RESUMEN
Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.
Asunto(s)
Trastorno Obsesivo Compulsivo/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Autoinforme , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Resultado del TratamientoRESUMEN
Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.
Asunto(s)
Salud de la Familia , Predisposición Genética a la Enfermedad/genética , Trastorno Obsesivo Compulsivo/genética , Adulto , Cromosomas Humanos Par 9/genética , Conducta Cooperativa , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Adulto JovenRESUMEN
Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Proteínas del Tejido Nervioso/genética , Trastorno Obsesivo Compulsivo/genética , Estudios de Casos y Controles , Lóbulo Frontal/metabolismo , Humanos , Padres , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Proteínas Asociadas a SAP90-PSD95 , Población Blanca/genéticaRESUMEN
A possible side effect of serotonin-enhancing drugs is the serotonin syndrome, which can be lethal. Here we examined possible hypersensitivity to two such drugs, the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) and the atypical opioid tramadol, in mice lacking the genes for both monoamine oxidase A (MAOA) and MAOB. MAOA/B-knockout (KO) mice displayed baseline serotonin syndrome behaviors, and these behavioral responses were highly exaggerated following 5-HTP or tramadol versus baseline and wild-type (WT) littermates. Compared with MAOA/B-WT mice, baseline tissue serotonin levels were increased â¼2.6-3.9-fold in MAOA/B-KO mice. Following 5-HTP, serotonin levels were further increased â¼4.5-6.2-fold in MAOA/B-KO mice. These exaggerated responses are in line with the exaggerated responses following serotonin-enhancing drugs that we previously observed in mice lacking the serotonin transporter (SERT). These findings provide a second genetic mouse model suggestive of possible human vulnerability to the serotonin syndrome in individuals with lesser-expressing MAO or SERT polymorphisms that confer serotonergic system changes.
Asunto(s)
Hipersensibilidad a las Drogas , Monoaminooxidasa/genética , Mutación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Secuencia de Bases , Cartilla de ADN , Ratones , Ratones Noqueados , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversosRESUMEN
The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.
Asunto(s)
Sistema de Transporte de Aminoácidos X-AG/genética , Neuronas/metabolismo , Trastorno Obsesivo Compulsivo/genética , Sistema de Transporte de Aminoácidos X-AG/química , Estudios de Casos y Controles , Femenino , Marcadores Genéticos , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Experts have proposed removing obsessive-compulsive disorder (OCD) from the anxiety disorders section and grouping it with putatively related conditions in DSM-5. The current study uses co-morbidity and familiality data to inform these issues. METHOD: Case family data from the OCD Collaborative Genetics Study (382 OCD-affected probands and 974 of their first-degree relatives) were compared with control family data from the Johns Hopkins OCD Family Study (73 non-OCD-affected probands and 233 of their first-degree relatives). RESULTS: Anxiety disorders (especially agoraphobia and generalized anxiety disorder), cluster C personality disorders (especially obsessive-compulsive and avoidant), tic disorders, somatoform disorders (hypochondriasis and body dysmorphic disorder), grooming disorders (especially trichotillomania and pathological skin picking) and mood disorders (especially unipolar depressive disorders) were more common in case than control probands; however, the prevalences of eating disorders (anorexia and bulimia nervosa), other impulse-control disorders (pathological gambling, pyromania, kleptomania) and substance dependence (alcohol or drug) did not differ between the groups. The same general pattern was evident in relatives of case versus control probands. Results in relatives did not differ markedly when adjusted for demographic variables and proband diagnosis of the same disorder, though the strength of associations was lower when adjusted for OCD in relatives. Nevertheless, several anxiety, depressive and putative OCD-related conditions remained significantly more common in case than control relatives when adjusting for all of these variables simultaneously. CONCLUSIONS: On the basis of co-morbidity and familiality, OCD appears related both to anxiety disorders and to some conditions currently classified in other sections of DSM-IV.
Asunto(s)
Trastornos de Ansiedad/epidemiología , Familia/psicología , Predisposición Genética a la Enfermedad , Trastornos Mentales/epidemiología , Adolescente , Adulto , Trastornos de Ansiedad/clasificación , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/patología , Niño , Preescolar , Comorbilidad , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Métodos Epidemiológicos , Femenino , Humanos , Entrevista Psicológica , Masculino , Trastornos Mentales/clasificación , Trastornos Mentales/genética , Persona de Mediana Edad , Trastorno Obsesivo Compulsivo/clasificación , Trastorno Obsesivo Compulsivo/epidemiología , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/patología , Fenotipo , Factores Socioeconómicos , Adulto JovenRESUMEN
Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj) = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.
