months in the combined sample of cases and controls (p < 0.001). The same statistical difference was observed when cases and controls were individually analyzed (p < 0.001). We found no significant difference in rTL between cases and controls at 12 months (p = 0.117). We found no significant influence of chronic stress on the association between IMDs and rTL at both baseline and 12 months. Conclusion: 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.
International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci
(Nature Research (part of Springer Nature), 2019) Nievergelt, Caroline M.; Maihofer, Adam X.; Klengel, Torsten; Atkinson, Elizabeth G.; Chen, Chia-Yen; Choi, Karmel W.; Coleman, Jonathan R. I.; Dalvie, Shareefa; Duncan, Laramie E.; Gelernter, Joel; Levey, Daniel F.; Logue, Mark W.; Polimanti, Renato; Provost, Allison C.; Ratanatharathorn, Andrew; Stein, Murray B.; Torres, Katy; Aiello, Allison E.; Almli, Lynn M.; Amstadter, Ananda B.; Andersen, Soren B.; Andreassen, Ole A.; Arbisi, Paul A.; Ashley-Koch, Allison E.; Austin, S. Bryn; Avdibegovic, Esmina; Babic, Dragan; Bækvad-Hansen, Marie; Baker, Dewleen G.; Beckham, Jean C.; Bierut, Laura J.; Bisson, Jonathan I.; Boks, Marco P.; Bolger, Elizabeth A.; Borglum, Anders D.; Bradley, Bekh; Brashear, Megan; Breen, Gerome; Bryant, Richard A.; Bustamante, Angela C.; Bybjerg-Grauholm, Jonas; Calabrese, Joseph R.; Caldas-de-Almeida, Jose M.; Dale, Anders M.; Daly, Mark J.; Daskalakis, Nikolaos P.; Deckert, Jurgen; Delahanty, Douglas L.; Dennis, Michelle F.; Disner, Seth G.; Domschke, Katharina; Dzubur-Kulenovic, Alma; Erbes, Christopher R.; Evans, Alexandra; Farrer, Lindsay A.; Feeny, Norah C.; Flory, Janine D.; Forbes, David; Franz, Carol E.; Galea, Sandro; Garrett, Melanie E.; Gelaye, Bizu; Geuze, Elbert; Gillespie, Charles; Uka, Aferdita Goci; Goci, Aferdita; Guffanti, Guia; Hammamieh, Rasha; Harnal, Supriya; Hauser, Michael A.; Heath, Andrew C.; Hemmings, Sian M. J.; Hougaard, David Michael; Jakovljevic, Miro; Jett, Marti; Johnson, Eric Otto; Jones, Ian; Jovanovic, Tanja; Qin, Xue-Jun; Junglen, Angela G.; Karstoft, Karen-Inge; Kaufman, Milissa L.; Kessler, Ronald C.; Khan, Alaptagin; Kimbre, Nathan A.; King, Anthony P.; Koen, Nastassja; Kranzler, Henry R.; Kremen, William S.; Lawford, Bruce R.; Lebois, Lauren A. M.; Lewis, Catrin E.; Linnstaedt, Sarah D.; Lori, Adriana; Lugonja, Bozo; Luykx, Jurjen J.; Lyons, Michael J.; Maples-Keller, Jessica; Marmar, Charles; Martin, Alicia R.; Maurer, Douglas; Mavissakalian, Matig R.; McFarlane, Alexander; McGlinchey, Regina E.; McLaughlin, Katie A.; McLean, Samuel A.; McLeay, Sarah; Mehta, Divya; Milberg, William P.; Miller, Mark W.; Morey, Rajendra A.; Morris, Charles Phillip; Mors, Ole; Mortensen, Preben B.; Neale, Benjamin M.; Nelson, Elliot C.; Nordentoft, Merete; Norman, Sonya B.; O'Donnell, Meaghan; Orcutt, Holly K.; Panizzon, Matthew S.; Peters, Edward S.; Peterson, Alan L.; Peverill, Matthew; Pietrzak, Robert H.; Polusny, Melissa A.; Rice, John P.; Ripke, Stephan; Risbrough, Victoria B.; Roberts, Andrea L.; Rothbaum, Alex O.; Rothbaum, Barbara O.; Roy-Byrne, Peter; Ruggiero, Ken; Rung, Ariane; Rutten, Bart P. F.; Saccone, Nancy L.; Sanchez, Sixto E.; Schijven, Dick; Seedat, Soraya, 1966-; Seligowski, Antonia V.; Seng, Julia S.; Sheerin, Christina M.; Smith, Alicia K.; Smoller, Jordan W.; Sponheim, Scott R.; Stein, Dan J.; Stevens, Jennifer S.; Sumner, Jennifer A.; Teicher, Martin H.; Thompson, Wesley K.; Trapido, Edward; Uddin, Monica; Ursano, Robert J.; Van Den Heuvel, Leigh Luella; Van Hooff, Miranda; Vermetten, Eric; Vinkers, Christiaan H.; Voisey, Joanne; Wang, Yunpeng; Wang, Zhewu; Werge, Thomas; Williams, Michelle A.; Williamson, Douglas E.; Winternitz, Sherry; Wolf, Christiane; Wolf, Erika J.; Wolff, Jonathan D.; Yehuda, Rachel; Young, Ross McD; Young, Keith A.; Zhao, Hongyu; Zoellner, Lori A.; Liberzon, Israel; Ressler, Kerry J.; Haas, Magali; Koenen, Karestan C.
