Transmission disequilibrium studies in early onset of obsessive–compulsive disorder for polymorphisms in genes of the dopaminergic system

The dopaminergic system has been shown to be involved in the aetiology of obsessive–compulsive disorder (OCD). Family studies suggest a higher genetic loading in patients with early onset OCD. Our investigation is the first family-based association study concerning polymorphisms in genes of the dopaminergic system in early onset OCD. We studied polymorphisms within the dopamine-4 receptor gene (DRD4), the dopamine transporter gene (DAT1) and the catecholamine-O-methyltransferase gene (COMT). Associations of alleles of DRD4 and COMT with OCD have previously been reported in adults, while a trend towards an association was found for DAT1 alleles. In our study we observed transmission disequilibrium for the 48-bp repeat polymorphism of the DRD4 gene using the ETDT (P = 0.047) in 69 trios comprising patients with early onset OCD and both of their parents. Post hoc TDT analysis of the DRD4 showed reduced transmission of the 4-repeat allele and a slightly increased transmission rate for the 7- and the 2-repeat allele. No evidence of transmission disequilibrium was detected for alleles of the DAT1 and COMT polymorphisms. These polymorphisms do not appear to play a major role in the genetic predisposition to early onset OCD in our study group.     

Association between genetic variants of serotonergic and glutamatergic pathways and the concentration of neurometabolites of the anterior cingulate cortex in paediatric patients with obsessive–compulsive disorder

Objectives: The present study aimed to assess the relationship between variability in genes related to the pathophysiology of obsessive–compulsive disorder (OCD) and the concentration of different neurometabolites in the anterior cingulate cortex (ACC). Methods: We concomitantly assessed neurometabolite concentrations using 3-T ¹H-MRS and 262 single nucleotide polymorphism (SNPs) in 35 genes in 41 paediatric OCD patients. Results: There were significant associations, after Bonferroni correction, between the concentration of inositol, glutamate and glutamine, and total choline and five polymorphisms located in genes related to serotonin and glutamate (i.e., the vesicular monoamine transporter 1 gene, SLC18A1 [rs6586896]; the serotonin receptor 1B gene, HTR1B [rs6296 and rs6298]; and the glutamate receptor, ionotropic, AMPA1 gene, GRIA1 [rs707176 and rs2963944]). Conclusions: The association observed between these polymorphisms and the neurometabolite concentrations could indicate the presence of a biological interaction between the serotonin and the glutamate pathways that could be involved in the pathophysiology of OCD. More studies with this methodology could increase our understanding of the aetiology and pathophysiology of OCD in children.     

Association analysis of SLC6A4 and HTR2A genes with obsessive-compulsive disorder: Influence of the STin2 polymorphism

BackgroundObsessive-Compulsive Disorder (OCD) is a complex and chronic disorder characterized by recurrent thoughts and/or repetitive behaviors. Given the potent anti-obsessional effects of the so-called serotonin reuptake inhibitors, genes related to serotonergic system may be well implicated in the etiopathogenesis of OCD. The gene encoding the serotonin transporter (SLC6A4), which shows a variable number of tandem repeat (VNTR) polymorphism in intron 2 (STin2), have been previously associated with OCD. Additionally, the serotonin 2A receptor gene (HTR2A) has two polymorphisms (A-1438G - rs6311, and T102C - rs6313), which have also been overrepresented among OCD patients. Therefore, the aim of this study is to evaluate the association of these three polymorphisms with OCD, through the examination of potential sources of heterogeneity in previous studies including age of onset, sex and symptom dimensions.MethodsPolymorphisms were genotyped by Polymerase Chain Reaction (PCR) in a sample of 203 OCD patients and 205 healthy controls from Brazil.ResultsAlthough we did not observe any statistically significant association between the HTR2A gene polymorphisms and OCD or its clinical features, SLC6A4 STin2 polymorphism was significantly more common among OCD patients as compared to health controls. Further, a significant association between the STin2.12 allele and OCD, as well as a dominant effect of the STin2.12 allele in OCD was seen. Of note, late-onset (> 18 years) OCD was significantly more often seen in association with homozygosis for STin2.12 allele. No significant associations were observed with different OCD symptom dimensions.ConclusionOur results indicate an important influence of the STin2 polymorphism in OCD, but more studies are warranted to confirm these results.     

Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample

Summary Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3′UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD.     

Association of the functional serotonin transporter haplotype with familial form of obsessive compulsive disorder in Iranian patients

Objective: Several polymorphisms have been reported in the 5-HTTLPR of the serotonin transporter gene (SLC6A4). Family-based evidences for the association of 5-HTTLPR polymorphisms with OCD were previously reported but results were controversial. The present study investigated the possible correlation of SLC6A4 polymorphisms (5-HTTLPR, rs25532, rs25531) in Iranian OCD patients considering gender, age of onset, family history of psychiatric disorders, obsessive and compulsive subtypes and severities.

Methods: The included OCD patients fulfilled the criteria for DSM-IV-TR whom Y-BOCS score was more than 9. Blood samples (184 cases and 192 controls) were genotyped by means of PCR-RFLP.

Results: Mean of Y-BOCS scores of included patients was 20.1?±?0.69. Rs25532?CC genotype showed significant association with OCD in men and were detected more in the patients reported positive family history of psychiatric disorders but the other single loci (5-HTTLPR and rs25531) did not associate with OCD. Haplotype analysis showed significant association of 14-A variant with OCD and revealed the association of 14-A/14-A genotype with familial form of OCD.

Conclusions: The findings of this study showed the association of SLC6A4 variants with familial form of OCD and proposed stratified analyses in the genetic studies facilitate identification of genetic risk factors for this heterogeneous disorder.     

Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD)

A recent study demonstrated that treatment of hyperactive mice with psychostimulants and serotonergic agents produced a calming effect that was dependent on serotonergic neurotransmission and was not associated with any changes in extracellular dopamine levels. The complex interaction between the serotonergic and dopaminergic neurotransmitter systems suggests that a balance between the two systems may be necessary for mediating hyperactive behaviour. Defects in serotonin system genes, therefore, may disrupt normal brain serotonin function causing an imbalance between these neurotransmitter systems leading to the development of attention deficit hyperactivity disorder (ADHD). Using the transmission disequilibrium test (TDT), the current study assesses for linkage disequilibrium between polymorphisms in the serotonin HTR2A receptor gene and ADHD. One hundred and fifteen families with a total of 143 children diagnosed with ADHD (DSM-IV) were genotyped for the His452 Tyr and the T102C polymorphisms in the serotonin HTR2A receptor gene. TDT analysis revealed a preferential transmission of the 452Tyr allele to the affected offspring (P = 0.03), suggesting linkage disequilibrium of this polymorphism with ADHD. This may open a new door in ADHD molecular genetics research, expanding the existing view of a catecholaminergic hypothesis to include a serotonergic hypothesis and should help elucidate the complex interplay among the neurotransmitter systems in the etiology of ADHD.     

Association study between obsessive-compulsive disorder and serotonergic candidate genes

BACKGROUND: To date, research examining the relationship between serotonergic genes and obsessive-compulsive disorder (OCD) has yielded conflicting results. The purpose of this study is to investigate the association between four serotonergic polymorphisms (STin2 VNTR and 5-HTTLPR of the SLC6A4 gene, and A-1438G (rs6311) and T102C (rs6313) of the HTR2A gene) and OCD. METHODS: 99 OCD patients, 456 non-OCD psychiatric patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS: All groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms were in complete linkage disequilibrium. OCD patients showed an excess of STin2.12 carriers (12/12, 12/10, and 12/9 genotypes) compared with healthy controls (chi(2) (1)=7.21, corrected p=0.021; OR=3.38, 95% CI=1.32-8.62) and non-OCD psychiatric patients (chi(2) (1)=6.70, corrected p=0.030; OR=3.24, 95% CI=1.27-8.26). However, no differences were found between non-OCD patients and healthy controls (chi(2) (1)=0.05, corrected p>1; OR=1.04, 95% CI=0.72-1.51). No significant differences were found with respect to A-1438G and 5-HTTLPR polymorphisms. CONCLUSIONS: Our data provide supporting evidence of an association between the STin2 VNTR polymorphism of the SLC6A4 gene and OCD.     

