OCD genetics


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(Updated 8/9/04)

Grados MA, Walkup J, Walford S.
Genetics of obsessive-compulsive disorders: new findings and challenges.
Brain Dev. 2003 Dec;25 Suppl 1:S55-61.
"A review of the current state of research in the genetics of obsessive-compulsive disorder (OCD) is presented. OCD is a neuropsychiatric condition that affects 1-2% of the population and often has an early age at onset of symptoms. OCD has been shown to be familial, and a major gene effect has been reported. However, phenotypic and genetic heterogeneity of OCD poses multiple challenges for locating susceptibility genes. Strategies such as the use of phenotypic subtyping (using tic disorders or other anxiety disorders) and endophenotyping based on brain mechanisms underlying OCD (functional brain imaging and neuropsychological measures) may open ways to understand the genetic components of OCD. Using child probands and extended families for linkage an association studies is another venue to obtain greater informative families for genetic studies. A better understanding of environmental triggers, OCD subtypes and OCD pathophysiology will lead to locating genes that confer risk to OCD." [Abstract]

Wolff M, Alsobrook JP 2nd, Pauls DL.
Genetic aspects of obsessive-compulsive disorder.
Psychiatr Clin North Am 2000 Sep;23(3):535-44
"Developments in molecular genetic methods have proved to be powerful tools in the search for genes involved in complex diseases, and they hold the promise of understanding the genetic basis of OCD. The next step in understanding the genetics of OCD is the localization and characterization of the genes that confer susceptibility. A more complete understanding of the genetic basis of OCD and of the interactions between relevant genotypes and relevant environmental factors is important for clarification of the cause, pathogenesis, and treatment of this complex disorder. These genetic methods must be combined with careful clinical and epidemiologic work to correctly elucidate the cause of OCD. Future research also should define subsets of endophenotypes of the disorder. Factors such as neuropsychological functioning, personality testing, comorbidity, and age of onset are extremely useful in the continued study of genetic mechanisms involved in the cause of OCD." [Abstract]

Alsobrook II JP, Leckman JF, Goodman WK, Rasmussen SA, Pauls DL.
Segregation analysis of obsessive-compulsive disorder using symptom-based factor scores.
Am J Med Genet 1999 Dec 15;88(6):669-75
"Obsessive-compulsive disorder (OCD) is a complex psychiatric disorder characterized by recurring obsessions or compulsions that cause significant distress to the patient or significantly interfere with the patient's normal home, work, or social activities [Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC: American Psychiatric Association, 1994]. Twin and family studies have suggested that OCD has a significant genetic component. We performed complex segregation analyses using POINTER with families ascertained through an OCD-affected proband. In an attempt to resolve the phenotypic heterogeneity observed among individuals with OCD these segregation analyses used four factor-analytic symptom dimensions to subset the family sample based upon probands' symptom factor scores. Analysis of the entire sample allowed rejection of only the no transmission model; that model was also rejected in all subsequent analyses. Limiting the analyses to families with at least one OCD-affected member in addition to the proband (the demonstrably familial form of OCD) allowed rejection of all models except the mixed model. Analyses limited to families of high-factor-3 (symmetry and ordering symptoms) probands led to rejection of the polygenic model, indicating the involvement of a major locus. Additionally, the relative risk of OCD or subclinical OCD was 1.7 for relatives of probands with a factor 3 score greater than zero compared with relatives of probands with a low factor score. The symptoms attributed to high factor 3 scores (symmetry and ordering) may constitute a genetically significant symptomatic subtype of OCD." [Abstract]

Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M.
Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder.
Am J Hum Genet. 2003 Aug;73(2):370-6. Epub 2003 Jun 27.
"We evaluated a possible association between the brain-derived neurotrophic factor (BDNF) gene and susceptibility to obsessive-compulsive disorder (OCD) by genotyping a number of single-nucleotide polymorphisms (SNPs) and one microsatellite marker from the extended BDNF locus in 164 triads with OCD. Extensive background linkage disequilibrium was observed at this locus. Single-locus transmission-distortion tests revealed significant evidence of association with the disease for all the BDNF gene markers tested, including a Val66Met variation affecting the sequence of the proBDNF protein. Analysis of multi-SNP haplotypes provided similar results. Haplotype transmission comparisons in this and previous studies point to a functionally distinct BDNF haplotype uniquely marked by the rare Met66 allele, which is undertransmitted and likely confers a protective effect in OCD and other psychiatric disorders."

Walitza S, Wewetzer C, Warnke A, Gerlach M, Geller F, Gerber G, Gorg T, Herpertz-Dahlmann B, Schulz E, Remschmidt H, Hebebrand J, Hinney A.
5-HT(2A) promoter polymorphism -1438G/A in children and adolescents with obsessive-compulsive disorders.
Mol Psychiatry 2002;7(10):1054-7
"Positive association between obsessive compulsive disorder (OCD) and the A-allele of the 5-HT(2A)-receptor promoter polymorphism -1438G/A has recently been reported in adults. We performed an association analysis of this polymorphism in 55 children and adolescents with OCD and in 223 controls consisting of unrelated students. We detected statistically significant differences in genotype (P < 0.05) and allele frequencies (P < 0.05) between individuals with OCD and controls. In this, to our knowledge, first association study based on children and adolescents with OCD, we confirm an association of the A-allele of the 5-HT2A receptor gene with OCD." [Abstract]

Enoch MA, Greenberg BD, Murphy DL, Goldman D.
Sexually dimorphic relationship of a 5-HT2A promoter polymorphism with obsessive-compulsive disorder.
Biol Psychiatry 2001 Feb 15;49(4):385-8
"BACKGROUND: In an earlier analysis of 73 subjects from this study, the reduced activity catechol O-methyltransferase variant was shown to be associated with obsessive-compulsive disorder in men only. We hypothesized that the 5-HT2A promoter polymorphism, -1438G>A, previously associated with anorexia nervosa, would be more abundant in women with obsessive-compulsive disorder. METHODS: One hundred and one Caucasian obsessive-compulsive disorder patients (48 women, 53 men) and 138 control subjects (77 women, 61 men), were genotyped. DSM-III-R psychiatric diagnoses were assigned based on the SCID-I. RESULTS: As hypothesized, the -1438A allele frequency was higher in obsessive-compulsive disorder women (.57) than female control subjects (.42) (p =.015). The genotype frequencies were also significantly different (p =.020). Allele frequencies did not differ between male obsessive-compulsive disorder patients (.44) and male control subjects (.41). CCONSLUSIONS: We have found that a 5-HT2A promoter polymorphism is associated with obsessive-compulsive disorder in women but not in men, strengthening the argument that there may be fundamental gender differences in the genetic susceptibility to obsessive-compulsive disorder." [Abstract]

Tot S, Erdal ME, Yazici K, Yazici AE, Metin O.
T102C and -1438 G/A polymorphisms of the 5-HT2A receptor gene in Turkish patients with obsessive-compulsive disorder.
Eur Psychiatry. 2003 Aug;18(5):249-54.
"OBJECTIVE: This study aimed to investigate the possible association between T102C and -1438 G/A polymorphism in the 5-HT2A receptor gene and susceptibility to and clinical features of obsessive-compulsive disorder (OCD). METHOD: Fifty-eight patients with OCD and 83 healthy controls were included in the study. All patients were interviewed and rated by Yale-Brown Obsessive-Compulsive Scale. T102C and -1438 G/A polymorphisms of 5-HT2A receptor gene were determined by PCR technique in DNAs of peripheral leucocytes. RESULTS: OCD patients and healthy controls did not show significant differences in genotype distribution for both polymorphisms investigated. We found that frequencies of the TT genotype for T102C polymorphism and the AA genotype for -1438 G/A polymorphism were significantly higher in patients with severe OCD compared to those with moderate or moderate-severe OCD. CONCLUSION: The -1438 G/A and T102C polymorphisms of the 5-HT2A receptor gene are not associated with an increased risk of OCD. Our data suggest that the TT genotype of T102C and the AA genotype of -1438 G/A polymorphism might be a factor in clinical severity of OCD." [Abstract]

Huang Y, Liu X, Li T, Guo L, Sun X, Xiao X, Ma X, Wang Y, Collier DA.
[Cases-Control association study and transmission disequilibrium test of T102C polymorphism in 5HT2A and Tourette syndrome]
Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2001 Feb;18(1):11-3
"OBJECTIVE: To investigate whether T102C polymorphism in 5HT2A (serotonin receptor 2A) is associated with Tourette syndrome. METHODS: Both case-control association analysis and Transmission Disequilibrium Test(TDT), in addition to polymerase chain reaction and RFLP technique were used in 157 trios with Tourette syndrome (TS) and 120 controls. A semi-structured "Schedule for Tourette and other behavioral syndrome" was used in family history-collecting. Both the criteria of "Diagnostic and Statistical Manual of Mental Disorders"(DSM-IV) and that of Tourette syndrome association (TSA) were used in the diagnosis of Tourette syndrome and related disorders. RESULTS: The association between T102C polymorphism in 5HT2A and Tourette syndrome comorbided with obsessive compulsive disorder (OCD) was found by genotype-wise analysis (chi(2)=8.38,P=0.004) and allele-wise analysis (chi(2)=4.84,P=0.028), which was further confirmed by TDT analysis (chi(2)=5.12,P=0.02). No evidence of association or transmission disequilibrium between 102T/C polymorphism in 5HT2A and this disease in pure TS and total TS sample was found. CONCLUSION: 102T/C polymorphism in 5HT2A is exclusively associated with Tourette syndrome comorbided with DSM-IV OCD, which may constitute an independent subtype of Tourette syndrome." [Abstract]

Meira-Lima I, Shavitt RG, Miguita K, Ikenaga E, Miguel EC, Vallada H.
Association analysis of the catechol-o-methyltransferase (COMT), serotonin transporter (5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive-compulsive disorder.
Genes Brain Behav. 2004 Apr;3(2):75-9.
"Family and twin studies have supported a strong genetic factor in the etiology of obsessive-compulsive disorder (OCD), although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. In this cross-sectional study, we have examined the allelic and genotypic frequencies of a Val-158-Met substitution in the COMT gene, a 44-base pair (bp) length variation in the regulatory region of the serotonin transporter gene (5-HTTLPR) and the T102C and C516T variants in the serotonin receptor type 2A (5HT2A) gene in 79 OCD patients and 202 control subjects. There were no observed differences in the frequencies of allele and genotype between patients and control groups for the COMT, the 5HTTLPR and the T102C 5HT2A gene polymorphisms. In contrast, a statistically significant difference between OCD patients and controls was observed on the genotypic distribution (chi(2) = 16.7, 2df, P = 0.0002) and on the allelic frequencies (chi(2) = 15.8, 1df, P = 0.00007) for the C516T 5HT2A gene polymorphism. The results suggest that the C516T variant of the 5HT2A gene may be one of the genetic risk factors for OCD in our sample. However, further studies using larger samples and family based methods are recommended to confirm these findings." [Abstract]

Mundo E, Richter MA, Zai G, Sam F, McBride J, Macciardi F, Kennedy JL.
5HT1Dbeta Receptor gene implicated in the pathogenesis of Obsessive-Compulsive Disorder: further evidence from a family-based association study.
Mol Psychiatry 2002;7(7):805-9
"Obsessive-Compulsive Disorder (OCD) is a psychiatric condition with strong evidence for a genetic component and for the involvement of genes of the serotonin system. In a recent family-based association study we reported an association between the G allele of the G861C polymorphism of the 5HT1Dbeta receptor gene and OCD. The aim of the present study was to further investigate for the presence of linkage disequilibrium between each of two polymorphisms of the 5HT1Dbeta receptor gene and OCD in a larger sample of OCD families. In a total of 121 families the G861C and the T371G polymorphisms of the 5HT1Dbeta receptor gene were genotyped using standard protocols. The genotyping data were analyzed with a new extension of the Transmission Disequilibrium Test (FBAT). The phenotypes considered in the analyses were the diagnosis of OCD and two quantitative phenotypes related to the diagnosis and clinically relevant, ie, the age at onset and the severity of OCD symptoms. We confirmed the previously found preferential transmission of the G861 allele to the affected subjects (z = 2.262, P = 0.02). No significant association was found between the polymorphism and the quantitative phenotypes considered. These results represent a confirmation of our previous published study and thus, could have important implications for the role of the 5HT1Dbeta receptor gene in the pathogenesis and treatment of OCD. Further genetic investigations on this marker considering additional polymorphisms and other quantitative phenotypes related to OCD are warranted." [Abstract]

