Sian Hemmings | Stellenbosch University (original) (raw)

Papers by Sian Hemmings

Genes Brain and Behavior

Genome-wide association studies (GWAS) have identified numerous disease-associated variants; howe... more Genome-wide association studies (GWAS) have identified numerous disease-associated variants; however, these variants have a minor effect on disease and explain only a small amount of the heritability of complex disorders. The search for the missing heritability has shifted attention to rare variants, copy number variants, copy neutral variants and epigenetic modifications. The central role of epigenetics, and specifically DNA methylation, in disease susceptibility and progression has become more apparent in recent years. Epigenetic mechanisms facilitate the response to environmental changes and challenges by regulating gene expression. This makes the study of DNA methylation in psychiatric disorders such as posttraumatic stress disorder (PTSD) highly salient, as the environment plays such a vital role in disease aetiology. The epigenome is dynamic and can be modulated by numerous factors, including learning and memory, which are important in the context of PTSD. Numerous studies hav...

Journal of Psychiatric Research, 2013

Childhood trauma has been linked to the development of later psychopathology, including obsessive... more Childhood trauma has been linked to the development of later psychopathology, including obsessivecompulsive disorder (OCD). Although evidence exists to suggest that genetic and environmental factors are involved in the aetiology of OCD, little attention has been paid to the interactions that exist between genes and environment. The aim of this study was to investigate gene-by-environment interactions between childhood trauma and the BDNF Val66Met variant in patients with OCD.

Psychiatry Research, 2004

There is increasing evidence that obsessive -compulsive disorder (OCD) is mediated by genetic fac... more There is increasing evidence that obsessive -compulsive disorder (OCD) is mediated by genetic factors. Although the precise mechanism of inheritance is unclear, recent evidence has pointed towards the involvement of the serotonergic and dopaminergic systems in the disorder's development. Furthermore, early-onset OCD appears to be a subtype that exhibits distinct clinical features and that is associated with greater familial loading. In the present investigation, South African OCD patients (n = 252) were stratified according to age of onset and were clinically assessed. Additionally, selected variants in genes encoding serotonergic and dopaminergic components were investigated in a Caucasian OCD subset (n = 180). This subgroup was further stratified to evaluate the role that these candidate genes may play in the genetically homogeneous Afrikaner subset (n = 80). Analysis of the clinical data revealed an association between early age of onset and an increased frequency of tics, Tourette's disorder, and trichotillomania (TTM). The genetic studies yielded statistically significant results when the allelic distributions of genetic variants in the dopamine receptor type 4 gene (DRD4) were analysed in the Caucasian OCD cohort. These data support a role for the dopaminergic system, which may be relevant to the development of early-onset OCD.

The Israel journal of psychiatry and related sciences, 2008

There is increasing evidence that obsessive-compulsive disorder (OCD) is a heterogeneous disorder... more 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. 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. 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. The data here are consistent w...

PLoS ONE, 2013

The neuropathogenesis of the human immunodeficiency virus (HIV) may manifest as various neurocogn... more 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 . As expected,

Depression and Anxiety, 2011

Background: Women are at an increased risk of depression and other mental health problems followi... more Background: Women are at an increased risk of depression and other mental health problems following rape. Various etiological factors for depression, including predisposing genetic factors, have been identified. Telomeres are repetitive nucleoprotein structures located at chromosomal ends that protect them from premature degradation. Telomeres reduce in length with each cell division, resulting in cellular senescence and apoptosis. Methods: Relative quantification of telomeric repeats using qPCR was performed to investigate whether shorter relative leukocyte telomere length (LTL) in a cohort of 64 rape victims was associated with resilience, the development of rape trauma-related major depressive disorder (MDD) or the development of posttraumatic stress disorder (PTSD) after 3 months. Results: Out of the 64 participants, 23 participants were diagnosed with MDD at baseline and 31 after 3 months. Nine participants were diagnosed with PTSD (MDD and PTSD specifically related to the trauma). No significant associations were observed between relative LTL and resilience or the development of MDD at either baseline or after 3 months in this cohort. However, a marginally significant association was evident between relative LTL and PTSD status. Conclusions: The significant association between relative LTL and PTSD suggests that shorter relative LTL might have acted as a predisposing factor in the development of PTSD after a severely traumatic event. The results of this study indicate that telomere shortening may be an important marker of PTSD risk, with implications for early intervention and timely treatment, and as such warrant replication in a larger cohort. Depression and Anxiety 0:1-5, 2011. r r 2011 Wiley Periodicals, Inc.