Association study of tryptophan hydroxylase-2 gene in schizophrenia and its clinical features in Chinese Han population

Schizophrenia is a chronic and severe mental illness which is characterized by the development of various detrimental clinical features, and its etiology still remains unknown. Based on the evidence from neurobiological and pharmacological research, dysfunctions in central serotonergic transmission may be involved in the development of schizophrenia. Tryptophan hydroxylase 2 (TPH2), a newly identified isoform of tryptophan hydroxylase (the rate limiting enzyme in the biosynthesis of serotonin), regulates the brain-specific serotonin synthesis. To further clarify the role of TPH2 in this disease, we performed a case-control study to examine the association of the TPH2 gene with schizophrenia and its clinical features. We genotyped three putative functional polymorphisms (rs4570625, rs7305115, and rs4290270) within the gene and carried out a case-control study consisting of 304 schizophrenia patients and 362 healthy subjects. The severity of psychotic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). The frequencies of genotypes and alleles of rs4570625, rs7305115, and rs4290270 did not differ significantly between schizophrenic patients and controls. However, the PANSS positive symptom subcore was significantly associated with rs4570625 (P = 0.022). These results suggest that rs4570625 of TPH2 may play an important role in the development of positive symptoms in Han Chinese schizophrenic patients.     

High‐density SNP screen of sodium channel genes by haplotype tagging and DNA pooling for association with idiopathic generalized epilepsy

We have investigated seven voltage‐gated sodium channel genes for association with idiopathic generalized epilepsy (IGE). Probands and control DNA were grouped into pools and used to screen 85 single‐nucleotide polymorphisms (SNPs), mostly HapMap SNPs tagging the common variation in these genes. Twelve SNPs exhibiting an allele frequency difference between pools were genotyped individually in our sample of 232 probands, 313 controls, and 95 parent–proband trios. Two SNPs, in SCN1A and SCN8A, were associated by allele and genotype at nominal level of significance, but were not significant after Bonferroni correction. Two SCN2A SNPs (rs3943809 and rs16850331) were associated by case–control with a subgroup with IGE and history of febrile seizures and also by transmission disequilibrium test (TDT) in parent–proband trios. Both SNPs are part of a linkage disequilibrium (LD) cluster of 38 SNPs, but none are obvious functional variants. The association of rs3943809 with the febrile seizure subgroup (p = 0.0004) remains significant after the conservative Bonferroni correction for multiple testing.     

Obsessive Compulsive Disorder: Serotonin and Beyond

Summary: OCD was considered a rare, treatment refractory disorder of psychological origin, up until 20 years ago. Research in the last two decades has altered the perspectives regarding OCD. It is now clear that OCD is a prevalent disorder—about 2% of the population suffer from OCD—and that it is amenable both to psychological (cognitive-behavioural approach) and pharmacological intervention (with serotonergic medication). The biochemical and neuroanatomical (the frontal basal-thalamo cortical circuit) pathophysiology of OCD is also beginning to emerge.

OCD is unique with regards to its specific response to serotonergic medication that blocks reuptake. Clomiprimine, fluoxetine, fluvoxemine, paroxetine, sertraline and citalopram were all found to be effective treatments for OCD based on large, multicentre, double-blind, placebo-controlled studies. As only serotonergic medications appear to be effective in OCD, the serotonergic hypothesis has been formulated and tested. Indeed, pharmacological challenges with specific serotonin agonists such as mCPP and sumatriptan, which were associated with transient exacerbation of OCD symptoms, are in line with the specific role of 5HT in the pathogenesis of OCD. However, this serotonergic hypothesis, while necessary, is not sufficient. It is clear that the dopaminergic and autoimmune mechanism are also implicated in the pathogenesis of OCD.