Camarena B, Aguilar A, Loyzaga C, Nicolini H.
A family-based association study of the 5-HT-1Dbeta receptor gene in obsessive-compulsive disorder.
Int J Neuropsychopharmacol. 2004 Mar;7(1):49-53. Epub 2004 Jan 20.
"Pharmacological studies have shown that sumatriptan, a selective ligand of the serotonin 5-HT-1Dbeta autoreceptor, modifies obsessive-compulsive disorder (OCD) symptoms. The current study analysed the G861C polymorphism of the 5-HT-1Dbeta gene in a sample of 72 trios. Genotyping data were analysed using the Family-Based Association Test (FBAT). We did not replicate the previously reported linkage disequilibrium between the G861 variant and OCD. However, a quantitative trait analysis, assessing severity of OCD symptoms and defined as YBOCS score, confirmed the finding that subjects with a preferential transmission of the G861 variant showed higher YBOCS Obsession scores compared to patients carrying the C861 allele. These preliminary findings may indicate that the 5-HT-1Dbeta receptor gene could be involved in the severity of obsession symptoms in OCD. However, it is important to perform the replication of these findings in larger sample sizes of informative families." [Abstract]

Di Bella D, Cavallini MC, Bellodi L.
No association between obsessive-compulsive disorder and the 5-HT(1Dbeta) receptor gene.
Am J Psychiatry 2002 Oct;159(10):1783-5
"OBJECTIVE: Serotonin abnormalities may be involved in the etiopathogenesis of obsessive-compulsive disorder (OCD). The silent G-to-C substitution at nucleotide 861 of the coding region of the 5-HT(1Dbeta) receptor gene may be associated with liability to OCD. The aim of this study was to investigate this association in an Italian OCD study group. METHOD: Genotyping for 5-HT(1Dbeta) was performed for 79 nuclear families of probands with OCD. The transmission/disequilibrium test was used to determine transmission of the alleles from parents to offspring. RESULTS: Of the 79 families, 48 were informative for the analysis, i.e., both parents were genotyped for 5-HT(1Dbeta), and at least one parent was heterozygous. No preferential transmission of either allele of the 5-HT(1Dbeta) gene was observed. CONCLUSIONS: These data do not support a role for the 5-HT(1Dbeta) receptor gene in conferring susceptibility to OCD." [Abstract]

Mundo E, Zai G, Lee L, Parikh SV, Kennedy JL.
The 5HT1Dbeta receptor gene in bipolar disorder: a family-based association study.
Neuropsychopharmacology 2001 Oct;25(4):608-13
"The serotonin (5HT) receptor genes are considered good candidates for Major Depression (MD), Bipolar Disorder (BP), and Obsessive-Compulsive Disorder (OCD). The 5HT1Dbeta receptor gene has at least three polymorphisms known: G861C, T-261G, and the functional T371G (Phe-124-Cys). The aim of this study was to investigate for the presence of linkage disequilibrium between the 5HT1Dbeta receptor gene and BP. Two hundred and ninety probands with DSM-IV BPI, BPII, or Schizoaffective Disorder (Bipolar type) with their living parents were recruited. Genotyping data for the G861C and T371G polymorphisms were analyzed using the Transmission Disequilibrium Test (TDT). One hundred and sixty triads were informative for the TDT on the G861C polymorphism, which showed no preferential transmission of either allele (chi-square = 0.438, df = 1, p =.508). Only four triads were suitable for the analysis on the T371G variant, with the T allele transmitted once and the G allele transmitted four times to the affected. These findings validate further the results of pharmacological studies excluding a direct involvement of the 5HT1Dbeta receptor in the pathogenesis of BP. Further investigations combining genetic and pharmacological strategies are warranted." [Abstract]

Mundo E, Richter MA, Sam F, Macciardi F, Kennedy JL.
Is the 5-HT(1Dbeta) receptor gene implicated in the pathogenesis of obsessive-compulsive disorder?
Am J Psychiatry 2000 Jul;157(7):1160-1
"OBJECTIVE: Obsessive-compulsive disorder (OCD) is a psychiatric condition for which strong evidence of a genetic component and serotonergic system involvement exists. Recent studies have shown that sumatriptan, a selective ligand of the serotonin (5-HT)(1Dbeta) autoreceptor, modifies OCD symptoms. The aim of this study was to investigate the presence of linkage disequilibrium between the 5-HT(1Dbeta) receptor gene, which has a variant caused by a silent G to C substitution at nucleotide 861 of the coding region, and OCD. METHOD: DNA was collected from 67 probands who met DSM-IV criteria for OCD and from their living parents or siblings. Transmission Disequilibrium Test/sib-Transmission Disequilibrium Test analyses were then conducted with the DNA data. RESULTS: Thirty-two families were informative for the analysis, which showed a preferential transmission of the G allele to the affected subjects. CONCLUSIONS: If the results are confirmed, there may be important implications for the 5-HT(1Dbeta) receptor gene in the pathogenesis and treatment of OCD." [Abstract]

Hemmings SM, Kinnear CJ, Niehaus DJ, Moolman-Smook JC, Lochner C, Knowles JA, Corfield VA, Stein DJ.
Investigating the role of dopaminergic and serotonergic candidate genes in obsessive-compulsive disorder.
Eur Neuropsychopharmacol. 2003 Mar;13(2):93-8.
"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." [Abstract]

Azzam A, Mathews CA.
Meta-analysis of the association between the catecholamine-O-methyl-transferase gene and obsessive-compulsive disorder.
Am J Med Genet. 2003 Nov 15;123B(1):64-9.
"Obsessive-compulsive disorder (OCD) is a chronic, severely debilitating mental illness that affects approximately 1-2% of the population. Data from twin and family studies have shown that genetic factors contribute to the expression of the disease. The dopaminergic system has been implicated in the pathogenesis of OCD, and catecholamine-O-methyl-transferase (COMT) is a key modulator of dopaminergic and noradrenergic neurotransmission. The gene for COMT has a common polymorphism that has been shown to be correlated with a three- to fourfold change in enzymatic activity. Several groups have searched for an association between the COMT gene polymorphism and the presence or absence of OCD, with contrasting results. We conducted a systematic review and meta-analysis of both the published literature and unpublished data. Available data were stratified according to the original study design as either case-control or family-based, and two separate meta-analyses were conducted, using both fixed-effects and random-effects models. These analyses showed insufficient evidence to support an association between the COMT gene polymorphism and OCD. Subgroup stratification based on gender generated no statistically significant associations. These results should be considered in any future work correlating the COMT gene with OCD." [Abstract]

Alsobrook JP 2nd, Zohar AH, Leboyer M, Chabane N, Ebstein RP, Pauls DL.
Association between the COMT locus and obsessive-compulsive disorder in females but not males.
Am J Med Genet 2002 Jan 8;114(1):116-20
"A polymorphism in the coding region of catechol-O-methyltransferase gene (COMT) was previously reported to be associated with obsessive-compulsive disorder (OCD), particularly in male probands. We attempted to replicate the previous finding using a family-based genetic design in haplotype relative risk (HRR) and transmission disequilibrium (TDT) analyses. Fifty-six OCD probands and their parents were genotyped for the COMT locus using established methods. Analysis of allele and genotype frequencies between the proband genotypes and the control (parental nontransmitted) genotypes failed to replicate the previous finding of gender divergence, gave no evidence of overall association, nor was linkage detected by TDT. However, further analysis of the COMT allele frequencies by proband gender gave evidence of a mildly significant association with the low-activity COMT allele in female probands (P=0.049), but not in male probands. These findings indicate that COMT may be etiologically relevant to OCD in a gender-specific manner opposite to that shown in previous studies." [Abstract]

Maria Karayiorgou, Margaret Altemus, Brandi L. Galke, David Goldman, Dennis L. Murphy, Jurg Ott, and Joseph A. Gogos
Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder
PNAS 94: 4572-4575, 1997.
"In the present study, we address the role of the gene for catechol-O-methyltransferase (COMT), a key modulator of dopaminergic and noradrenergic neurotransmission, in the genetic predisposition to obsessive-compulsive disorder (OCD). We show that a common functional allele of this gene, which results in a 3- to 4-fold reduction in enzyme activity, is significantly associated in a recessive manner with susceptibility to OCD, particularly in males. This association is further supported by psychiatric evaluation of patients who carry microdeletions encompassing the comt gene. The mechanism underlying this sex-selective association remains to be defined and may include a sexual dimorphism in COMT activity, although close linkage with a nearby disease susceptibility locus cannot be excluded at this point." [Full Text]

Schindler KM, Richter MA, Kennedy JL, Pato MT, Pato CN.
Association between homozygosity at the COMT gene locus and obsessive compulsive disorder.
Am J Med Genet 2000 Dec 4;96(6):721-4
"A functional polymorphism in the coding region of the catechol O-methyltransferase (COMT) gene has been reported in previous studies to be associated with obsessive compulsive disorder (OCD), particularly in males [Karayiorgou et al., 1997, 1999]. Using a family-based population analysis, we attempted to replicate these findings in a group of 72 OCD patient/parent trios collected from Buffalo, New York, and Toronto, Canada. Analysis of allele and genotype frequencies using the haplotype relative risk (HRR) and transmission disequilibrium test (TDT) did not identify an association between a particular allele and OCD as had been previously reported. Furthermore, no evidence was found to support the findings of a gender-based association for COMT when the patients and the parents of the same gender were compared. However, our genotype results (n = 72) demonstrate a tendency for association between homozygosity at the COMT locus and OCD (homozygosity analysis: chi(2) = 5.66, P = 0.017; genotypic analysis: chi(2) = 5.78, P = 0.056). Although these findings do not replicate the previous reports, they do provide limited support to demonstrate a trend for homozygosity at the COMT locus in the OCD patients and, in turn, further implicate a potential role for COMT in the genetic etiology of OCD." [Abstract]

Erdal ME, Tot S, Yazici K, Yazici A, Herken H, Erdem P, Derici E, Camdeviren H.
Lack of association of catechol-O-methyltransferase gene polymorphism in obsessive-compulsive disorder.
Depress Anxiety. 2003;18(1):41-5.
"The COMT gene has been implicated to be involved in the pathogenesis of obsessive-compulsive disorder (OCD) and various other psychiatric disorders. COMT enzyme activity is governed by a common genetic polymorphism at codon 158 that results in substantial 3- to 4-fold variation in enzymatic activity [a high-activity COMT variant (H) and a low activity variant (L)]. This study evaluates the association between OCD and the COMT gene polymorphism. Fifty-nine OCD patients that were diagnosed according to DSM-IV criteria and 114 healthy control subjects were included in the study. PCR technique was used for molecular analysis. The genotypic pattern of distribution of the COMT gene (H/H, H/L, and L/L genotypes) was not different between the OCD patients and controls. There were no significant differences among the patients with positive family history for OCD, those with negative family history for OCD, and the controls with respect to allele frequencies of the COMT gene polymorphisms. Patients that were homozygous or heterozygous for the L allele had significantly higher insight scores (i.e., poorer insight) on Y-BOCS compared to those homozygous for the H allele. We did not find an association between OCD, family history for OCD, and the COMT gene polymorphism. This study suggests that the COMT gene polymorphism is not directly associated with OCD in our patient group." [Abstract]

Niehaus DJ, Kinnear CJ, Corfield VA, du Toit PL, van Kradenburg J, Moolman-Smook JC, Weyers JB, Potgieter A, Seedat S, Emsley RA, Knowles JA, Brink PA, Stein DJ.
Association between a catechol-o-methyltransferase polymorphism and obsessive-compulsive disorder in the Afrikaner population.
J Affect Disord 2001 Jun;65(1):61-5
"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." [Abstract]