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.
Investigating the molecular aetiology of Obsessive-compulsive disorder (OCD) and clinically-defined subsets of OCD
(Stellenbosch : Stellenbosch University, 2006-03) Hemmings, Sian M. J.; Stein, Dan J.; Moolman-Smook, Johanna C.; Corfield, Valerie A.; Stellenbosch University . Faculty of Medicine & Health Sciences. Dept. of Psychiatry.
ENGLISH ABSTRACT: Obsessive-compulsive disorder (OCD), a debilitating psychiatric disorder, affects 2-3% of the general population, and represents a global health problem. Evidence from family studies suggests that genetic factors play a role in mediating disease development. However, the pattern of inheritance is not consistent with monogenic disorders, but is “genetically complex”. Case-control association analysis, which facilitates dissection of the genetic aetiology of complex disorders, has yielded many inconsistent results in OCD studies, making identification of predisposing alleles difficult. These discrepant findings can largely be attributed to inappropriate statistical methodology and the lack of OCD phenotypic resolution. Although classified as a single clinical entity according to structured algorithms, OCD probably represents a final common outcome of multiple underlying aetiologies. Thus, numerous clinical subtypes of the disorder have been proposed; these “intermediate” phenotypes may be more closely related to a particular genetic substrate than the higher order construct of OCD. Furthermore, although genes encoding serotonergic (5-HT) and dopaminergic components are most commonly investigated, it is likely that the behavioural manifestations of OCD are mediated by a broader network of interconnected neurotransmitter and signalling pathways. Consequently, the aim of the present study was two-fold: to address the factors that may have confounded previous genetic case-control association studies and to investigate the genetic aetiology of OCD phenotypes while accounting for these factors. Case and control individuals were drawn from the reportedly genetically homogeneous Afrikaner population. However, as no empirical evidence existed to support the absence of genetic substructure, which would confound genetic association studies, a Bayesian modelbased clustering algorithm (Structure), that groups individuals on the basis of observed genotype data, was employed to assess population stratification in both case and control Afrikaner subjects. OCD patients were clinically stratified by gender, symptom severity, age at onset, the presence of selected co-morbid disorders and the presence of selected symptom dimensions, to facilitate the identification of susceptibility genes more closely related with these subtypes. Candidate genes included those coding for components of the 5-HT (5-HT receptors 1Dβ, 2A, 2C and 6), dopaminergic (dopamine receptors 1, 2, 3 and 4, dopamine transporter and catechol-O-methyltransferase [COMT]), glutamatergic (glutamate receptor subunit 2B [GRIN2B]) and neurodevelopmental pathways (brain-derived neurotrophic factor [BDNF] and homeobox 8 [HoxB8]), as well as previously uninvestigated genes (angiotensinconverting enzyme I, inositol-trisphosphate, phospholipase-C-gamma 1 and estrogen receptor alpha). The relationship between variants in these genes and OCD (or OCD subtypes) was investigated in a single locus and a haplotype context, while meta-analyses using published population-based case-control association data were also conducted. Significant associations noted between distinct COMT variants and OCD implicated COMT in the development of a genetically discrete, gender-dependant, early-onset, tic-related phenotype in males. Furthermore, investigations of variations in BDNF and GRIN2B point towards a genetically distinct, neurodevelopmental subtype of the disorder, mediated, in males at least, primarily by dysfunctions in BDNF. The striking gender dimorphism noted in these associations indicates the possibility of an epigenetic hormonal influence. Moreover, the significant association of polymorphisms within GRIN2B, in both a single locus and haplotype context, suggests the involvement of this gene in mediating a phenotypic subtype characterised by an early-onset, more severe form of the disorder. The present investigation forms part of ongoing research to elucidate genetic components involved in the aetiopathology of OCD and OCD-related subtypes. Such studies may pave the way towards more efficacious pharmacotherapeutic strategies, which will ease the suffering of individuals who are afflicted with this incapacitating condition.