Further studies are required to understand the relevance of the serotonergic and non-serotonergic systems in OCD, and to highlight the various possible subtypes of this intriguing disorder.     

Elevated brain serotonin transporter availability in patients with obsessive-compulsive disorder.

BACKGROUND: A central serotonergic dysfunction is considered to be involved in the pathophysiology of obsessive-compulsive disorder (OCD). The aim of this study was to investigate the serotonin transporter availability in patients with OCD as an in vivo marker of the central serotonergic system. METHODS: Nine unmedicated (7 drug-naive) patients with OCD and 10 healthy control subjects were included and received single photon emission computed tomography (SPECT) 20.75 +/- 1.51 hours after injection of a mean 147.20 +/- 6.74 MBq [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([(123)I]beta-CIT). As a measure of brain serotonin transporter availability, a ratio of specific-to-nonspecific [(123)I]beta-CIT binding for the midbrain-pons (V(3)" = [midbrain/pons-occipital]/occipital) was used. RESULTS: Mean specific-to-nonspecific ratios showed a 25% higher midbrain-pons [(123)I]beta-CIT binding in the patients as compared with healthy controls (2.26 +/-.37 vs. 1.81 +/-.23, p <.01). The difference remained significant after adjustment for clinical variables and controlling for age and gender. Stratification of the patients according to onset of the disorder revealed significant differences between controls and patients with early (childhood, adolescence) but not late (adult) onset of OCD. CONCLUSIONS: The study provides evidence of a serotonergic dysfunction in patients with OCD and suggests a serotonergic component in the pathophysiology of the disorder.     

Family-based association study of the serotonin-2A receptor gene (5-HT2A) and bipolar disorder

Objectives: The serotonin 2A receptor gene (5-HT2A) is of great interest for research in neuropsychiatric disorders based on the observation that various neuroleptic agents and antidepressants bind with relatively high affinity at 5-HT2A receptors, and the fact that the receptor density in platelets tends to increase in depression. To test for the presence of association between 5-HT2A and bipolar disorder (BP), we studied a large number of triad families having probands affected with DSM-IV bipolar I (BPI), bipolar II (BPII) or schizoaffective disorder, bipolar type. Methods: Two polymorphisms of 5-HT2A, 102T/C, and His452Tyr were analyzed in the 274 bipolar triad families. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data. We also calculated the maternal transmission and paternal transmission for each allele and compared the mean ages of onset across probands grouped by genotype at each of the two markers. Results: No significant transmission disequilibrium between the alleles of 5-HT2A and BP was found. Separate studies of the sub-phenotypes also failed to demonstrate significant association. However, we found a trend towards transmission disequilibrium with the haplotype 102C.His452 (p=0.0504). This trend may become more significant with a larger sample size. Significance: At present, results of this study suggest that the 5-HT2A is unlikely to play a major role in the genetic susceptibility to BP. Future studies will be directed towards increasing sample size, focusing on subtypes of BP or biochemical measures as phenotypes, and investigating other polymorphisms of 5-HT2A to provide more information at the DNA level.     

Common and rare alleles of the serotonin transporter gene,SLC6A4, associated with Tourette's disorder

