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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."
[Abstract] 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 1.13.2.2
(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 t |