Investigation of telomere length and psychological stress in rape victims
(2011) Malan S.; Hemmings, Sian M. J.; Kidd M.; Martin L.; Seedat S.
No gene-by-environment interaction of BDNF Val66Met polymorphism and childhood maltreatment on anxiety sensitivity in a mixed race adolescent sample
(Taylor & Francis Open, 2018) Martin, Lindi; Hemmings, Sian M. J.; Kidd, Martin; Seedat, Soraya
Background: Anxiety disorders in youth are attributable to multiple causal mechanisms, comprising biological vulnerabilities, such as genetics and temperament, and unfavourable environmental influences, such as childhood maltreatment (CM). Objective: A gene-environment (G x E) interaction study was conducted to determine the interactive effect of the BDNF Val66Met polymorphism and CM to increase susceptibility to anxiety sensitivity (AS) in a sample of mixed race adolescents. Method: Participants (n = 308, mean age = 15.8 years) who were all secondary school students and who completed measures for AS and CM were genotyped for the BDNF Val66Met polymorphism. Hierarchical multiple regression analysis was conducted to assess G x E influences on AS. Age and gender were included in the models as covariates as age was significantly associated with AS total score (p < .05), and females had significantly higher AS scores than males (p < .05). Results: A main effect of CM on AS was evident (p < .05), however, no main effect of BDNF genotype on AS was observed (p> .05). A non-significant G x E effect on AS was revealed (p <.05). Conclusions: Our results suggest that CM does not have a moderating role in the relationship between the BDNF Val66Met genotype and the increased risk of anxiety-related phenotypes, such as AS. Given the exploratory nature of this study, findings require replication in larger samples and adjustment for population stratification to further explore the role of BDNF Val66Met and CM on AS in mixed race adolescents.
Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture
(PLoS, 2013-10) Davis, Lea K.; Yu, Dongmei; Keenan, Clare L.; Gamazon, Eric R.; Konkashbaev, Anuar I.; Derks, Eske M.; Neale, Benjamin M.; Yang, Jian; Lee, S. Hong; Evans, Patrick; Barr, Cathy L.; Bellodi, Laura; Benarroch, Fortu; Berrio, Gabriel Bedoya; Bienvenu, Oscar J.; Bloch, Michael H.; Blom, Rianne M.; Bruun, Ruth D.; Budman, Cathy L.; Camarena, Beatriz; Campbell, Desmond; Cappi, Carolina; Silgado, Julio C. Cardona; Cath, Danielle C.; Cavallini, Maria C.; Chavira, Denise A.; Chouinard, Sylvain; Conti, David. V.; Cook, Edwin H.; Coric, Vladimir; Cullen, Bernadette A.; Deforce, Dieter; Delorme, Richard; Dion, Yves; Edlund, Christopher K.; Egberts, Karin; Falkai, Peter; Fernandez, Thomas V.; Gallagher, Patience J.; Garrido, Helena; Geller, Daniel; Girard, Simon L.; Grabe, Hans J.; Grados, Marco A.; Greenberg, Benjamin D.; Gross-Tsur, Varda; Haddad, Stephen; Heiman, Gary A.; Hemmings, Sian M. J.; Hounie, Ana G.; Illmann, Cornelia; Jankovic, Joseph; Jenike, Michael A.; Kennedy, James L.; King, Robert A.; Kremeyer, Barbara; Kurlan, Roger; Lanzagorta, Nuria; Leboyer, Marion; Leckman, James F.; Lennertz, Leonhard; Liu, Chunyu; Lochner, Christine; Lowe, Thomas L.; Macciardi, Fabio; McCracken, James T.; McGrath, Lauren M.; Mesa Restrepo, Sandra C.; Moessner, Rainald; Morgan, Jubel; Muller, Heike; Murphy, Dennis L.; Naarden, Allan L.; Ochoa, William Cornejo; Ophoff, Roel A.; Osiecki, Lisa; Pakstis, Andrew J.; Pato, Michele T.; Pato, Carlos N.; Piacentini, John; Pittenger, Christopher; Pollak, Yehuda; Rauch, Scott L.; Renner, Tobias J.; Reus, Victor I.; Richter, Margaret A.; Riddle, Mark A.; Robertson, Mary M.; Romero, Roxana; Rosario, Maria C.; Rosenberg, David; Rouleau, Guy A.; Ruhrmann, Stephan; Ruiz-Linares, Andres; Sampaio, Aline S.; Samuels, Jack; Sandor, Paul; Sheppard, Brooke; Singer, Harvey S.; Smit, Jan H.; Stein, Dan J.; Strengman, E.; Tischfield, Jay A.; Valencia Duarte, Ana V.; Vallada, Homero; Van Nieuwerburgh, Filip; Veenstra-VanderWeele, Jeremy; Walitza, Susanne; Wang, Ying; Wendland, Jens R.; Westenberg, Herman G. M.; Shugart, Yin Yao; Miguel, Euripedes C.; McMahon, William; Wagner, Michael; Nicolini, Humberto; Posthuma, Danielle; Hanna, Gregory L.; Heutnik, Peter; Denys, Damiaan; Arnold, Paul D.; Oostra, Ben A.; Nestadt, Gerald; Freimer, Nelson B.; Pauls, David L.; Wray, Naomi R.; Stewart, S. Evelyn; Mathews, Carol A.; Knowles, James A.; Cox, Nancy J.; Shcarf, Jeremiah M.