Asunto(s)
Trastorno Obsesivo Compulsivo/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adolescente , Adulto , Niño , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido Simple , Distribución por Sexo , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Despite evidence that obsessive-compulsive disorder (OCD) is a familial neuropsychiatric condition, progress aimed at identifying genetic determinants of the disorder has been slow. The OCD Collaborative Genetics Study (OCGS) has identified several OCD susceptibility loci through linkage analysis. METHODS: In this study we investigate two regions on chromosomes 15q and 1q by first refining the linkage region using additional short tandem repeat polymorphic (STRP) markers. We then performed association analysis on single nucleotide polymorphisms (SNP) genotyped (markers placed every 2-4 kb) in the linkage regions in the OCGS sample of 376 rigorously phenotyped affected families. RESULTS: Three SNPs are most strongly associated with OCD: rs11854486 (P = 0.00005 [0.046 after adjustment for multiple tests]; genetic relative risk (GRR) = 11.1 homozygous and 1.6 heterozygous) and rs4625687 [P = 0.00007 (after adjustment = 0.06); GRR = 2.4] on 15q; and rs4387163 (P = 0.0002 (after adjustment = 0.08); GRR = 1.97) on 1q. The first SNP is adjacent to NANOGP8, the second SNP is in MEIS2, and the third is 150 kb between PBX1 and LMX1A. CONCLUSIONS: All the genes implicated by association signals are homeobox genes and are intimately involved in neurodevelopment. PBX1 and MEIS2 exert their effects by the formation of a heterodimeric complex, which is involved in development of the striatum, a brain region involved in the pathophysiology of OCD. NANOGP8 is a retrogene of NANOG, a homeobox transcription factor known to be involved in regulation of neuronal development. These findings need replication; but support the hypothesis that genes involved in striatal development are implicated in the pathogenesis of OCD.
Asunto(s)
Genes Homeobox/genética , Predisposición Genética a la Enfermedad , Trastorno Obsesivo Compulsivo/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 15/genética , Ligamiento Genético , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
SLC1A1, which encodes the neuronal and epithelial glutamate transporter, is a promising candidate gene for obsessive-compulsive disorder (OCD). In this study, we conducted capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) screen for all 12 identified exons, including all coding regions and approximately 50 bp of flanking introns of the human SLC1A1 in 378 OCD-affected individuals. Full sequencing was completed on samples that showed an aberrant SSCP tracing for identification of the underlying sequence variants. Our aim was to determine if there are differences in the frequencies of relatively common alleles, or rare functional alleles, in 378 OCD cases and 281 ethnically matched controls. We identified one nonsynonymous coding SNP (c.490A > G, T164A) and three synonymous coding SNP (c.81G > C, A27A; c.414A > G, T138T; c.1110T > C, T370T) in case samples. We found no statistical differences in genotype and allele frequencies of common cSNPs in SLC1A1 between the OCD cases and controls. The rare variant T164A was found only in one family. Further investigation of this variant is necessary to determine whether and how it is related to OCD. There was no other evidence of significant accumulation of deleterious coding mutations in SLC1A1 in the OCD cases.
Asunto(s)
Alelos , Transportador 3 de Aminoácidos Excitadores/genética , Trastorno Obsesivo Compulsivo/genética , Polimorfismo Genético , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Variación Genética , Genotipo , Humanos , Masculino , Mutación , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADN , Factores SexualesRESUMEN
BACKGROUND: Obsessive-compulsive disorder (OCD) is probably an etiologically heterogeneous condition. Many patients manifest other psychiatric syndromes. This study investigated the relationship between OCD and co-morbid conditions to identify subtypes. METHOD: Seven hundred and six individuals with OCD were assessed in the OCD Collaborative Genetics Study (OCGS). Multi-level latent class analysis was conducted based on the presence of eight co-morbid psychiatric conditions [generalized anxiety disorder (GAD), major depression, panic disorder (PD), separation anxiety disorder (SAD), tics, mania, somatization disorders (Som) and grooming disorders (GrD)]. The relationship of the derived classes to specific clinical characteristics was investigated. RESULTS: Two and three classes of OCD syndromes emerge from the analyses. The two-class solution describes lesser and greater co-morbidity classes and the more descriptive three-class solution is characterized by: (1) an OCD simplex class, in which major depressive disorder (MDD) is the most frequent additional disorder; (2) an OCD co-morbid tic-related class, in which tics are prominent and affective syndromes are considerably rarer; and (3) an OCD co-morbid affective-related class in which PD and affective syndromes are highly represented. The OCD co-morbid tic-related class is predominantly male and characterized by high conscientiousness. The OCD co-morbid affective-related class is predominantly female, has a young age at onset, obsessive-compulsive personality disorder (OCPD) features, high scores on the 'taboo' factor of OCD symptoms, and low conscientiousness. CONCLUSIONS: OCD can be classified into three classes based on co-morbidity. Membership within a class is differentially associated with other clinical characteristics. These classes, if replicated, should have important implications for research and clinical endeavors.