Comprehensive Psychiatry, 2011

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by repea... more 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. 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. 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. 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.

European Neuropsychopharmacology, 2004

Background: There is increasing recognition that obsessive -compulsive disorder (OCD) is not a ho... more Background: There is increasing recognition that obsessive -compulsive disorder (OCD) is not a homogeneous entity. It has been suggested that gender may contribute to the clinical and biological heterogeneity of OCD. Methods: Two hundred and twenty patients (n = 220; 107 male, 113 female) with DSM-IV OCD (age: 36.40 F 13.46) underwent structured interviews. A subset of Caucasian subjects (n = 178), including subjects from the genetically homogeneous Afrikaner population (n = 81), and of matched control subjects (n = 161), was genotyped for polymorphisms in genes involved in monoamine function. Clinical and genetic data were statistically analyzed across gender. Results: Compared with females, males with OCD (1) had an earlier age of onset, and a trend toward having more tics and worse outcome, (2) had somewhat differing patterns of OCD symptomatology and axis I comorbidity, and (3) in the Caucasian group, were more likely to have the high activity T allele of the EcoRV variant of the monoamine oxidase A (MAO-A) gene compared to controls, and (4) in the Afrikaner subgroup, were more frequently homozygous for the G allele at the G861C variant of the 5HT 1Db gene than controls. Females with OCD (1) reported more sexual abuse during childhood than males, (2) often noted changes in obsessive -compulsive symptoms in the premenstrual/menstrual period as well as during/shortly after pregnancy, and with menopause, and (3) in the Caucasian subgroup, were more frequently homozygous for the low activity C allele of the EcoRV variant of the MAO-A gene compared to controls, with this allele also more frequent in female patients than controls. Conclusion: This study supports the hypothesis that gender contributes to the clinical and biological heterogeneity of OCD. A sexually dimorphic pattern of genetic susceptibility to OCD may be present. Further work is, however, needed to delineate the mechanisms that are responsible for mediating the effects of gender. D

The Journal of Clinical Psychiatry, 2005

Hoarding may be an important symptom dimension in obsessive-compulsive disorder (OCD). Hoarding i... more 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. 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. 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. 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.

Neuropsychobiology, 2007

Dissociation is defined as the disruption of the usually integrated functions of consciousness, s... more Dissociation is defined as the disruption of the usually integrated functions of consciousness, such as memory, identity, and perceptions of the environment. Causes include various psychological, neurological and neurobiological mechanisms, none of which have been consistently supported. To our knowledge, the role of gene-environment interactions in dissociative experiences in obsessive-compulsive disorder (OCD) has not previously been investigated. Eighty-three Caucasian patients (29 male, 54 female) with a principal diagnosis of OCD were included. The Dissociative Experiences Scale was used to assess dissociation. The role of childhood trauma (assessed with the Childhood Trauma Questionnaire), and a functional 44-bp insertion/deletion polymorphism in the promoter region of the serotonin transporter, or 5-HTT, in mediating dissociation, was investigated using multiple regression analysis and path analysis using the partial least squares model. Both analyses indicated that an interaction between physical neglect and the S/S genotype of the 5-HTT gene significantly predicted dissociation in patients with OCD. Dissociation may be a predictor of poorer treatment outcome in patients with OCD; therefore, a better understanding of the mechanisms that underlie this phenomenon may be useful. Here, two different but related statistical techniques (multiple regression and partial least squares), confirmed that physical neglect and the 5-HTT genotype jointly play a role in predicting dissociation in OCD.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2011

Introduction: Comorbid obsessive-compulsive personality disorder (OCPD) is well-described in obse... more Introduction: Comorbid obsessive-compulsive personality disorder (OCPD) is well-described in obsessivecompulsive 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.

Concepts and Controversies in Obsessive-Compulsive Disorder, 2005

1 In this chapter we argue that it is a useful heuristic to conceptualize trichotillomania (TTM) ... more 1 In this chapter we argue that it is a useful heuristic to conceptualize trichotillomania (TTM) as belonging to an obsessive-compulsive spectrum of disorders.

BMC Research Notes, 2012

Background: Exposure to early adverse events can result in the development of later psychopatholo... more 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.