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.
Shorter telomere length : a potential susceptibility factor for HIV-associated neurocognitive impairments in South African woman
(PLoS, 2013-03) Malan-Muller, Stefanie; Hemmings, Sian M. J.; Spies, Georgina; Kidd, Martin; Fennema-Notestine, Christine; Seedat, Soraya
The neuropathogenesis of the human immunodeficiency virus (HIV) may manifest as various neurocognitive impairments (NCI). HIV-positive individuals also have significantly shorter telomere length (TL) in peripheral blood mononuclear cells (PBMCs) and CD8+ T cells compared to HIV-negative individuals. Additionally, reduced TL has been found to be associated with chronic psychological stress. This study focused on the effects of HIV-infection and chronic stress associated with childhood trauma on telomere length, and investigated whether leukocyte TL (LTL), in particular, represents a risk factor for NCI. Eighty-three HIV-positive and 45 HIV-negative women were assessed for childhood trauma and were subjected to detailed neurocognitive testing. Blood from each participant was used to extract Deoxyribonucleic acid (DNA). Relative LTL were determined by performing real time quantitative PCR reactions as described by Cawthon et al. (2002). As expected, relative LTL in the HIV-positive individuals was significantly shorter than that of HIV-negative individuals (F = 51.56, p=,0.01). Notably, a significant positive correlation was evident between relative LTL and learning performance in the HIVpositive group. In addition, a significant negative correlation was observed between relative LTL and verbal fluency, but this association was only evident in HIV-positive individuals who had experienced trauma. Our results suggest that reduced LTL is associated with worse learning performance in HIV-positive individuals, indicating that TL could act as a susceptibility factor in increasing neurocognitive decline in HIV-infected individuals.
Symmetry symptoms in obsessive-compulsive disorder : clinical and genetic correlates
(Associacao Brasileira de Psiquiatria, 2016) Lochner, Christine; McGregor, Nathaniel; Hemmings, Sian M. J.; Harvey, Brian H.; Breet, Elsie; Swanevelder, Sonja; Stein, Dan J.
Objective: In obsessive-compulsive disorder (OCD), symmetry-related symptoms may be important. Although clinical correlates of symmetry-related symptoms have been identified in OCD, few data exist on genetic associations. Animal studies indicate involvement of dopamine in symmetry-related behavior, suggesting this may be relevant to analogous symptoms in OCD. Alterations in dopamine may also reflect environmental influences. However, the association of symmetry-related symptomatology, early adversity, and polymorphisms in dopaminergic genes has not been investigated in OCD. Methods: Clinical information and polymorphisms in key dopaminergic genes were compared between OCD patients with primary symmetry symptoms and those without. Results: OCD patients with primary symmetry symptoms comprised 46.6% (n=210) of the sample (n=451), and were older (p < 0.01), had longer illness duration (p < 0.01), higher OCD severity scores (p = 0.01), and greater comorbidity (p < 0.01) than those without. In Caucasians (n=343), genotype frequency differed significantly between groups for ANKK1 rs1800497, with more OCD patients with symmetry symptoms being homozygous for the A2 (CC) genotype (χ2 = 7.296; p = 0.026). Conclusion: Symmetry symptoms have some distinct clinical features and may represent a marker of severity in OCD. However, clinical associations, in combination with the association found with the ANKK1 rs1800497 A2 variant, suggest that primary symmetry symptoms may represent a distinctive clinical and psychobiological profile.

Browsing by Author "Hemmings, Sian M. J."

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