Karayiorgou M, Sobin C, Blundell ML, Galke BL, Malinova L, Goldberg P, Ott J, Gogos JA.
Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder.
Biol Psychiatry 1999 May 1;45(9):1178-89
"BACKGROUND: Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1-3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-methyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene modulating monoamine metabolism. METHODS: A sample of 110 nuclear OCD families was collected, and lifetime diagnoses were ascertained using the Diagnostic Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO genes, and allele inheritance was examined using the Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) test. RESULTS: We provide evidence supporting the previously reported sexually dimorphic association between low COMT enzymatic activity and OCD. We also provide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic activity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD probands with co-morbid MDD, who represent more than 50% of our male OCD sample. CONCLUSIONS: Our analysis indicates that variants of two genes modulating monoamine metabolism contribute significantly to OCD susceptibility. Most importantly, an unexpected sexually dimorphic pattern of genetic susceptibility to OCD is revealed and suggests the possibility that profound gender differences in genetic predisposition may exist not only for other OCD susceptibility genes, but for an array of other psychiatric disorders as well." [Abstract]

Camarena B, Rinetti G, Cruz C, Gomez A, de La Fuente JR, Nicolini H.
Additional evidence that genetic variation of MAO-A gene supports a gender subtype in obsessive-compulsive disorder.
Am J Med Genet 2001 Apr 8;105(3):279-82
"Studies have recently reported a sexually dimorphic association between obsessive-compulsive disorder (OCD) and a polymorphism related with variations in MAO-A activity. These observations suggest the possibility of gender differences in genetic susceptibility for OCD. We thus reexamined the MAO-A/EcoRV polymorphism in a sample of 122 OCD patients and 124 healthy subjects. An excess of allele 1 in OCD females with major depression disorder was confirmed as previously reported. This difference was more strongly associated with OCD females than males in the total sample. Finally, we analyzed a sample of 51 OCD trios. Haplotype-based haplotype relative risk (HHRR) analysis of the inheritance of the MAO-A variants revealed in the female probands that 14 out of 19 transmitted the allele 1, providing significant evidence for an allelic association between OCD and MAO-A gene. In conclusion, our findings may provide molecular evidence to identify a clinically meaningful gender subtype. However, an effort should be made to replicate the analysis in larger samples of informative parents using strategies such as transmission disequilibrium test to allow definite conclusions." [Abstract]

Lochner C, Hemmings SM, Kinnear CJ, Moolman-Smook JC, Corfield VA, Knowles JA, Niehaus DJ, Stein DJ.
Gender in obsessive-compulsive disorder: clinical and genetic findings.
Eur Neuropsychopharmacol. 2004 Mar;14(2):105-13.
"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." [Abstract]

Chabane N, Millet B, Delorme R, Lichtermann D, Mathieu F, Laplanche JL, Roy I, Mouren MC, Hankard R, Maier W, Launay JM, Leboyer M.
Lack of evidence for association between serotonin transporter gene (5-HTTLPR) and obsessive-compulsive disorder by case control and family association study in humans.
Neurosci Lett. 2004 Jun 10;363(2):154-6.
"Association studies of the serotonin transporter (SLC6A4) gene in obsessive-compulsive disorder (OCD) have generated discrepant results. Here, we genotyped the 5-HTTLPR polymorphism in 106 French OCD patients and 171 healthy controls (case control study). We also performed a family association study on 116 trios including an OCD patient (73 French and 43 German). No association was detected between the 5-HTTLPR polymorphism and OCD in either the case control study or the family study." [Abstract]

Cavallini MC, Di Bella D, Siliprandi F, Malchiodi F, Bellodi L.
Exploratory factor analysis of obsessive-compulsive patients and association with 5-HTTLPR polymorphism.
Am J Med Genet 2002 Apr 8;114(3):347-53
"The determination of a genetic basis for obsessive-compulsive disorder (OCD) depends on how phenotypic boundaries are defined. Although a hypothesis for serotonin dysfunction in OCD has been advanced, no genes specifically responsible for serotonin regulation have as yet been definitively related to the etiology of OCD. The phenotypic variability of OCD could be at the basis of the failure of molecular biology investigations to find any genes involved in the liability to the disorder. Obsessive and compulsive contents can aggregate in OCD patients differently; multifactorial description may therefore be able to account for OCD phenotypic variance. Using principal component analysis, we derived five factors from 13 main contents of the Yale-Brown Obsessive-Compulsive Scale (YBOCS), and considered them as quantitative phenotypes to evaluate their possible association with an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR). A trend toward positive association between the fifth factor, including counting and repeating rituals, and 5-HTTLPR was found. However, only considering the subgroup of patients with tic codiagnosis, we found a significantly higher score for the fifth factor for patients with L/L genotype with respect to L/S and S/S genotypes." [Abstract]

Di Bella D, Erzegovesi S, Cavallini MC, Bellodi L.
Obsessive-Compulsive Disorder, 5-HTTLPR polymorphism and treatment response.
Pharmacogenomics J 2002;2(3):176-81
"Recently, a role for a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR) in conferring susceptibility to Obsessive Compulsive Disorder (OCD) has been suggested. The aim of this study was to test the hypothesis that allelic variation of the 5-HTTLPR could be associated with OCD susceptibility or influence the drug response in OCD. One hundred and eighty-one OCD patients were recruited; 92 patients underwent a standardized treatment with fluvoxamine. No significant differences in allele/genotype distribution of the 5-HTTLPR were found between 191 controls and OCD. No differences in fluvoxamine response in the three genotypes groups in OCD were found, considering Yale-Brown Obsessive Compulsive Scale (YBOCS) total scores. Nevertheless, a significant time per genotype interaction was found for the YBOCS subtotal compulsion scores. Considering patients without tic disorder co-diagnosis, a significant time per genotype interaction for both YBOCS total scores and compulsion scores was found." [Abstract]

Walitza S, Wewetzer C, Gerlach M, Klampfl K, Geller F, Barth N, Hahn F, Herpertz-Dahlmann B, Gossler M, Fleischhaker C, Schulz E, Hebebrand J, Warnke A, Hinney A.
Transmission disequilibrium studies in children and adolescents with obsessive-compulsive disorders pertaining to polymorphisms of genes of the serotonergic pathway.
J Neural Transm. 2004 Jul;111(7):817-25. Epub 2004 Apr 13.
"Pharmacological and challenge study data showed an involvement of the serotonergic system in the development of obsessive-compulsive disorder (OCD). We studied transmission disequilibrium of polymorphisms in three candidate genes of the serotonergic pathway in 64 trios comprising patients with early onset OCD and both of their parents. Polymorphisms of the following genes were studied: tryptophan hydroxylase 1 (rs1800532), serotonin transporter (polymorphism in the promoter region; 5-HTTLPR) and the serotonin 1 B receptor (rs6296). This is, to our knowledge, one of the first family based association studies pertaining to children and adolescents with OCD. We did not detect transmission disequilibrium of the investigated polymorphisms in OCD. Hence, these polymorphisms do not play a major role in the genetic predisposition to early onset OCD." [Abstract]

Kinnear CJ, Niehaus DJ, Moolman-Smook JC, du Toit PL, van Kradenberg J, Weyers JB, Potgieter A, Marais V, Emsley RA, Knowles JA, Corfield VA, Brink PA, Stein DJ.
Obsessive-compulsive disorder and the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4): a negative association study in the Afrikaner population.
Int J Neuropsychopharmacol 2000 Dec;3(4):327-331
"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." [Abstract]

Bengel D, Greenberg BD, Cora-Locatelli G, Altemus M, Heils A, Li Q, Murphy DL.
Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder.
Mol Psychiatry 1999 Sep;4(5):463-6
"Although modulation of symptoms of obsessive-compulsive disorder (OCD) by serotonergic agents is well established, it is unclear whether an abnormality in the central serotonergic system is involved in its etiology. The serotonin (5-HT) transporter (5-HTT), which is the key modulator of serotonergic neurotransmission, is the target for serotonin reuptake inhibiting drugs (SRIs) that are uniquely effective in the treatment of OCD. In this preliminary study we report an association of a functional polymorphism in the 5-HTT 5' regulatory-region and OCD. Seventy-five OCD Caucasian patients and 397 ethnically-matched individuals from a non-patient control group were genotyped for the 5-HTTLPR. Population-based association analysis revealed that patients with OCD were more likely to carry two copies of the long allele (l) as compared to controls (46.7% vs 32.3%: chi2 = 5.19, P = 0.023). This finding replicates a recent family-based study of this polymorphism in OCD, and thus indicates that the 5-HTTLPR may be associated with susceptibility to OCD." [Abstract]

McDougle CJ, Epperson CN, Price LH, Gelernter J.
Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder.
Mol Psychiatry 1998 May;3(3):270-3
"Obsessive compulsive disorder (OCD) is characterized by recurrent and intrusive thoughts that are distressing (obsessions) and/or repetitive behaviors or mental acts that the person feels driven to perform (compulsions). OCD has a partly genetic basis. For treatment of OCD, potent serotonin reuptake inhibitor (SRI) drugs (clomipramine (Anafranil), fluvoxamine (Luvox), fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil)), which act on the serotonin transporter protein, are uniquely efficacious. A polymorphism in the promoter region of the gene (SLC6A4) encoding this protein, was recently reported to affect protein expression and to be associated with measures of anxiety and depression and with autism (using a family-controlled transmission disequilibrium test (TDT) design). SLC6A4 therefore has strong a priori support for potentially influencing risk for OCD: the protein it encodes is a medication target; a polymorphism in the gene affects function; and that polymorphism has been shown to be associated with behavioral phenotypes. We used the TDT with a set of 34 European-American family trios, 30 unrelated and four drawn from an extended pedigree, to test for linkage disequilibrium between OCD and alleles at the SLC6A4 promoter polymorphic locus. Of 35 heterozygous parents, 24 transmitted the 'l' SLC6A4 allele and 11 transmitted the 's' allele (chi 2 TDT = 4.83; P < 0.03). Considering only the 13 SRI drug nonresponders, there were 13 heterozygous parents, of whom 10 transmitted the 'l' allele and three the 's' allele (chi 2 TDT = 3.77; P < 0.052). These data provide preliminary support for association and linkage disequilibrium between the SLC6A4 'l' allele and OCD." [Abstract]

Billett EA, Richter MA, King N, Heils A, Lesch KP, Kennedy JL.
Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene.
Mol Psychiatry 1997 Sep;2(5):403-6
"Obsessive compulsive disorder (OCD) is a common illness, characterized by anxiety-provoking thoughts and the need to perform rituals. OCD is most commonly treated with a class of pharmacological agents known as serotonin reuptake inhibitors (SRIs). SRIs block the reuptake of serotonin (5-HT) into the presynaptic neuron, a process mediated by the serotonin transporter (5-HTT). The successful use of SRIs in OCD has led to the hypothesis that 5-HTT may play a pivotal role in the pathogenesis of OCD. We decided to study this hypothesis from a genetic perspective, because family and twin studies suggest that there is a strong genetic component to OCD. In addition, the sequence of the gene for 5-HTT is available, and a 44-bp insertion/deletion polymorphism has been detected in the promoter region of the gene. There is evidence that this polymorphism alters expression of the transporter protein. We typed 72 OCD patients and 72 matched controls, and found no statistically significant difference between the two groups (chi 2 = 4.319, P = 0.115, 2 d.f.). We observed however a trend towards increased homozygosity in the patient group. We also rated (retrospectively) the patients' clinical responses to SRIs. No association was observed between these ratings and the promoter region polymorphism in the serotonin transporter gene. Given the pharmacological evidence favoring a role for 5-HTT in OCD and SRI response, further genetic evaluation of the serotonin transporter in OCD is indicated." [Abstract]

Altemus M, Murphy DL, Greenberg B, Lesch KP.
Intact coding region of the serotonin transporter gene in obsessive-compulsive disorder.
Am J Med Genet 1996 Jul 26;67(4):409-11
"Epidemiologic studies indicate that obsessive-compulsive disorder is genetically transmitted in some families, although no genetic abnormalities have been identified in individuals with this disorder. The selective response of obsessive-compulsive disorder to treatment with agents which block serotonin reuptake suggests the gene coding for the serotonin transporter as a candidate gene. The primary structure of the serotonin-transporter coding region was sequenced in 22 patients with obsessive-compulsive disorder, using direct PCR sequencing of cDNA synthesized from platelet serotonin-transporter mRNA. No variations in amino-acid sequence were found among the obsessive-compulsive disorder patients or healthy controls. These results do not support a role for alteration in the primary structure of the coding region of the serotonin-transporter gene in the pathogenesis of obsessive-compulsive disorder." [Abstract]