Asunto(s)
Trastornos Mentales/clasificación , Trastorno Obsesivo Compulsivo/clasificación , Adulto , Factores de Edad , Edad de Inicio , Comorbilidad , Estudios Transversales , Trastorno Depresivo Mayor/clasificación , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/psicología , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/genética , Trastornos Mentales/psicología , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/psicología , Determinación de la Personalidad/estadística & datos numéricos , Trastornos de la Personalidad/clasificación , Trastornos de la Personalidad/diagnóstico , Trastornos de la Personalidad/genética , Trastornos de la Personalidad/psicología , Psicometría , Factores Sexuales , Trastornos de Tic/clasificación , Trastornos de Tic/diagnóstico , Trastornos de Tic/genética , Trastornos de Tic/psicologíaRESUMEN
Storage-body diameter and volume, and the number of molecules of serotonin contained in a storage body, were estimated for blood platelets. In the human, 5.23 x 10(5) molecules of serotonin are contained in a storage body 198 nanometers in diameter, while in the cat, 31.2 x 10(5) molecules of this amine are contained in a storage body 298 nanometers in diameter.
Asunto(s)
Plaquetas/análisis , Serotonina/sangre , Animales , Plaquetas/citología , Gatos , Humanos , Organoides/análisisRESUMEN
A population of individuals potentially at risk for psychiatric disorders was identified by screening 375 college student volunteers for low platelet monoamine oxidase (MAO) activity levels. The lower and upper 10 per cent in MAO activity were interviewed and family history data were obtained. Low-MAO probands reported more frequent psychiatric or psychological counseling and problems with the law. Families of low MAO probands had an eightfold increase in the incidence of suicide or suicide attempts over those of high-MAO probands. This suggests that reduced MAO levels, reported previously in patients with affective disorders and chronic schizophrenia, may predict a vulnerability to psychiatric disorder.
Asunto(s)
Plaquetas/enzimología , Monoaminooxidasa/sangre , Trastornos Psicóticos/enzimología , Adolescente , Adulto , Femenino , Humanos , Masculino , Factores Sexuales , SuicidioRESUMEN
Markedly elevated nighttime concentrations of serotonin in rhesus monkey cerebrospinal fluid were reduced to daytime levels by exposing the monkeys to continuous light or to the beta-adrenergic antagonist propranolol. Nighttime elevations of melatonin in cerebrospinal fluid were also suppressed by propranolol and light. Serotonin released in large quantities at night appears to be regulated like melatonin, and may act as a cerebroventricular hormone to influence brain and pituitary function at night.
Asunto(s)
Ritmo Circadiano , Luz , Propranolol/farmacología , Serotonina/líquido cefalorraquídeo , Animales , Ritmo Circadiano/efectos de los fármacos , Humanos , Macaca mulatta , Masculino , Melatonina/fisiología , Ratas , Serotonina/fisiologíaRESUMEN
In humans and rhesus monkeys, dexamethasone decreased concentrations of plasma cortisol but did not alter circulating beta-endorphin immunoreactivity. Contrary to current theory suggesting that pituitary beta-endorphin and adrenocorticotropic hormone are controlled by identical regulatory mechanisms for synthesis and release, our evidence suggests that in higher primates the established glucocorticoid feedback mechanism for the adrenocorticotropic hormone-cortisol system does not regulate beta-endorphin secretion in the same way.
Asunto(s)
Dexametasona/farmacología , Endorfinas/sangre , Hormona Adrenocorticotrópica/metabolismo , Adulto , Animales , Endorfinas/metabolismo , Retroalimentación , Femenino , Haplorrinos , Humanos , Hidrocortisona/sangre , Macaca mulatta , Masculino , Adenohipófisis/metabolismo , Precursores de Proteínas/metabolismo , Especificidad de la Especie , Estrés Fisiológico/sangreRESUMEN
Administration of physostigmine to normal volunteers produced significant elevations in plasma cortisol and beta-endorphin immunoreactivity as well as alterations in mood, cognition, and behavior. These observations might be explained by a cholinergically mediated stress syndrome. However, peak elevations in plasma beta-endorphin immunoreactivity (but not in plasma cortisol) were significantly correlated with physostigmine-induced increases in depression ratings. These results suggest that a cholinergically mediated beta-endorphin pathway may be involved in the observed affective changes.