To evaluate the hypothesis that functionally over‐expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, SLC6A4) are present in Tourette's disorder (TD), just as we previously observed in obsessive compulsive disorder (OCD), we evaluated TD probands (N = 151) and controls (N = 858). We genotyped the refined SERT‐linked polymorphic region 5‐HTTLPR/rs25531 and the associated rs25532 variant in the SLC6A4 promoter plus the rare coding variant SERT isoleucine‐to‐valine at position 425 (I425V). The higher expressing 5‐HTTLPR/rs25531 L_A allele was more prevalent in TD probands than in controls (χ² = 5.75; P = 0.017; odds ratio [OR], 1.35); and, in a secondary analysis, surprisingly, it was significantly more frequent in probands who had TD alone than in those who had TD plus OCD (Fisher's exact test; P = 0.0006; OR, 2.29). Likewise, the higher expressing L_AC haplotype (5‐HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls (P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group (P = 0.0013; OR, 2.14). Furthermore, the rare gain‐of‐function SERT I425V variant was observed in 3 male siblings with TD and/or OCD and in their father. Thus, the cumulative count of SERT I425V becomes 1.57% in OCD/TD spectrum conditions versus 0.15% in controls, with a recalculated, family‐adjusted significance of χ² = 15.03 (P < 0.0001; OR, 9.0; total worldwide genotyped, 2914). This report provides a unique combination of common and rare variants in one gene in TD, all of which are associated with SERT gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. The present results call for replication in a similarly intensively evaluated sample. © 2013 Movement Disorder Society     

Dysbindin (DTNBP1, 6p22.3) is Associated with Childhood-Onset Psychosis and Endophenotypes Measured by the Premorbid Adjustment Scale (PAS)

Straub et al. (2002) recently identified the 6p22.3 gene dysbindin (DTNBP1) through positional cloning as a schizophrenia susceptibility gene. We studied a rare cohort of 102 children with onset of psychosis before age 13. Standardized ratings of early development, medication response, neuropsychological and cognitive performance, premorbid dysfunction and clinical follow-up were obtained. Fourteen SNPs were genotyped in the gene DTNBP1. Family-based pairwise and haplotype transmission disequilibrium test (TDT) analysis with the clinical phenotype, and quantitative transmission disequilibrium test (QTDT) explored endophenotype relationships. One SNP was associated with diagnosis (TDT p=.01). The QTDT analyses showed several significant relationships. Four adjacent SNPs were associated (p values=.0009–.003) with poor premorbid functioning. These findings support the hypothesis that this and other schizophrenia susceptibility genes contribute to early neurodevelopmental impairment.     

5HT1Dbeta Receptor gene implicated in the pathogenesis of Obsessive-Compulsive Disorder: further evidence from a family-based association study

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.     

Examination of association of genes in the serotonin system to autism

Autism is characterized as one of the pervasive developmental disorders, a spectrum of often severe behavioral and cognitive disturbances of early development. The high heritability of autism has driven multiple efforts to identify genetic variation that increases autism susceptibility. Numerous studies have suggested that variation in peripheral and central metabolism of serotonin (5-hydroxytryptamine) may play a role in the pathophysiology of autism. We screened 403 autism families for 45 single nucleotide polymorphisms in ten serotonin pathway candidate genes. Although genome-wide linkage scans in autism have provided support for linkage to various loci located within the serotonin pathway, our study does not provide strong evidence for linkage to any specific gene within the pathway. The most significant association (p = 0.0002; p = 0.02 after correcting for multiple comparisons) was found at rs1150220 (HTR3A) located on chromosome 11 (∼113 Mb). To test specifically for multilocus effects, multifactor dimensionality reduction was employed, and a significant two-way interaction (p value = 0.01) was found between rs10830962, near MTNR1B (chromosome11; 92,338,075 bp), and rs1007631, near SLC7A5 (chromosome16; 86,413,596 bp). These data suggest that variation within genes on the serotonin pathway, particularly HTR3A, may have modest effects on autism risk. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Reduced availability of serotonin transporters in obsessive-compulsive disorder correlates with symptom severity – a [11C]DASB PET study

Summary Reduced availability of brainstem serotonin transporters (5-HTT) has been observed in vivo in obsessive-compulsive disorder (OCD). However, results vary and may be influenced by competition with endogenous serotonin. Using positron emission tomography (PET) and [¹¹C]DASB, a specific 5-HTT ligand that showed no competition with serotonin for 5-HTT binding in vitro, we tested the hypothesis that 5-HTT availability is reduced in OCD patients and correlated with OCD severity. Methods. 5-HTT availability in the thalamus and the midbrain was measured in nine drug-free OCD patients and compared with 19 healthy controls, matched for the individual combination of 5-HTT genotype, gender and smoking status. OCD severity was assessed with the Yale-Brown obsessive compulsive scale (Y-BOCS). Results. 5-HTT availability was significantly reduced in the thalamus and midbrain of OCD patients. Age and 5-HTT in the thalamus explained 83% of OCD severity in patients that were drug-free for at least 1 year. Conclusion. This PET study confirms a central role of the serotonergic system, particularly the thalamus in the pathogenesis of obsessive compulsive disorder. The first two authors contributed equally     

Obsessive-compulsive disorder and serotonin: is there a connection?