Kinnear C, Niehaus DJ, Seedat S, Moolman-Smook JC, Corfield VA, Malherbe G, Potgieter A, Lombard C, Stein DJ.
Obsessive-compulsive disorder and a novel polymorphism adjacent to the oestrogen response element (ERE 6) upstream from the COMT gene.
Psychiatr Genet 2001 Jun;11(2):85-7
"Family and twin studies have consistently provided evidence for involvement of genetic mechanisms in obsessive-compulsive disorder (OCD). This has given rise to association studies involving several candidate genes in an endeavour to identify susceptibility factors. One of the more promising candidate genes appears to be the catecol-O-methyltransferase (COMT) gene. Recent association studies in North American and Afrikaner populations have reported a likely association between a functional polymorphism of COMT (linked with COMT enzyme activity levels) and OCD. COMT expression has been demonstrated to be regulated by oestrogen through the oestrogen-response elements (EREs) in the promoter region of the gene. In the light of this association, the authors tested for an association between a novel polymorphism (C --> T transition) adjacent to ERE 6 in the promoter area of COMT and OCD in 48 Afrikaners and 48 ethnically matched controls. The C --> T transition was not significantly associated with OCD (P = 0.93) or gender (P = 0.67). These findings, although limited by a small sample size, suggest that the novel polymorphism adjacent to ERE 6 in the promoter area of COMT does not play a major role in the genetic predisposition to OCD." [Abstract]

Zai G, Bezchlibnyk YB, Richter MA, Arnold P, Burroughs E, Barr CL, Kennedy JL.
Myelin oligodendrocyte glycoprotein (MOG) gene is associated with obsessive-compulsive disorder.
Am J Med Genet. 2004 Aug 15;129B(1):64-8.
"Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric disorder with a strong genetic component, and may involve autoimmune processes. Support for this latter hypothesis comes from the identification of a subgroup of children, described by the term pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS), with onset of OCD symptoms following streptococcal infections. Genes involved in immune response therefore represent possible candidate genes for OCD, including the myelin oligodendrocyte glycoprotein (MOG) gene, which plays an important role in mediating the complement cascade in the immune system. Four polymorphisms in the MOG gene, a dinucleotide CA repeat (MOG2), a tetranucleotide TAAA repeat (MOG4), and 2 intronic single nucleotide polymorphisms, C1334T and C10991T, were investigated for the possibility of association with OCD using 160 nuclear families with an OCD proband. We examined the transmission of alleles of these four polymorphisms with the transmission disequilibrium test (TDT). A biased transmission of the 459-bp allele (allele 2: chi2 = 5.255, P = 0.022) of MOG4 was detected, while MOG2, C1334T, and C10991T showed no statistically significant bias in the transmission of alleles. The transmission of the C1334T.MOG2.C10991T.MOG4 haplotype (chi2 = 6.426, P = 0.011) was also significant. Quantitative analysis using the family-based association test (FBAT) was significant for MOG4 in total Yale-Brown Obsessive-Compulsive Scale severity score (allele 2: z = 2.334, P = 0.020). Further investigations combining genetic, pathological, and pharmacological strategies, are warranted." [Abstract]

Millet B, Chabane N, Delorme R, Leboyer M, Leroy S, Poirier MF, Bourdel MC, Mouren-Simeoni MC, Rouillon F, Loo H, Krebs MO.
Association between the dopamine receptor D4 (DRD4) gene and obsessive-compulsive disorder.
Am J Med Genet 2003 Jan 1;116(1 Suppl):55-9
"Obsessive-compulsive disorder (OCD) is a frequent and disabling anxiety disorder. Dopamine (DA) might be involved in its pathophysiology, therefore DA receptors are candidate genes in OCD. A 48-base pairs (bp) polymorphism located in the third exon of the dopamine receptor type 4 (DRD4) gene has been described. Previous case control studies, however, have reported inconclusive results in OCD. The aim of the study was to study this polymorphism in a family-based association study of 55 trios. Extended transmission-disequilibrium test (ETDT) for preferential allele transmission in this group showed an absence of transmission of the allele 2 for the 48 bp repeat polymorphism of the DRD4 gene (P = 0.005). Moreover, in a population-based association study, we found a significantly lower frequency of the allele 2 in patients suffering from OCD compared to ethnically-matched controls (P = 0.02). We found no association of DRD4 48 bp polymorphism with OCD in the subgroup of patients with comorbid tics. This study is the first to report on a significant association of variants of the DRD4 gene in OCD, found on both family- and population-based studies. The results suggest that the 2 allele or a nearby genetic variation could have a protective effect against OCD symptoms." [Abstract]

Di Bella D, Catalano M, Cichon S, Nothen MM.
Association study of a null mutation in the dopamine D4 receptor gene in Italian patients with obsessive-compulsive disorder, bipolar mood disorder and schizophrenia.
Psychiatr Genet 1996 Fall;6(3):119-21
"Although serotonergic dysregulation is a leading pathogenetic hypothesis for obsessive-compulsive disorder (OCD), some evidence also suggests a possible dysregulation of the dopaminergic system in this disorder. Therefore, individual differences in deoxyribonucleic acid (DNA) coding for dopamine receptor proteins might contribute to the genetic background of this disorder. Previously we reported a null mutation in exon 1 of the dopamine D4 receptor gene. The variant type is characterized by a 13 bp deletion and is predicted to code for a truncated, non-functional receptor. We assessed the frequency of this polymorphism in 157 OCD patients, 196 schizophrenics, 111 bipolars and 162 healthy controls of Italian descent. Our findings do not implicate a role for this mutation in conferring a susceptibility to OCD and confirm previous negative results regarding its involvement in schizophrenia and bipolar disorder." [Abstract]

Billett EA, Richter MA, Sam F, Swinson RP, Dai XY, King N, Badri F, Sasaki T, Buchanan JA, Kennedy JL.
Investigation of dopamine system genes in obsessive-compulsive disorder.
Psychiatr Genet 1998 Autumn;8(3):163-9
"Evidence from anatomical, pharmacological, and animal studies on the involvement of the dopamine system in obsessive-compulsive disorder (OCD) is mounting. This, along with evidence for a genetic diathesis provided by family and twin studies, prompted us to conduct genetic association studies of dopamine system genes in OCD. We genotyped OCD patients (n > 100) and matched controls for four loci: (1) a 40-base-pair repeat in the dopamine transporter gene; (2) the TaqIA polymorphism and the serine/cysteine variation in the D2 dopamine receptor gene; (3) an MscI polymorphism in the D3 dopamine receptor gene; and (4) a 48-base-pair repeat in the D4 dopamine receptor gene. Significant differences in allele frequencies were found between patients and controls for the D4 receptor gene, although replication is required with family-based controls before any conclusions can be entertained. This study represents the first comprehensive assessment of the roles of dopamine system genes in OCD." [Abstract]

Joyce PR, Rogers GR, Miller AL, Mulder RT, Luty SE, Kennedy MA.
Polymorphisms of DRD4 and DRD3 and risk of avoidant and obsessive personality traits and disorders.
Psychiatry Res. 2003 Jul 15;119(1-2):1-10.
"We investigated whether polymorphisms of the dopamine D4 receptor (DRD4) and polymorphisms of the dopamine D3 receptor (DRD3) were associated with personality disorder symptomatology rather than with personality traits such as novelty seeking. DNA was obtained from 145 depressed patients in a clinical trial. These patients were assessed for the presence of personality disorder symptoms and disorders. The 2-repeat allele of the DRD4 exon III polymorphism was associated with increased rates of avoidant and obsessive personality disorder symptomatology. The T,T genotype of the DRD4 -521 C>T polymorphism was also associated with increased rates of avoidant and obsessive personality disorder symptomatology. The Gly9,Gly9 genotype of the DRD3 Ser9Gly polymorphism was associated with increased rates of obsessive personality disorder symptomatology. None of these three polymorphisms were associated with novelty seeking or other temperament traits on the Temperament and Character Inventory. Our results suggest that genetic polymorphisms of DRD4 and DRD3 may well be associated with personality traits, and that conflicting findings to date may arise from the problem of phenotype definition." [Abstract]

Nicolini H, Cruz C, Paez F, Camarena B.
[Dopamine D2 and D4 receptor genes distinguish the clinical presence of tics in obsessive-compulsive disorder]
Gac Med Mex 1998 Sep-Oct;134(5):521-7
"An allelic association study between dopamine receptor gene polymorphisms D2 (DRD2) and D4 (DRD4), in obsessive-compulsive patients (OCD) with or without chronic motor or vocal tics (OCD+ or OCD-) was performed. Molecular genotypes were obtained using the polymerase chain reaction method (PCR) in 66 patients diagnosed according DSMIV criteria, 12/66 OCD patients presented tics, 54 Control subjects were also typed. OCD patients with tics compared to control had a higher frequency of TaqI A2 allele (p = 0.014); and an excess of homozygous individuals A2A2 (p = 0.001). In DRD4 genes polymorphisms, allele 7 showed a higher prevalence and frequency in those OCD+ tics compared to OCD- tics (91% vs. 48%). Most of the OCD patients with tics compared to those without tics showed an increased frequency of the DRD2-A2 (58% vs 27% respectively, p = 0.048) as well as an increased frequency of the DRD4-7-fold variant (48% in OCD with tics vs 9% in OCD without tics, p = 0.018). Similarly, when both alleles were combined (at least one copy of DRD2-A2 and DRD4-R7), patients with tics showed a higher frequency of this haplotype (83.3% vs. 40%, p = 0.016). OCD patients with tics may represent a different clinical and genetic subtype of the disorder." [Abstract]

Cruz C, Camarena B, King N, Paez F, Sidenberg D, de la Fuente JR, Nicolini H.
Increased prevalence of the seven-repeat variant of the dopamine D4 receptor gene in patients with obsessive-compulsive disorder with tics.
Neurosci Lett 1997 Aug 1;231(1):1-4
"The polymorphism characterized by a varying number of 48 bp repeats (VNTR) in the dopamine D4 receptor (DRD4) gene was examined in 61 obsessive-compulsive disorder (OCD) probands with and without tics. Most of the OCD patients with tics showed at least one copy of the 7-fold variant compared to those affected subjects without tics (91 vs. 48%, respectively, Yates corrected chi2 = 5.54, P = 0.018). Similarly, a higher number of copies of this common variant were detected in the group of probands displaying tics compared to those OCD's without tics (Yates corrected chi2 = 4.66, P = 0.03). Our study suggests that the seven-repeat allele of the DRD4 gene could be a factor in the phenotypic variance of tics among OCD individuals." [Abstract]

Nicolini H, Cruz C, Camarena B, Orozco B, Kennedy JL, King N, Weissbecker K, de la Fuente JR, Sidenberg D.
DRD2, DRD3 and 5HT2A receptor genes polymorphisms in obsessive-compulsive disorder.
Mol Psychiatry 1996 Dec;1(6):461-5
"We performed an association analysis of the DRD2, DRD3 and 5HT2A genes polymorphisms in 67 Obsessive-Compulsive Disorder (OCD) patients and 54 healthy controls. There were no statistically significant differences in genotype or allele frequencies for any of the polymorphisms studied between OCD subjects and controls. For the subgrouped analysis, no results were significant after correction for multiple testing, although homozygosity of DRD2/A2A2 in subjects displaying vocal or motor tics approached significance compared to controls (Fisher exact test, P = 0.008). Our results may follow the notion that OCD patients with tics represent a different genetic subtype of the disease." [Abstract]

Catalano M, Sciuto G, Di Bella D, Novelli E, Nobile M, Bellodi L.
Lack of association between obsessive-compulsive disorder and the dopamine D3 receptor gene: some preliminary considerations.
Am J Med Genet 1994 Sep 15;54(3):253-5
"Controversial results possibly suggesting an association between Tourette's Syndrome (TS) and excess of homozygosity at a Msc I polymorphism in the Dopamine D3 receptor (DRD3) gene have recently been reported. Since a relationship between Obsessive-Compulsive Disorder (OCD) and Tourette's Syndrome (TS) has been suggested, in this study we assessed the frequency of this 2-allele polymorphism in a sample of 97 OCD patients and in 97 control subjects. No statistically significant differences in allele or genotype frequencies were found. Thus this mutation in the coding sequence of the DRD3 gene is unlikely to confer susceptibility to OCD." [Abstract]