Journal of the American Academy of Child and Adolescent Psychiatry, 2014

Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental d... more 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…

We evaluated the role that selected variants in serotonin transporter (5-HTT), dopamine receptor ... more 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. 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. 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. 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.

by Cathy Budman, James McCracken, Michael Jenike, Daniel Geller, Danielle Posthuma, Jan Smit, Danielle Cath, Tobias Renner, Dieter Deforce, Damiaan Denys, Joseph Jankovic, Yves Dion, Ana Victoria Valencia Duarte, Peter Heutink, Guy Rouleau, Patrick Evans, S. Stewart, Jay Tischfield, Gerald Nestadt, Dongmei Yu, Edwin Cook, Eric Gamazon, Aline Sampaio, Ana Hounie, Yehuda Pollak, Jeremiah Scharf, Dan J Stein, Sian Hemmings, and James Leckman

PLoS genetics, 2013

The direct estimation of heritability from genome-wide common variant data as implemented in the ... more 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 ...

European Neuropsychopharmacology, 2007

Background: Social anxiety disorder (SAD) is among the most common of all psychiatric disorders w... more Background: Social anxiety disorder (SAD) is among the most common of all psychiatric disorders with lifetime prevalence estimates ranging from 7% to 13%. Although there is evidence that SAD has a strong familial basis, there are few studies of potential candidate genes. In addition to a genetic association, there is also the possibility that temperamental risk factors for the disorder may be genetically transmitted. Against this background, our aims were threefold: i.) to compare patients and controls with respect to personality traits, ii.) to genotype a subgroup of these participants to investigate the role of genes encoding components of serotonergic (5-HT) and dopaminergic (DA) pathways in patients with SAD and iii.) to compare differences in temperament dimensions between carriers of different (dominant vs. recessive) alleles for selected polymorphisms in SAD patients. Methods: Sixty-three patients (n = 63; 35 male, 28 female) with a DSM-IV diagnosis of generalized SAD and SPIN-scores N 18, and age-matched control participants (n = 150; 31 male, 119 female) were included in the study. The Temperament and Character Inventory (TCI) was used to measure behaviours associated with specific personality dimensions (i.e. temperament/ character). DNA was extracted and genotyped to investigate the role of select candidate genes 0924-977X/$ -see front matter D

Comprehensive Psychiatry, 2004

A link between dissociation proneness in adulthood and self-reports of childhood traumatic events... more A link between dissociation proneness in adulthood and self-reports of childhood traumatic events (including familial loss in childhood, sexual/physical abuse and neglect) has been documented. Several studies have also provided evidence for an association between dissociative experiences and trauma in patients with various psychiatric disorders, including post-traumatic stress disorder, borderline personality, dissociative identity and eating disorders. Based on the relative paucity of data on dissociation and trauma in obsessive-compulsive disorder (OCD) and trichotillomania (TTM), the primary objective of this study was to examine the relationship between trauma and dissociative experiences (DE) in these two diagnostic groups. Furthermore, the availability of clinical and genetic data on this sample allowed us to explore clinical and genetic factors relevant to this association. A total of 110 OCD and 32 TTM patients were compared with respect to the degree of dissociation (using the Dissociative Experiences Scale [DES]) and childhood trauma (using the Childhood Trauma Questionnaire [CTQ]). Patients were classified on the DES as either "high" (mean DES score > 30) or "low" (mean DES score < 30) dissociators. Additional clinical and genetic factors were also explored with chi-square and t tests as appropriate. A total of 15.8% of OCD patients and 18.8% of TTM patients were high dissociators. OCD and TTM groups were comparable on DES and CTQ total scores, and in both OCD and TTM groups, significant positive correlations were found between mean DES scores and mean CTQ subscores of emotional abuse, physical abuse, sexual abuse, and physical neglect. In the OCD group, high dissociators were significantly younger than low dissociators, and significantly more high dissociators than low dissociators reported a lifetime (current and past) history of tics (P < .001), Tourette's syndrome (P ‫؍‬ .019), bulimia nervosa (P ‫؍‬ .003), and borderline personality disorder (P ‫؍‬ .027). In the TTM group, significantly more high dissociators than low dissociators reported (lifetime) kleptomania (P ‫؍‬ .005) and depersonalisation disorder (P ‫؍‬ .005). In the Caucasian OCD patients (n ‫؍‬ 114), investigation of genetic polymorphisms involved in monoamine function revealed no significant differences between high and low dissociator groups. This study demonstrates a link between childhood trauma and DE in patients with OCD and TTM. High dissociative symptomatology may be present in a substantial proportion of patients diagnosed with these disorders. High dissociators may also be differentiated from low dissociators on some demographic features (e.g., lower age) and comorbidity profile (e.g., increased incidence of impulse dyscontrol disorders). Additional work is necessary before conclusions about the role of monoaminergic systems in mediating such dissociation can be drawn.