Reports of the antiobsessional efficacy of clomipramine have led to a "serotonin hypothesis" of obsessive-compulsive disorder (OCD). To test this hypothesis, 16 outpatients with DSM-III OCD were studied using several measures of serotonergic function. Platelet 3H-imipramine binding and serotonin uptake were not significantly different between the OCD patients and a normal, age-matched control group. The level of the metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) was significantly higher in a small cohort of obsessionals compared with healthy volunteers, possibly reflecting increased brain serotonin turnover. In a direct test of the role of serotonin uptake in clomipramine's antiobsessional effects, the serotonin uptake inhibitor zimelidine was compared with the noradrenergic uptake inhibitor desipramine in a double-blind, controlled study. Zimelidine reduced CSF 5-HIAA, but was clinically ineffective in this group. Desipramine had weak but significant clinical effects. Nonresponders to zimelidine or desipramine improved significantly during a subsequent double blind trial of clomipramine. These findings demonstrate that pharmacological blockade of serotonin reuptake alone is not sufficient for an antiobsessional response.     

Physiogenomic association of statin-related myalgia to serotonin receptors

We employed physiogenomic analyses to investigate the relationship between myalgia and selected polymorphisms in serotonergic genes, based on their involvement with pain perception and transduction of nociceptive stimuli. We screened 195 hypercholesterolemic, statin-treated patients, all of whom received either atorvastatin, simvastatin, or pravastatin. Patients were classified as having no myalgia, probable myalgia, or definite myalgia, and assigned a myalgia score of 0, 0.5, or 1, respectively. Fourteen single nucleotide polymorphisms (SNPs) were selected from candidates within the 5-HT receptor gene families [5a-hydroxytryptamine receptor genes (HTR) 1D, 2A, 2C, 3A, 3B, 5A, 6, 7] and the serotonin transporter gene (SLC6A4). SNPs in the HTR3B and HTR7 genes, rs2276307 and rs1935349, respectively, were significantly associated with the myalgia score. Individual differences in pain perception and nociception related to specific serotonergic gene variants may affect the development of myalgia in statin-treated patients.     

Association studies of serotonin system candidate genes in early-onset obsessive-compulsive disorder.

BACKGROUND: Family-based evidence for association at serotonin system genes SLC6A4, HTR1B, HTR2A, and brain-derived neurotrophic factor (BDNF) has been previously reported in obsessive-compulsive disorder (OCD). Early-onset OCD is a more familial form of the disorder. METHODS: We used the transmission-disequilibrium test of association at common polymorphisms in each of these genes in 54 parent-child trios ascertained through probands with early-onset OCD. RESULTS: No evidence for association was detected at any of the polymorphisms in the entire set of subjects. Nominally significant association was found at the HTR2A rs6311 polymorphism in subjects with tic disorder and OCD (p = .05), replicating a previous finding in Tourette syndrome and OCD. Nominally significant association was also found for the SLC6A4 HT transporter gene-linked polymorphic region (5-HTTLPR) polymorphism for female subjects (p = .03). Neither association would remain significant after statistical correction for multiple testing. Despite no individual study reporting replication, a pooled analysis of five replication studies of the SLC6A4 5-HTTLPR polymorphism supports association (p = .02). CONCLUSIONS: Low power across individual association studies in OCD may lead to a false acceptance of the null hypothesis. Accumulation of evidence from multiple studies will be necessary to evaluate the potential role for these genes in contributing to susceptibility to OCD.