Novelli E, Nobile M, Diaferia G, Sciuto G, Catalano M.
A molecular investigation suggests no relationship between obsessive-compulsive disorder and the dopamine D2 receptor.
Neuropsychobiology 1994;29(2):61-3
"Some studies suggest a relationship between obsessive-compulsive disorder (OCD) and Gilles de la Tourette's syndrome. The pathophysiology of the latter may involve the dopamine system. We screened three important exons of the dopamine D2 receptor (DRD2) gene for mutations in a group of OCD patients with or without tics. No structural changes were found, suggesting no relationship between DRD2 and OCD. Moreover, the frequency of the polymorphism in exon 6 was different from that found in schizophrenics." [Abstract]

Frisch A, Michaelovsky E, Rockah R, Amir I, Hermesh H, Laor N, Fuchs C, Zohar J, Lerer B, Buniak SF, Landa S, Poyurovsky M, Shapira B, Weizman R.
Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways.
Eur Neuropsychopharmacol 2000 May;10(3):205-9
"Obsessive-compulsive disorder (OCD) is a severe and disabling anxiety disorder with a marked genetic contribution. Pharmacological data indicated involvement of the serotonergic and dopaminergic systems. We studied the association between OCD and six candidate genes encoding important components of the serotonergic and dopaminergic pathways in 75 biologically unrelated patients and 172 ethnically matched controls (Ashkenazi and non-Ashkenazi Jews). Polymorphisms in the following genes were studied: tryptophan hydroxylase (TPH), serotonin 2A receptor (HTR2A), serotonin 2C receptor (HTR2C), serotonin transporter (5-HTT), dopamine receptor D4 (DRD4), and dopamine transporter (DAT1). The genotypic and allelic distribution of all polymorphisms tested did not show statistically significant differences between patients and controls. Our results suggest that these polymorphisms do not play a major role in the genetic predisposition to OCD, although a minor contribution cannot be ruled out." [Abstract]

Cavallini MC, Di Bella D, Pasquale L, Henin M, Bellodi L.
5HT2C CYS23/SER23 polymorphism is not associated with obsessive-compulsive disorder.
Psychiatry Res 1998 Feb 9;77(2):97-104
"A great deal of evidence suggests that a genetic component underlies obsessive-compulsive disorder (OCD). The response to serotonergic medications and the worsening of obsessive symptoms after administration of serotonergic agonists indicate that serotonergic mechanisms are involved in OCD. We investigated the role of the Cys23Ser mutation of the 5HT2C receptor gene in the etiology of this disorder by performing an association study comparing a sample of 109 OCD patients with a sample of 107 healthy control subjects. No allelic or genotypic association of OCD with the 5HT2C receptor gene mutation was revealed in our data. We also extended the association analysis to a subsample of 39 OCD patients that had previously been submitted to a challenge test with clomipramine. In the subsample of OCD patients that received the challenge with clomipramine, no association between the 5HT2C receptor gene mutation and response to the challenge test was found. Our results exclude any specific role of the Cys23Ser mutation of 5HT2C receptor gene in the etiology of OCD: it seems probable that more complex genetic models are needed to explain the involvement of serotonergic elements in the etiology of this disorder." [Abstract]

Arnold PD, Rosenberg DR, Mundo E, Tharmalingam S, Kennedy JL, Richter MA.
Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study.
Psychopharmacology (Berl). 2004 Apr 9 [Epub ahead of print]
"RATIONALE. Recent investigation suggests that a reversible glutamatergically mediated thalamocortical-striatal dysfunction may serve as a reliable pathophysiological and treatment response marker for obsessive-compulsive disorder (OCD). We postulated that N-methyl- d-aspartate (NMDA) receptors were involved in OCD, and specifically that polymorphisms in the 3' untranslated region of GRIN2B (glutamate receptor, ionotropic, N-methyl- d-aspartate 2B) were associated with OCD in affected families. OBJECTIVES. The objective of this investigation was to test the association between GRIN2B variants and transmission of the OCD trait using a family-based design. METHODS. Using the Family Based Association Test (FBAT), we tested for association with OCD diagnosis in 130 families, and also performed a haplotype analysis. FBAT was additionally used in a subset of 98 families to test for association with the quantitative phenotype of lifetime OCD symptom severity. RESULTS. Under a non-additive model of inheritance, the 5072T/G variant was significantly associated with OCD even after correcting for the number of models tested ( P=0.014). In addition, there was a significant positive association with OCD diagnosis ( P=0.002) for the 5072G-5988T haplotype under the recessive model. CONCLUSIONS. Although preliminary and requiring replication in larger samples, these results provide evidence that GRIN2B may be associated with susceptibility to OCD. Coupled with basic neuroscience and clinical neuroimaging findings in patients with OCD, our results provide new and converging support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD." [Abstract]

Delorme R, Krebs MO, Chabane N, Roy I, Millet B, Mouren-Simeoni MC, Maier W, Bourgeron T, Leboyer M.
Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder.
Neuroreport. 2004 Mar 22;15(4):699-702.
"Several lines of evidence suggest that obsessive compulsive disorder (OCD) could be the consequence of glutamatergic dysfunction. We performed a case-control study in 156 patients and 141 controls and the transmission disequilibrium test in 124 parent-offspring trios to search for association between OCD and two kainate receptors, GRIK2 and GRIK3. Using three single nucleotide polymorphisms (SNP) in GRIK2 and one in GRIK3, we found no evidence for association in case-control or family-based analyses. Only the GRIK2 SNP I867, recently associated with autism, was less transmitted than expected (p < 0.03), supporting a functional role for this variant. These findings suggest the need for further investigation of the role of GRIK2 in OCD." [Abstract]

Urraca N, Camarena B, Gomez-Caudillo L, Esmer MC, Nicolini H.
Mu opioid receptor gene as a candidate for the study of obsessive compulsive disorder with and without tics.
Am J Med Genet. 2004 May 15;127B(1):94-6.
"Obsessive compulsive disorder (OCD) is a complex psychiatric disease characterized by recurring obsessions or compulsions that cause significant distress to the patient. The etiology of this disorder remains largely unknown, although a genetic component has been suggested. Many candidates genes have been evaluated based on a possible serotoninergic and dopaminergic brain dysfunction. We postulate the micro opioid receptor (MOR) gene as a candidate because some observations support a role of the opioid system in OCD. The opioid antagonist, naloxone, rapidly exacerbates OCD symptoms and the opioid agonist, tramadol, was reported to be effective in the treatment of some patients. We studied two single nucleotide polymorphisms (C17T and A118G) in 51 trios with OCD. Genotyping was analyzed with transmission desequilibrium test (TDT). The allelic variant +17T of the C17T polymorphism had a low frequency (1%) in our population that did not allow for statistic analysis. However, for the allelic variant +G of the A118G polymorphism we were able to performed statistical comparisons. Our results showed a trend toward significance (chi(2) McNemar = 3.6, P = 0.065) for TDT in patients with comorbid tics. It is an interesting finding that should be tested in a larger sample of OCD patients with tics." [Abstract]

Hudziak JJ, Van Beijsterveldt CE, Althoff RR, Stanger C, Rettew DC, Nelson EC, Todd RD, Bartels M, Boomsma DI.
Genetic and environmental contributions to the Child Behavior Checklist Obsessive-Compulsive Scale: a cross-cultural twin study.
Arch Gen Psychiatry. 2004 Jun;61(6):608-16.
"CONTEXT: We have reported elsewhere on the development of an 8-item Obsessive-Compulsive Scale (OCS) contained in the Child Behavior Checklist (CBCL) to identify children who meet criteria for DSM-IV obsessive-compulsive disorder. Twin studies of obsessive-compulsive disorder have indicated a significant genetic component to its expression. OBJECTIVE: To determine the relative contributions of genetic and environmental influences on childhood obsessive-compulsive behavior using the CBCL OCS in twin samples. DESIGN: The CBCL data were received by survey of twins in the Netherlands Twin Registry (NTR) and the Missouri Twin Study (USA/MOTWIN). SETTING: General community twin samples. PARTICIPANTS: Participants were 4246 twin pairs aged 7 years, 2841 aged 10 years, and 1562 aged 12 years (who also participated in the study at 7 and 10 years of age) from the NTR and 1461 mixed-age twin pairs (average age, approximately 9 years) from the USA/MOTWIN. MAIN OUTCOME MEASURES: Model fitting to test for genetic and environmental influences, sex differences, and sibling interaction/rater contrast effects on the CBCL OCS. RESULTS: In each case, the best-fitting model was one that indicated significant additive genetic influences (range, 45%-58%; 95% confidence interval [CI], 45%-61%), and unique environmental influences (range, 42%-55%; 95% CI, 39%-55%), with shared environmental influences in the NTR sample aged 12 years (16%). Sex differences were seen in the mixed-age USA/MOTWIN model, but not in the NTR samples. No evidence of dominance, sibling interaction, or rater-contrast effects was seen. These data were relatively consistent across age and cultures. CONCLUSIONS: The CBCL OCS is influenced by genetic factors (approximately 55%) and unique environmental factors (approximately 45%) in the younger sample, with common environmental influences only at 12 years of age. These effects do not vary with differences in sex or sibling interaction/rater contrast effects. Our data reveal higher genetic influences for obsessive-compulsive behavior and do not demonstrate genetic differences across sex." [Abstract]

Leckman JF, Pauls DL, Zhang H, Rosario-Campos MC, Katsovich L, Kidd KK, Pakstis AJ, Alsobrook JP, Robertson MM, McMahon WM, Walkup JT, Van De Wetering BJ, King RA, Cohen DJ.
Obsessive-compulsive symptom dimensions in affected sibling pairs diagnosed with Gilles de la Tourette syndrome.
Am J Med Genet 2003 Jan 1;116(1 Suppl):60-8
"Obsessive-compulsive disorder (OCD) is an etiologically heterogeneous disorder. Recent factor analyses have consistently identified several symptom dimensions, two of which are associated with increased familial risk for OCD; aggressive, sexual, and religious obsessions and checking compulsions (FACTOR 1) and symmetry and ordering obsessions and compulsions (FACTOR 2). Both of these symptom dimensions are also frequently seen in association with Gilles de la Tourette syndrome (GTS). The purpose of this study was to determine whether these obsessive-compulsive (OC) symptom dimensions are correlated within families (between sibs and between parent-child pairs). Using data collected by the Tourette Syndrome Association International Consortium for Genetics Affected Sibling Pair Study, the authors selected all available GTS sib pairs and their parents for which these OC symptom dimensions (factor scores) could be generated. This group included 128 full sibs and their mothers (54) and fathers (54). Four OC symptom dimension scores were computed for each family member using an algorithm derived from item endorsements from the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) symptom checklist. In addition to a series of univariate analyses, complex segregation analyses were also completed using these quantitative OC symptom dimension scores. FACTOR 1 and FACTOR 2 scores were significantly correlated in sib pairs concordant for GTS. The mother-child correlations, but not father-child correlations, were also significant for these two factors. Segregation analyses were consistent with dominant major gene effects for both FACTOR 1 and FACTOR 2. We conclude that familial factors contribute significantly to OC symptom dimension phenotypes in GTS families. This familial contribution could be genetic or environmental." [Abstract]

Lichter DG, Dmochowski J, Jackson LA, Trinidad KS.
Influence of family history on clinical expression of Tourette's syndrome.
Neurology 1999 Jan 15;52(2):308-16
"OBJECTIVE: To determine the influence of family history on clinical expression of Tourette's syndrome (TS). BACKGROUND: Recent studies have suggested that clinical expression of TS is similar among sporadic (SP) and familial patients but may be influenced by bilineal (BIL) transmission of tics or obsessive-compulsive behavior (OCB) in high-density pedigrees. METHODS: The authors used family history methodology, supported by direct examination of affected relatives in 73% of familial patients, to determine the frequency of SP TS, and of unilineal (UNL) and BIL transmission of tics or OCB in 111 consecutively ascertained juvenile TS patients. For individuals in each group, severity of tics, attention deficit hyperactivity disorder (ADHD), and OCB were assessed at presentation and after a mean follow-up interval of 2.6 years, using the Tourette's Syndrome Global Scale and the Clinical Global Impression scales. The phenomenology of OCB was evaluated using the symptom checklist of the Children's Yale-Brown Obsessive Compulsive Scale. RESULTS: The authors documented BIL transmission of tics in seven patients (6%). Patient age and sex were similar for the SP (n = 21; 19%), UNL (n = 66; 59%), and BIL (n = 24; 22%) groups, as was ADHD and tic severity at presentation and follow-up. Severity of OCB differed significantly between groups, with moderate to severe OCB affecting 5% of SP, 12% of UNL, and 37% of BIL patients at presentation (p = 0.007), and 5% of SP, 17% of UNL, and 54% of BIL patients at follow-up (p = 0.0001). Relative to UNL or SP patients, BIL patients were more likely to exhibit self-injurious behaviors (p = 0.0005). CONCLUSIONS: OCB is less prominent in SP than in familial TS, perhaps reflecting a more restricted pathophysiology in this subgroup. Although BIL transmission of tics is relatively infrequent in consecutive TS pedigrees, cotransmission of OCB from an otherwise unaffected parent is common and significantly influences development of OCB and self-injurious behaviors, but not tics, in offspring. Genetic heterogeneity, epigenetic factors, and gene-environment interactions may play a more important role than genetic dosage effects in determining tic severity in TS." [Abstract]