Psychiatric Clinics of North America, 2006

During the last 2 decades, a large number of association studies have been dedicated to disentang... more During the last 2 decades, a large number of association studies have been dedicated to disentangling the genetic components that may be involved in the etiology of OCD. The preliminary and frequently in consistent nature of the data represented in the majority of OCD psychiatric genetic-association studies may seem discouraging. Failure to replicate, and thus to confirm, previously identified susceptibility loci could result from a number of reasons, including the potential for population admixture, the clinical heterogeneity of OCD, small sample sizes (and subsequent lack of power),publication bias, epistasis, or failure to account for multiple testing. Various methods of accounting for these confounders do exist and should be implemented in any genetic-association study that is to be regarded as robust and replicable. Discrepancy between results, however, might be ascribed to the underlying genetic differences between the populations in the respective studies (ie, the investigated variant may be in linkage disequilibrium with the causal variant in one population but not in another). Such discrepancies are difficult to reconcile in single-locus association studies; haplotype analyses(in which a number of variants, usually single-nucleotide polymorphisms occurring on the same gene, are analyzed as a unit) may be able to resolve these uncertainties. Investigating epistatic interactions between variants in other genes that might be involved in the same physiologic pathways would be an alternative means of deciphering the reason for discrepant genetic association results.A valid means of increasing the power (by reducing background noise)would be to stratify the patient sample according to clinically defined sub-types, such as obsession and compulsion subtypes, age at onset of the disorder, and severity of the disorder. Although many of the OCD genetics studies have incorporated investigations of these subtypes [65,66,68,77,84-86,89,107,118,132,133,145,148,149], the number of subjects decreases after stratification, thereby limiting the power of the studies. It may therefore be useful to employ other quantitative approaches in the design of the investigation: the possibility should be considered that OCD symptoms can be broken down into multiple dimensions that are continuous with the normal population [150]. This division would represent an important route to disentangling the complex inheritance of OCD. The results obtained from genetic investigations should be incorporated with clinical and epidemiologic parameters to elucidate correctly the cause of OCD. Future studies should also be extended to incorporate the screening of more polymorphisms, because high-resolution mapping within specific chromosomes will improve knowledge regarding the impact of genetic diversity within the genes or linked chromosomal regions in OCD. The advantages ofa gene-based over a single-nucleotide polymorphism based approach are becoming ever more apparent [151]. Therefore, a more complete assessment of candidate genes, possibly using haplotype blocks that span larger regions,is proposed. In addition, increasing the amount of information on human genome sequences and polymorphisms will make it possible to characterize the amount of sequence variation expressed in the brain and to delineate the potential effects that these variations may have on the development of OCD. Knowledge of new functional variants will emerge as researchers gain an understanding of the potential for genetic variants in the coding and regulatory regions to impact gene expression.

World Journal of Biological Psychiatry, 2008

Multiple sclerosis (MS) is a common, heterogeneous disorder of the central nervous system with a ... more Multiple sclerosis (MS) is a common, heterogeneous disorder of the central nervous system with a complex trait composed of both genetic and environmental factors. Recently, scientific interest has increased in defining factors that possibly contribute to brain functional plasticity; the results might be useful to assess the relationship between MS lesion burden and clinical events, as well as explaining the well-known phenotypic heterogeneity of the disease. In this study, we explored the effect of the Val66Met brain-derived neurotrophic factor (BDNF) functional polymorphism on cognitive performances and volumetric measurements obtained by magnetic resonance imaging of the brain in a selected population of relapsing-remitting MS (RRMS) patients, with relatively short disease duration and minimal clinical disability, compared to gender, age and educationallevel matched healthy subjects. We found that in the RRMS group, the BDNF Met-allele was significantly associated with the lower volume of cerebral grey matter (GM) (P = 0.005). Furthermore, a significant (P = 0.013) interaction effect between 'MS-status' and the BDNF genotype was found for GM volumes, with the result that patients carrying the BDNF Met-allele showed a higher risk of developing global GM atrophy than the homozygous Val/Val. No BDNF-related impact on global neuropsychological functions resulted in either RRMS patients or controls. Our data seem to be consistent with the reported influence of BDNF in neuronal plasticity, thus suggesting that the Met-allele might have a negative prognostic effect on cortical morphometry in RRMS patients.