Craig J. Kinnear

Gender in obsessive–compulsive disorder: clinical and genetic findings

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+/-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 C allele at the G861C variant of the 5HT(1D beta) 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.

Early- versus late-onset obsessive–compulsive disorder: investigating genetic and clinical correlates

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 disorders 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, Tourettes 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.

Investigating the role of dopaminergic and serotonergic candidate genes in obsessive-compulsive disorder

There is increasing evidence that the aetiology of obsessive-compulsive disorder (OCD) has a marked genetic component, although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. This study investigated the role of attractive candidate genes in the serotonergic and dopaminergic pathways in the development of OCD. The distribution of selected polymorphic variants in the serotonin receptor type 2A and 1Dbeta (5-HT(2A), 5-HT(1Dbeta)), dopamine transporter (DAT), dopamine receptor type 4 (DRD4) and monoamine-oxidase A (MAO-A) genes were analysed in 71 OCD cases and 129 control individuals in the genetically homogeneous Afrikaner population, by means of case-control association studies. Although no statistically significant genotypic or allelic associations were detected, the data yielded interesting preliminary results that warrant further discussion and investigation.

Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD)

Although evidence from family studies suggest that genetic factors play an important role in mediating obsessive-compulsive disorder (OCD), results from genetic case–control association analyses have been inconsistent. Discrepant findings may be attributed to the lack of phenotypic resolution, and population stratification. The aim of the present study was to investigate the role that the val66met variant within the gene encoding brain-derived neurotrophic factor (BDNF) may play in mediating the development of selected OCD subtypes accounting for the aforementioned confounding factors. One hundred and twelve OCD subjects and 140 controls were selected from the South African Afrikaner population. A significant association was observed in the male subgroup, with the met66 allele implicated as the risk allele in the development of OCD. This allele was also found to be associated with an earlier age at onset of OCD in males. On the other hand, the val66val genotype was associated with more severe OCD in the female population. No evidence of population stratification was observed in Afrikaner control subjects. These preliminary results point towards genetically distinct characteristics of OCD mediated by dysfunctions in BDNF. The present investigation forms part of ongoing research to elucidate the genetic components involved in the aetiology of OCD and OCD-related characteristics.

Association between a catechol-o-methyltransferase polymorphism and obsessive–compulsive disorder in the Afrikaner population

BACKGROUND It has been proposed that the catechol-o-methyl transferase gene (COMT) may play a role in the pathogenesis of obsessive-compulsive disorder (OCD). Whereas studies in a North American population showed that the low activity (L) allele of a functional polymorphism in COMT was associated with OCD in male patients, this result was not supported by studies in a Japanese population. The present association study assessed the risk for OCD conferred by this COMT polymorphism in a geographically different patient group, namely, the relatively genetically homogeneous Afrikaner population of South Africa. METHODS Fifty-four unrelated OCD patients and fifty-four sex-matched controls were recruited from the same Afrikaner community. Patients and controls were phenotyped (DSM-IV) and genotyped for a NlaIII polymorphism with H (high activity) or L (low activity) alleles in the COMT gene. RESULTS The H/L genotype was significantly more common than expected in the OCD patient group (P = 0.0017). LIMITATIONS Replication studies with related individuals may be useful in discovering factors underpinning the H/L genotype abundance in the Afrikaner population. CONCLUSIONS These results emphasise the need for further studies in genetically homogeneous populations to help define the complex etiology of this disease.

Obsessive–compulsive disorder and the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4): a negative association study in the Afrikaner population

A polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been reported to have functional significance and to be associated with obsessive-compulsive disorder (OCD). However, other studies have generated confounding results. A study was undertaken to re-evaluate this association in subjects drawn from the relatively genetically homogeneous Afrikaner population of South Africa. Fifty-four OCD patients of Afrikaner descent and 82 ethnically matched control individuals were phenotyped and genotyped. No significant association was found between the distribution of the 5-HTTLPR genotypes at the SLC6A4 locus and OCD. A similar result (p = 0.108) was generated when a meta-analysis of the 5-HTTLPR polymorphism, combining the current study with a previously reported Caucasian group, was performed; the meta-study comprised 129 OCD patients and 479 control individuals. However, both studies lacked power. Therefore, evidence that variation in SLC6A4 plays a significant role in the development of OCD in the population groups studied is inconclusive. Future association studies in Caucasian populations may extend the power of such meta-analyses and assist in delineating the role of SLC6A4 in OCD.

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

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.