Pauls DL.
The genetics of obsessive compulsive disorder and Gilles de la Tourette's syndrome.
Psychiatr Clin North Am 1992 Dec;15(4):759-66
"This article reviews the evidence that obsessive compulsive disorder (OCD) and Gilles de la Tourette's syndrome (GTS) are both familial and genetic. Studies are summarized that suggest that (1) some forms of OCD are related to GTS, (2) some forms of OCD are familial and may not be related to GTS, and (3) the patterns of inheritance of GTS and OCD within the same families are consistent with the transmission of an autosomal dominant genetic locus." [Abstract]

Grados MA, Riddle MA, Samuels JF, Liang KY, Hoehn-Saric R, Bienvenu OJ, Walkup JT, Song D, Nestadt G.
The familial phenotype of obsessive-compulsive disorder in relation to tic disorders: the Hopkins OCD family study.
Biol Psychiatry 2001 Oct 15;50(8):559-65
"BACKGROUND: Obsessive-compulsive disorder (OCD) and tic disorders have phenomenological and familial-genetic overlaps. An OCD family study sample that excludes Tourette's syndrome in probands is used to examine whether tic disorders are part of the familial phenotype of OCD. METHODS: Eighty case and 73 control probands and their first-degree relatives were examined by experienced clinicians using the Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety version. DSM-IV psychiatric diagnoses were ascertained by a best-estimate consensus procedure. The prevalence and severity of tic disorders, age-at-onset of OCD symptoms, and transmission of OCD and tic disorders by characteristics and type of proband (OCD + tic disorder, OCD - tic disorder) were examined in relatives. RESULTS: Case probands and case relatives had a greater lifetime prevalence of tic disorders compared to control subjects. Tic disorders spanning a wide severity range were seen in case relatives; only mild severity was seen in control relatives. Younger age-at-onset of OCD symptoms and possibly male gender in case probands were associated with increased tic disorders in relatives. Although relatives of OCD + tic disorder and OCD - tic disorder probands had similar prevalences of tic disorders, this result is not conclusive. CONCLUSIONS: Tic disorders constitute an alternate expression of the familial OCD phenotype." [Abstract]

Dykens E, Shah B.
Psychiatric disorders in prader-willi syndrome : epidemiology and management.
CNS Drugs 2003;17(3):167-78
"Although people with intellectual disabilities are at increased risk for psychiatric disorders, the type and rate of these problems differ between those with different causes for their retardation. In this paper, we review behavioural and psychiatric problems in persons with Prader-Willi syndrome, a disorder caused by a paternally derived deletion at chromosome 15(q11-q13) in about 70% of affected patients, and by maternal uniparental disomy in the majority of the remaining patients. In addition to the syndrome's characteristic hyperphagia and food seeking, individuals with Prader-Willi syndrome also have increased risks of nonfood, compulsive behaviours. These include skin picking, which is highly prevalent, as well as more variable rates of hoarding, redoing and concerns with symmetry, exactness, cleanliness, ordering and arranging. Relative to others with mental retardation, persons with Prader-Willi syndrome are at a marked increased risk for developing full-blown, obsessive-compulsive disorder. In addition, many people with Prader-Willi syndrome show increased rates of tantrums, oppositionality and aggression. Recent findings suggest that they also have an increased risk of psychotic disorder or affective illness with a psychotic component, especially young adult patients and those with the maternal uniparental disomy as opposed to paternal deletion." [Abstract]

Comings DE, Wu S, Chiu C, Muhleman D, Sverd J.
Studies of the c-Harvey-Ras gene in psychiatric disorders.
Psychiatry Res 1996 Jun 26;63(1):25-32
"Herault et al. (1993) previously reported a significant association between autism and the larger fragments of the c-Harvey-Ras (HRAS) Bam H1 polymorphism. We have sought to verify this finding and determine if there was any evidence for an association with other psychiatric disorders. Because of its greater sensitivity, we have examined the HRAS Msp 1 polymorphism. We found a just significant increase in the prevalence of the > 2.1 kb alleles in 48 subjects with autism versus 50 control subjects. There was no increase in the prevalence of the > 2.1 kb alleles in 164 probands with Tourette's syndrome. Examination of 16 preselected symptom clusters, however, showed a significant trend toward higher scores for obsessive-compulsive and phobic symptoms in > 2.1 kb homozygotes. While this locus requires further study, in conjunction with the results of Herault et al., the present findings suggest that genetic defects in HRAS, and possibly other components of the G protein secondary messenger system, may play a role in some psychiatric disorders." [Abstract]

Zhang H, Leckman JF, Pauls DL, Tsai CP, Kidd KK, Campos MR; Tourette Syndrome Association International Consortium for Genetics.
Genomewide scan of hoarding in sib pairs in which both sibs have Gilles de la Tourette syndrome.
Am J Hum Genet 2002 Apr;70(4):896-904
"A genome scan of the hoarding phenotype (a component of obsessive-compulsive disorder) was conducted on 77 sib pairs collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). All sib pairs were concordant for a diagnosis of Gilles de la Tourette syndrome (GTS). However, the analyses reported here were conducted for hoarding as both a dichotomous trait and a quantitative trait. Not all sib pairs in the sample were concordant for hoarding. Standard linkage analyses were performed using GENEHUNTER and Haseman-Elston methods. In addition, novel analyses with a recursive-partitioning technique were employed. Significant allele sharing was observed for both the dichotomous and the quantitative hoarding phenotypes for markers at 4q34-35 (P=.0007), by use of GENEHUNTER, and at 5q35.2-35.3 (P=.000002) and 17q25 (P=.00002), by use of the revisited Haseman-Elston method. The 4q site is in proximity to D4S1625, which was identified by the TSAICG as a region linked to the GTS phenotype. The recursive-partitioning technique examined multiple markers simultaneously. Results suggest joint effects of specific loci on 5q and 4q, with an overall P value of.000003. Although P values were not adjusted for multiple comparison, nearly all were much smaller than the customary significance level of.0001 for genomewide scans." [Abstract]

Hanna GL, Veenstra-VanderWeele J, Cox NJ, Boehnke M, Himle JA, Curtis GC, Leventhal BL, Cook EH Jr.
Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands.
Am J Med Genet 2002 Jul 8;114(5):541-52
"The goal of this study was to identify chromosomal regions likely to contain susceptibility alleles for early-onset obsessive-compulsive disorder (OCD). A genome scan was done in 56 individuals from seven families ascertained through pediatric OCD probands; 27 of the 56 subjects had a lifetime diagnosis of definite OCD. Denser mapping of regions on chromosomes 2, 9, and 16 was subsequently done with those subjects and ten additional subjects from the largest family in the study. Direct interviews were completed with 65 of the 66 genotyped individuals. Relatives were interviewed blind to proband status. Of the 65 interviewed individuals, 32 had a lifetime diagnosis of definite OCD. Three of the seven probands had a history of Tourette disorder. Two of the 25 relatives with OCD had a tic history, whereas none of the 33 relatives without OCD had tics. The genome scan consisted of 349 microsatellite markers with an average between-marker distance of 11.3 centiMorgan (cM). Fine mapping was done with 24 additional markers at an average spacing of 1.6 cM. Parametric and nonparametric linkage analyses were conducted using GENEHUNTER(+). The maximum multipoint LOD score with a dominant model was 2.25 on 9p. However, with fine mapping and additional subjects, that LOD score decreased to 1.97. The maximum multipoint nonparametric LOD* score was 1.73 on 19q. The maximum multipoint LOD score with a recessive model was 1.40 on 6p. The results provide suggestive evidence for linkage on 9p and identify regions requiring further study with much larger samples." [Abstract]

Cavallini MC, Bertelli S, Chiapparino D, Riboldi S, Bellodi L.
Complex segregation analysis of obsessive-compulsive disorder in 141 families of eating disorder probands, with and without obsessive-compulsive disorder.
Am J Med Genet 2000 Jun 12;96(3):384-91
"Probands affected with eating disorders (ED) present a higher number of relatives affected with obsessive-compulsive disorders/tic disorders than a comparison population. Therefore, we hypothesized that ED and obsessive-compulsive disorder (OCD) might share the same biological liability, and that a single major gene might account for that liability. We tested this hypothesis by applying a complex segregation analysis to 141 families of probands affected with ED (89 with anorexia nervosa, restricting and binge-eating types, 52 with bulimia nervosa). Given the hypothesized relationship between OCD and genetic spectrum disorders, we considered these diagnoses as affected phenotype in relatives. In Italian ED families, ED and OCD followed a Mendelian dominant model of transmission. When probands were divided according to co-diagnosis of OCD, best fit in the subgroup of families of 114 probands without OCD co-diagnosis was for a Mendelian dominant model of transmission whereas a Mendelian additive model of transmission represented best fit in the subgroup of families of 27 probands with an OCD co-diagnosis. Genetic transmission was not shown in those families where the only affected phenotype was ED. The existence of a Mendelian mode of genetic transmission within ED families supports the hypothesis that a common genetic liability could account for both ED and OCD." [Abstract]

Saunders-Pullman R, Shriberg J, Heiman G, Raymond D, Wendt K, Kramer P, Schilling K, Kurlan R, Klein C, Ozelius LJ, Risch NJ, Bressman SB.
Myoclonus dystonia: possible association with obsessive-compulsive disorder and alcohol dependence.
Neurology 2002 Jan 22;58(2):242-5
"BACKGROUND: Inherited myoclonus-dystonia (M-D) is a disorder that is characterized primarily by myoclonic jerks and is often accompanied by dystonia. In addition to motor features, psychiatric disease is reported in some families. METHODS: To determine whether the same genetic etiology underlies both neurologic and psychiatric signs, the authors studied psychiatric symptoms in nonmanifesting carriers (NMC), noncarriers (NC), and manifesting carriers (MC) in three families demonstrating linkage of M-D to the 7q21 locus. Interviewers administered the computerized version of the Composite International Diagnostic Interview. Algorithms for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of obsessive-compulsive disorder (OCD), generalized anxiety disorder, major affective disorder, alcohol abuse, alcohol dependence, drug abuse, and drug dependence were used. Rates of disorders among the MC, NMC, and NC were compared. RESULTS: Of 55 participating individuals, 16 were MC, 11 were NMC, and 28 were NC. The rate of OCD was greater in carriers (5/27) compared with NC (0/28) (p = 0.023). It was also greater in the symptomatic gene carriers (4/16) compared with the asymptomatic group (1/11) (p = 0.022). Alcohol dependence was increased in the symptomatic carriers (7/16) (p = 0.027), but not in the carrier group overall (7/27). CONCLUSION: OCD may be associated with the DYT11 M-D gene; however, a larger sample is necessary to confirm this finding. Alcohol dependence is highly associated with expressing symptoms of M-D. This may be explained by self-medication with alcohol to improve motor symptoms of M-D." [Abstract]

Veenstra-VanderWeele J, Kim SJ, Gonen D, Hanna GL, Leventhal BL, Cook EH Jr.
Genomic organization of the SLC1A1/EAAC1 gene and mutation screening in early-onset obsessive-compulsive disorder.
Mol Psychiatry 2001 Mar;6(2):160-7
"The first genome scan conducted in early-onset obsessive-compulsive disorder used a non-parametric analysis to identify a peak in a region of chromosome 9 containing the gene SLC1A1, which codes for the neuronal and epithelial glutamate transporter EAAC1. Interaction between the glutamatergic and serotonergic systems within the striatum suggests EAAC1 as a functional candidate in OCD as well. We determined the genomic organization of SLC1A1 primarily by using primers designed from cDNA sequence to amplify from adaptor-ligated genomic DNA restriction fragments. In order to confirm SLC1A1 as a positional candidate in early-onset OCD, common single nucleotide polymorphisms (SNPs) were identified that enabled mapping of SLC1A1 within the region of the lod score peak. Based on the linkage evidence, the coding region was sequenced in the probands of the seven families included in the genome scan. No evidence was found for a functional mutation, but several SNPs were identified. Capillary electrophoresis SSCP typing of a haplotype consisting of two common SNPs within EAAC1 revealed no significant linkage disequilibrium." [Abstract]