Genetics and personality traits in patients with social anxiety disorder: A case-control study in South Africa

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 >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 encoding components in serotonergic and dopaminergic pathways in mediating the development of SAD. To achieve this, the frequency of variants in 5-HT and DA genes was compared between a Caucasian subset of SAD patients (n=41) and a convenience sample of Caucasian controls (n=88), using case-control association analyses. We also investigated the frequency of variants in 5-HT and DA-related genes across temperament characteristics in SAD patients, using analyses of variance (ANOVA). RESULTS Patients scored significantly higher on harm avoidance (p<0.001) but lower on novelty seeking (p=0.04) and self-directedness (p=0.004) compared to controls. In the Caucasian subset, there was a difference between patients and controls in distribution of the 5-HT(2A)T102C polymorphism, with significantly more patients harboring T-containing genotypes (T-containing genotypes: [T/T+T/C] vs. [C/C]) (chi2=7.55; p=0.012). Temperament dimensions did not, however, differ significantly between carriers of different (dominant vs. recessive) alleles for the 5-HT(2A)T102C polymorphism in SAD patients. CONCLUSIONS The results suggest a possible role for the 5-HT(2A)T102C polymorphism in the development of SAD. To date genetic findings in SAD have been inconsistent; nevertheless, serotonergic variants, and their associations with temperaments (e.g. reward dependence) deserve further exploration, in the hope that endophenotypes relevant to SAD can ultimately be delineated.

Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C.

BackgroundCardiac contractility is regulated by dynamic phosphorylation of sarcomeric proteins by kinases such as cAMP-activated protein kinase A (PKA). Efficient phosphorylation requires that PKA be anchored close to its targets by A-kinase anchoring proteins (AKAPs). Cardiac Myosin Binding Protein-C (cMyBPC) and cardiac troponin I (cTNI) are hypertrophic cardiomyopathy (HCM)-causing sarcomeric proteins which regulate contractility in response to PKA phosphorylation.ResultsDuring a yeast 2-hybrid (Y2H) library screen using a trisphosphorylation mimic of the C1-C2 region of cMyBPC, we identified isoform 4 of myomegalin (MMGL) as an interactor of this N-terminal cMyBPC region. As MMGL has previously been shown to interact with phosphodiesterase 4D, we speculated that it may be a PKA-anchoring protein (AKAP).To investigate this possibility, we assessed the ability of MMGL isoform 4 to interact with PKA regulatory subunits R1A and R2A using Y2H-based direct protein-protein interaction assays. Additionally, to further elucidate the function of MMGL, we used it as bait to screen a cardiac cDNA library. Other PKA targets, viz. CARP, COMMD4, ENO1, ENO3 and cTNI were identified as putative interactors, with cTNI being the most frequent interactor.We further assessed and confirmed these interactions by fluorescent 3D-co-localization in differentiated H9C2 cells as well as by in vivo co-immunoprecipitation. We also showed that quantitatively more interaction occurs between MMGL and cTNI under β-adrenergic stress. Moreover, siRNA-mediated knockdown of MMGL leads to reduction of cMyBPC levels under conditions of adrenergic stress, indicating that MMGL-assisted phosphorylation is requisite for protection of cMyBPC against proteolytic cleavage.ConclusionsThis study ascribes a novel function to MMGL isoform 4: it meets all criteria for classification as an AKAP, and we show that is involved in the phosphorylation of cMyBPC as well as cTNI, hence MMGL is an important regulator of cardiac contractility. This has further implications for understanding the patho-aetiology of HCM-causing mutations in the genes encoding cMyBPC and cTNI, and raises the question of whether MMGL might itself be considered a candidate HCM-causing or modifying factor.

Violence in male patients with schizophrenia: risk markers in a South African population

OBJECTIVE We investigate the role of functional variants in the catecholamine-O-methyl transferase gene (COMT) and the monoamine oxidase-A gene (MOA-A), as well as previously identified non-genetic risk factors in the manifestation of violent behaviour in South African male schizophrenia patients. METHOD A cohort of 70 acutely relapsed male schizophrenia patients was stratified into violent and non-violent subsets, based on the presence or absence of previous or current violent behaviour. Standardized violence rating scales were also applied and the COMT/NlaIII and MAO-A promoter region variable number of tandem repeats (VNTR) polymorphisms were genotyped. RESULTS A multiple logistic regression model based on the clinical, genetic and socio-demographic variables indicated that delusions of control (OR = 3.7, 95% CI = 1.21-11.61) and the combined use of cannabis and alcohol (OR = 6.89, 95% CI = 1.28-37.05) were two significant predictors of violent behaviour in this schizophrenia population. No association was found between the tested polymorphisms and violent behaviour. CONCLUSIONS Although the sample size may have limited power to exclude a minor role for these specific gene variants, such a small contribution would have limited clinical relevance given the strong significance of the non-genetic markers. These findings suggest that currently proactive management of violent behaviour in this schizophrenia population should continue to be based on clinical predictors of violence.