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Recent Obsessive-Compulsive Disorder Genetic Research

1) Real E, Gratacòs M, Labad J, Alonso P, Escaramís G, Segalàs C, Subirà M, López-Solà C, Estivill X, Menchón JM
Interaction of SLC1A1 gene variants and life stress on pharmacological resistance in obsessive-compulsive disorder.
Pharmacogenomics J. 2012 Jul 10;
Genetic and environmental factors seem to interact and influence both the onset and the course of obsessive-compulsive disorder (OCD), but the role of glutamate transporter variants (SLC1A1) in pharmacological resistance is not known. We aimed to assess whether genetic variants in SLC1A1 and life stress at onset of the disorder interact and modulate pharmacological resistance in OCD. A single-marker association study of several single-nucleotide polymorphisms in the SLC1A1 genomic region was performed in a sample of 238 OCD patients. For the most strongly associated SNP (rs3087879), one copy of the risk allele increased the probability of higher treatment resistance (odds ratio=2.42; 95% confidence interval=1.39-4.21; P=0.0018), but only in OCD patients without life stress at onset of the disorder. These results suggest a gene-by-environment interaction effect on treatment resistance in OCD and strengthen the existing evidence of the role of the glutamatergic system in the phenomenology of OCD.The Pharmacogenomics Journal advance online publication, 10 July 2012; doi:10.1038/tpj.2012.30. [PubMed Citation] [Order full text from Infotrieve]

2) Lei X, Chen C, He Q, Chen C, Moyzis RK, Xue G, Chen X, Cao Z, Li J, Li H, Zhu B, Chun Hsu AS, Li S, Li J, Dong Q
Sex determines which section of the SLC6A4 gene is linked to obsessive-compulsive symptoms in normal Chinese college students.
J Psychiatr Res. 2012 Jun 22;
Previous case-control and family-based association studies have implicated the SLC6A4 gene in obsessive-compulsive disorder (OCD). Little research, however, has examined this gene's role in obsessive-compulsive symptoms (OCS) in community samples. The present study genotyped seven tag SNPs and two common functional tandem repeat polymorphisms (5-HTTLPR and STin2), which together cover the whole SLC6A4 gene, and investigated their associations with OCS in normal Chinese college students (N = 572). The results revealed a significant gender main effect and gender-specific genetic effects of the SLC6A4 gene on OCS. Males scored significantly higher on total OCS and its three dimensions than did females (ps < .01). The 5-HTTLPR in the promoter region showed a female-specific genetic effect, with the l/l and l/s genotypes linked to higher OCS scores than the s/s genotype (ps < .05). In contrast, a conserved haplotype polymorphism (rs1042173| rs4325622| rs3794808| rs140701| rs4583306| rs2020942) covering from intron 3 to the 3' UTR of the SLC6A4 gene showed male-specific genetic effects, with the CGAAGG/CGAAGG genotype associated with lower OCS scores than the other genotypes (ps < .05). These effects remained significant after controlling for OCS-related factors including participants' depressive and anxiety symptoms as well as stressful life events, and correction for multiple tests. These results are discussed in terms of their implications for our understanding of the sex-specific role of the different sections of the SLC6A4 gene in OCD. [PubMed Citation] [Order full text from Infotrieve]

3) Newbury AJ, Rosen GD
Genetic, morphometric, and behavioral factors linked to the midsagittal area of the corpus callosum.
Front Genet. 2012;3:91.
The corpus callosum is the main commissure connecting left and right cerebral hemispheres, and varies widely in size. Differences in the midsagittal area of the corpus callosum (MSACC) have been associated with a number of cognitive and behavioral phenotypes, including obsessive-compulsive disorders, psychopathy, suicidal tendencies, bipolar disorder, schizophrenia, autism, and attention deficit hyperactivity disorder. Although there is evidence to suggest that MSACC is heritable in normal human populations, there is surprisingly little evidence concerning the genetic modulation of this variation. Mice provide a potentially ideal tool to dissect the genetic modulation of MSACC. Here, we use a large genetic reference panel - the BXD recombinant inbred line - to dissect the natural variation of the MSACC. We estimated the MSACC in over 300 individuals from nearly 80 strains. We found a 4-fold difference in MSACC between individual mice, and a 2.5-fold difference among strains. MSACC is a highly heritable trait (h(2)?=?0.60), and we mapped a suggestive QTL to the distal portion of Chr 14. Using sequence data and neocortical expression databases, we were able to identify eight positional and plausible biological candidate genes within this interval. Finally, we found that MSACC correlated with behavioral traits associated with anxiety and attention. [PubMed Citation] [Order full text from Infotrieve]

4) Taylor S
Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies.
Mol Psychiatry. 2012 Jun 5;
Twin studies indicate that obsessive-compulsive disorder (OCD) is strongly influenced by additive genetic factors. Yet, molecular genetic association studies have yielded inconsistent results, possibly because of differences across studies in statistical power. Meta-analysis can yield greater power. This study reports the first comprehensive meta-analysis of the relationship between OCD and all previously examined polymorphisms for which there was sufficient information in the source studies to compute odds ratios (ORs). A total of 230 polymorphisms from 113 genetic association studies were identified. A full meta-analysis was conducted for 20 polymorphisms that were examined in 5 or more data sets, and a secondary meta-analysis (limited to the computation of mean effect sizes) was conducted for 210 polymorphisms that were examined in fewer than 5 data sets. In the main meta-analysis, OCD was associated with serotonin-related polymorphisms (5-HTTLPR and HTR2A) and, in males only, with polymorphisms involved in catecholamine modulation (COMT and MAOA). Nonsignificant trends were identified for two dopamine-related polymorphisms (DAT1 and DRD3) and a glutamate-related polymorphism (rs3087879). The secondary meta-analysis identified another 18 polymorphisms with significant ORs that merit further investigation. This study demonstrates that OCD is associated with multiple genes, with most having a modest association with OCD. This suggests a polygenic model of OCD, consistent with twin studies, in which multiple genes make small, incremental contributions to the risk of developing the disorder. Future studies, with sufficient power to detect small effects, are needed to investigate the genetic basis of OCD subtypes, such as early vs late onset OCD.Molecular Psychiatry advance online publication, 5 June 2012; doi:10.1038/mp.2012.76. [PubMed Citation] [Order full text from Infotrieve]

5) Gunther J, Tian Y, Stamova B, Lit L, Corbett B, Ander B, Zhan X, Jickling G, Bos-Veneman N, Liu D, Hoekstra P, Sharp F
Catecholamine-related gene expression in blood correlates with tic severity in tourette syndrome.
Psychiatry Res. 2012 May 28;
Tourette syndrome (TS) is a heritable disorder characterized by tics that are decreased in some patients by treatment with alpha adrenergic agonists and dopamine receptor blockers. Thus, this study examines the relationship between catecholamine gene expression in blood and tic severity. TS diagnosis was confirmed using Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria and tic severity measured using the Yale Global Tic Severity Scale (YGTSS) for 26 un-medicated subjects with TS. Whole blood was collected and Ribonucleic acid (RNA) processed on Affymetrix Human Exon 1.0 ST arrays. An Analysis of Covariance (ANCOVA) identified 3627 genes correlated with tic severity (p<0.05). Searches of Medical Subject Headings, Gene Ontology, Allen Mouse Brain Atlas, and PubMed determined genes associated with catecholamines and located in the basal ganglia. Using GeneCards, PubMed, and manual curation, seven genes associated with TS were further examined: DRD2, HRH3, MAOB, BDNF, SNAP25, SLC6A4, and SLC22A3. These genes are highly associated with TS and have also been implicated in other movement disorders, Attention Deficit Hyperactivity Disorder (ADHD), and Obsessive-Compulsive Disorder (OCD). Correlation of gene expression in peripheral blood with tic severity may allow inferences about catecholamine pathway dysfunction in TS subjects. Findings built on previous work suggest that at least some genes expressed peripherally are relevant for central nervous system (CNS) pathology in the brain of individuals with TS. [PubMed Citation] [Order full text from Infotrieve]

6) Mathews CA, Badner JA, Andresen JM, Sheppard B, Himle JA, Grant JE, Williams KA, Chavira DA, Azzam A, Schwartz M, Reus VI, Kim SW, Cook EH, Hanna GL
Genome-wide Linkage Analysis of Obsessive-Compulsive Disorder Implicates Chromosome 1p36.
Biol Psychiatry. 2012 May 24;
BACKGROUND: Obsessive-compulsive disorder (OCD) has a complex etiology involving both genetic and environmental factors. However, the genetic causes of OCD are largely unknown, despite the identification of several promising candidate genes and linkage regions. METHODS: Our objective was to conduct genetic linkage studies of the type of OCD thought to have the strongest genetic etiology (i.e., childhood-onset OCD), in 33 Caucasian families with ?2 childhood-onset OCD-affected individuals from the United States (n = 245 individuals with genotype data). Parametric and nonparametric genome-wide linkage analyses were conducted with Morgan and Merlin in these families using a selected panel of single nucleotide repeat polymorphisms from the Illumina 610-Quad Bead Chip. The initial analyses were followed by fine-mapping analyses in genomic regions with initial heterogeneity logarithm of odds (HLOD) scores of ?2.0. RESULTS: We identified five areas of interest (HLOD score ?2) on chromosomes 1p36, 2p14, 5q13, 6p25, and 10p13. The strongest result was on chromosome 1p36.33-p36.32 (HLOD = 3.77, suggestive evidence for linkage after fine mapping). At this location, several of the families showed haplotypes co-segregating with OCD. CONCLUSIONS: The results of this study represent the strongest linkage finding for OCD in a primary analysis to date and suggest that chromosome 1p36, and possibly several other genomic regions, may harbor susceptibility loci for OCD. Multiple brain-expressed genes lie under the primary linkage peak (approximately 4 megabases in size). Follow-up studies, including replication in additional samples and targeted sequencing of the areas of interest, are needed to confirm these findings and to identify specific OCD risk variants. [PubMed Citation] [Order full text from Infotrieve]

7) Veenstra-Vanderweele J, Xu T, Ruggiero AM, Anderson LR, Jones ST, Himle JA, Kennedy JL, Richter MA, Hanna GL, Arnold PD
Functional studies and rare variant screening of SLC1A1/EAAC1 in males with obsessive-compulsive disorder.
Psychiatr Genet. 2012 May 19;
Several studies have found that the neuronal glutamate transporter gene SLC1A1/EAAC1 is associated with obsessive-compulsive disorder (OCD), with a stronger association in males. Previous studies have primarily focused on common single-nucleotide polymorphisms, rather than rare functional variants that are likely to have larger effects. We screened 184 males with OCD for rare variation in SLC1A1 exons; however, no new coding variation was found. When combined with previous screens, only one SLC1A1 amino acid variant has been detected among the 841 individuals screened, which is less than for other neurotransmitter transporter genes (P=0.0001). We characterized the function of the one SLC1A1 missense variant reported previously in OCD, Thr164Ala, and found that the Ala164 allele leads to decreased Vmax and Km (P<0.0001) in transfected human embryonic kidney cells. Further work will be necessary to understand the impact of this rare SLC1A1/EAAC1 Ala164 variant on neuronal function and circuitry relevant to OCD. [PubMed Citation] [Order full text from Infotrieve]

8) Liu S, Liu Y, Zhang X, Ma X
Lack of association of -251T/A polymorphism in Interleukin 8 gene with susceptibility to obsessive-compulsive disorder in Chinese Han population.
Cytokine. 2012 Aug;59(2):209-10.
[PubMed Citation] [Order full text from Infotrieve]

9) Liu S, Yin Y, Liu Y, Sun Y, Zhang X, Ma X
Lack of an association between obsessive-compulsive disorder and polymorphisms in the 3' untranslated region of GRIN2B in a Chinese Han population.
Psychiatry Res. 2012 Mar 30;196(1):142-4.
Previous investigations have provided evidence that some polymorphisms in the 3' untranslated region (3'-UTR) of GRIN2B are associated with susceptibility to obsessive-compulsive disorder (OCD). We evaluated the genetic contribution of the rs1805502, rs1805476 and rs890 polymorphisms in the 3'-UTR of GRIN2B in 206 OCD patients and 413 controls in a Chinese Han population, and found no significant differences in genotypic and allelic frequencies between OCD cases and the controls. Our results suggest the lack of an association between OCD and polymorphisms in the 3'-UTR of GRIN2B in a Chinese Han population. [PubMed Citation] [Order full text from Infotrieve]

10) Flessner CA, Knopik VS, McGeary J
Hair pulling disorder (trichotillomania): Genes, neurobiology, and a model for understanding impulsivity and compulsivity.
Psychiatry Res. 2012 Apr 24;
Hair pulling disorder (trichotillomania) affects at least 3.7 million people in the United States and results in marked functional impairment. This article reviews empirical research investigating the genetics and neurobiology of hair pulling disorder (HPD). We also discuss recent advances in the characterization of this phenotype which have led to evidence supporting the existence of at least two disparate pulling styles-automatic and focused pulling. These pulling styles exhibit facets of behavioral processes, impulsivity and compulsivity, characteristic of several classes of disorders (e.g., obsessive-compulsive spectrum disorders, impulse control disorders). Available genetic, neurobiological, and clinical data support the importance of impulsivity for conceptualizing HPD. Impulsivity alone is insufficient to fully understand this complex phenotype. Characterizations of both automatic and focused pulling as well as preliminary findings from affective neuroscience across species highlight the importance of compulsivity for understanding HPD. Opposing and complementary aspects to impulsivity-compulsivity provide a more comprehensive conceptualization of HPD and supports HPD's potential importance for advancing scientific inquiry in relation to the pathogenesis and treatment of related phenotypes. This review concludes with a description of areas-phenotype, neurobiology, and genes-in need of further study. [PubMed Citation] [Order full text from Infotrieve]

11) Schirmbeck F, Nieratschker V, Frank J, Englisch S, Rausch F, Meyer-Lindenberg A, Rietschel M, Zink M
Polymorphisms in the glutamate transporter gene SLC1A1 and obsessive-compulsive symptoms induced by second-generation antipsychotic agents.
Psychiatr Genet. 2012 Apr 23;
BACKGROUND: A large subgroup of schizophrenic patients develops obsessive-compulsive symptoms (OCS) during treatment with second-generation antipsychotics (SGA). A genetic risk factor for these secondary OCS was recently described in the gene SLC1A1 encoding the neuronal glutamate transporter excitatory amino acid carrier 1. The aim of this study was to replicate these findings in a European sample. METHODS: A total of 103 schizophrenic patients treated with SGAs were included. Three single nucleotide polymorphisms in SLC1A1 (rs2228622, rs3780412 and rs3780413), which had been associated with SGA-induced OCS, were investigated. Single marker and haplotype analyses were tested with logistic regressions using age, sex and medication type as covariates. RESULTS: Treatment with markedly antiserotonergic SGAs such as clozapine was more prevalent in the subgroup of patients with comorbid OCS (P<0.001). The dosage and duration of clozapine treatment correlated significantly with the severity of OCS. In contrast to the Asian sample, no genetic associations were found with OCS. CONCLUSION: Larger samples are necessary to unravel the interplay of pharmacological and genetic risk factors for OCS in schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

12) Corregiari FM, Bernik M, Cordeiro Q, Vallada H
Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive-compulsive disorder.
Clinics (Sao Paulo). 2012;67(4):335-40.
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13) Hashim HM, Fawzy N, Fawzi MM, Karam RA
Brain-derived neurotrophic factor Val66Met polymorphism and obsessive-compulsive symptoms in Egyptian schizophrenia patients.
J Psychiatr Res. 2012 Jun;46(6):762-6.
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14) Zilles D, Meyer J, Schneider-Axmann T, Ekawardhani S, Gruber E, Falkai P, Gruber O
Genetic polymorphisms of 5-HTT and DAT but not COMT differentially affect verbal and visuospatial working memory functioning.
Eur Arch Psychiatry Clin Neurosci. 2012 Mar 28;
Working memory deficits are found in different psychiatric populations and are most pronounced in schizophrenia. There is preliminary evidence from pharmacological studies that the verbal and visuospatial subcomponents of working memory are subject to differential neurotransmitter modulation. Here, we investigated the impact of well-known polymorphisms of the dopamine transporter gene (SLC6A3, DAT) and the catechol-O-methyl-transferase gene (COMT) as well as the serotonin transporter gene (SLC6A4, 5-HTT) on these specific working memory subcomponents in a mixed sample of patients and healthy individuals. Twenty healthy subjects and 80 patients diagnosed with schizophrenia, bipolar I disorder, or obsessive-compulsive disorder underwent genotyping for the DAT variable number of tandem repeats (VNTR), the COMT val/met-, and the 5-HTT promoter length polymorphism (5-HTTLPR) and neuropsychological testing using a battery of well-characterized, brain circuit-specific working memory tasks. DAT genotype revealed a significant and selective effect on visuospatial working memory, while there was no effect on verbal working memory functioning. 5-HTT genotype, by contrast, exerted a significant and selective effect on verbal working memory task performance. COMT genotype did not show any influence on either working memory domain. The results of the present study provide evidence for a differential impact of genetic polymorphisms of the dopaminergic and serotonergic systems on verbal and visuospatial working memory functioning. Together with prior evidence suggesting the existence of subgroups of schizophrenia patients exhibiting isolated deficits in only one working memory domain, this finding further supports the idea of endophenotypically and pathophysiologically distinct subgroups of schizophrenia with implications for personalized therapeutic approaches. [PubMed Citation] [Order full text from Infotrieve]

15) Bilgic B, Bayram A, Arslan AB, Hanagasi H, Dursun B, Gurvit H, Emre M, Lohmann E
Differentiating symptomatic Parkin mutations carriers from patients with idiopathic Parkinson's disease: contribution of automated segmentation neuroimaging method.
Parkinsonism Relat Disord. 2012 Jun;18(5):562-6.
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16) Angoa-Pérez M, Kane MJ, Briggs DI, Sykes CE, Shah MM, Francescutti DM, Rosenberg DR, Thomas DM, Kuhn DM
Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.
J Neurochem. 2012 Jun;121(6):974-84.
Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis. [PubMed Citation] [Order full text from Infotrieve]

17) Robertson MM
The Gilles De La Tourette syndrome: the current status.
Arch Dis Child Educ Pract Ed. 2012 Mar 22;
Gilles de la Tourette syndrome (GTS) is characterised by multiple motor and one or more vocal/phonic tics. GTS was once thought to be rare, but many relatively recent studies suggest that the prevalence is about 1% of the worldwide community, apart from in Sub-Saharan Black Africa. Comorbidity and coexistent psychopathology are common, occurring in about 90% of clinical cohorts and individuals in the community. The most common comorbidities are attention deficit hyperactivity disorder, obsessive-compulsive behaviours, and disorder, and autistic spectrum disorders, while the most common coexisting psychopathologies are depression, anxiety and behavioural disorders such as oppositional defiant and conduct disorder. There has been an increasing amount of evidence to show that the quality of life in young people is reduced when compared with normative data or healthy control populations. It is widely accepted that most cases of GTS are inherited, but the genetic mechanisms appear much more complex than previously understood, as evidenced by many recent studies; indeed, there have been suggestions of 'general neurodevelopmental genes' which affect the brain development after which the 'specific GTS gene(s)' may further affect the phenotype. Other aetiopathogenetic suggestions have included environmental factors such as neuro-immunological factors, infections, prenatal and peri-natal difficulties and androgen influences. Few studies have addressed aetiology and phenotype, but initial results are exciting. The search for endophenotypes has followed subsequently. Intriguing neuroanatomical and brain circuitry abnormalities have now been suggested in GTS; the most evidence is for cortical thinning and a reduction in the size of the caudate nucleus. Thorough assessment is imperative and multidisciplinary management is the ideal. Treatment should be 'symptom targeted', and in mild cases, psycho-education and reassurance for the patient and the family may be sufficient. Behavioural treatments such as Comprehensive Behavioural Intervention for Tics including Habit Reversal Training have been shown to be significantly better than other behavioural/psychological treatments and 'placebo'. Medication is often necessary for moderately affected individuals. In more severe cases, medical treatment is not simple and referral to an expert may be advisable. In general, neuroleptics and clonidine or guanfacine are the medications of choice for the tics. Other treatments which may be needed for loud and severe phonic tics include botulinum toxin. In severe adult GTS patients who are refractory to medication and other therapies, deep brain stimulation looks promising. [PubMed Citation] [Order full text from Infotrieve]

18) Alonso P, Gratacós M, Segalàs C, Escaramís G, Real E, Bayés M, Labad J, López-Solà C, Estivill X, Menchón JM
Association between the NMDA glutamate receptor GRIN2B gene and obsessive-compulsive disorder.
J Psychiatry Neurosci. 2012 Jul;37(4):273-81.
Background: Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neuro transmission in the pathogenesis of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes. Methods: Between 2003 and 2008, we performed a case-control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3' UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions. Results: We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37-4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22-3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions. Limitations: Study limitations included the risk of population stratification associated with the case-control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3' UTR and exon 13 of GRIN2B. Conclusion: Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder. [PubMed Citation] [Order full text from Infotrieve]

19) Vulink NC, Westenberg HG, Nieuwerburgh FV, Deforce D, Fluitman SB, Meinardi JS, Denys D
Catechol-O-methyltranferase gene expression is associated with response to citalopram in obsessive-compulsive disorder.
Int J Psychiatry Clin Pract. 2012 Mar 13;
Objective. To determine whether polymorphisms of the dopamine D(2) receptor (DRD2) and catechol-O-methyl-transferase (COMT) receptor genes affect the efficacy of quetiapine addition to citalopram in patients with OCD. Methods. Sixty-four drug-free or drug-naïve patients meeting DSM-IV criteria for OCD were randomized to 10 weeks double-blind treatment with citalopram (60 mg/day) with quetiapine (300 -450 mg/day) or with placebo. The change from baseline to endpoint on the total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the response to treatment were the primary outcome measures. Response was defined as a 25% decrease in Y-BOCS score. Responders and nonresponders were stratified according to DRD2 TaqI A and COMT Val(158)Met genotypes. Results. No significant differences in genotype distribution or allele frequencies of the COMT or DRD2 receptor were found between responders and nonresponders to citalopram with quetiapine. However, nearly half of responders to citalopram with placebo carried the Met/Met (48%) genotype of the COMT polymorphism compared to none of the nonresponders (?(2) = 10.06, df = 2, P = 0.007). Conclusions. The Met allele load of the COMT receptor gene was associated with response to 10 weeks of treatment with citalopram in drug-free or drug-naïve OCD patients. [PubMed Citation] [Order full text from Infotrieve]

20) Deng H, Gao K, Jankovic J
The genetics of Tourette syndrome.
Nat Rev Neurol. 2012 Apr;8(4):203-13.
Tourette syndrome is a complex neurological disorder that usually becomes evident between 4 and 18 years of age. The disorder is characterized by chronic motor and phonic tics, often with a variety of behavioural comorbidities; in particular, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and impulse control disorder. The cause of Tourette syndrome is poorly understood. Although environmental factors are proposed to have a role, genetic factors are thought to be the primary contributors to the pathogenesis of this disorder. However, identification of the causative gene mutations or risk alleles has proved to be difficult. Early studies on the genetics of Tourette syndrome focused on multigenerational lineages and suggested Mendelian inheritance, but subsequent segregation analyses point to a more-complex inheritance pattern. A monogenic inheritance model has been proposed following the identification of rare genetic mutations associated with the Tourette syndrome phenotype. Although no specific mutations have found to directly cause Tourette syndrome, genetic findings may enable identification of the affected pathways, and could lead to the development of new treatment strategies. In this Review, we provide an overview of the genetics of Tourette syndrome and highlight how this knowledge has improved our understanding of the possible pathogenic mechanisms of this neurological disorder. [PubMed Citation] [Order full text from Infotrieve]