Asunto(s)
Emociones/efectos de los fármacos , Endorfinas/sangre , Hidrocortisona/sangre , Fisostigmina/farmacología , Conducta/efectos de los fármacos , HumanosRESUMEN
Monoamine oxidase activity in blood platelets was measured, with [(14)C]tryptamine as substrate, in 13 monozygotic twin pairs discordant for schizophrenia and in 23 normal volunteers. The monoamine oxidase activity of both schizophrenic and nonschizophrenic co-twins was significantly lower than it was for the normals, and it was highly correlated between twins. In addition, there was a significant inverse correlation between a measure of the degree of the schizophrenic disorder and the monoamine oxidase activity. These data suggest, but do not prove, that reduced platelet monoamine oxidase activity may provide a genetic marker for vulnerability to schizophrenia.
Asunto(s)
Plaquetas/enzimología , Monoaminooxidasa/sangre , Esquizofrenia/genética , Adulto , Isótopos de Carbono , Enfermedades en Gemelos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monoaminooxidasa/metabolismo , Fenotiazinas/uso terapéutico , Esquizofrenia/sangre , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/enzimología , Esquizofrenia Paranoide/enzimología , Esquizofrenia Paranoide/genética , Triptaminas/metabolismoRESUMEN
Increases in plasma prolactin concentrations produced by alpha-methyl-p-tyrosine, a catecholamine synthesis inhibitor, varied inversely with baseline platelet monoamine oxidase activity in 12 patients with chronic schizophrenia. In normal volunteers with low monoamine oxidase activity and in unmedicated patients with chronic schizophrenia, plasma prolactin concentrations varied directly with platelet monoamine oxidase activity. No such relationship was found in normal subjects with high platelet monoamine oxidase activity. These data suggest that platelet monoamine oxidase activity reflects monoaminergic activity in the tubero-infundibular system, which in turn affects plasma prolactin concentrations. This relationship may be important in patients with low platelet monoamine oxidase activity, such as some chronic schizophrenics.
Asunto(s)
Plaquetas/enzimología , Monoaminooxidasa/sangre , Prolactina/sangre , Humanos , Hipotálamo/fisiología , Metiltirosinas/farmacología , Esquizofrenia/sangreRESUMEN
Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.
Asunto(s)
Trastornos de Ansiedad/genética , Proteínas Portadoras/genética , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Trastornos Neuróticos/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Serotonina/metabolismo , Adolescente , Adulto , Alelos , Línea Celular , Femenino , Marcadores Genéticos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Núcleo Familiar , Pruebas de Personalidad , Fenotipo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , TransfecciónRESUMEN
SLC1A encodes the neuronal and epithelial glutamate transporter and was previously tested as a candidate for obsessive-compulsive disorder (OCD) by several research groups. Recently, three independent research groups reported significant association findings between OCD and several genetic variants in SLC1A1. This study reports the results from a family-based association study, which examined the association between 13 single nucleotide polymorphisms (SNPs) within or in proximity to the SLC1A1 gene. Although we did not replicate association findings for those significant SNPs reported by previous studies, our study indicated a strong association signal with the SNP RS301443 (P-value = 0.000067; Bonferroni corrected P-value = 0.0167) under a dominant model, with an estimated odds ratio of 3.5 (confidence interval: 2.66-4.50). Further, we conducted single SNP analysis after stratifying the full data set by the gender status of affected in each family. The P-value for RS301443 in families with the male affected was 0.00027, and the P-value in families with female affected was 0.076. The fact that we identified a signal which was not previously reported by the other research groups may be due to differences in study designs and sample ascertainment. However, it is also possible that this significant SNP may be part of a regulator for SLC1A1, given that it is roughly 7.5 kb away from the boundary of the SLC1A1 gene. However, this potential finding needs to be validated biologically. Further functional studies in this region are planned by this research group.
Asunto(s)
Transportador 3 de Aminoácidos Excitadores/genética , Familia , Predisposición Genética a la Enfermedad , Trastorno Obsesivo Compulsivo/genética , Adolescente , Edad de Inicio , Niño , Femenino , Genotipo , Humanos , Masculino , Núcleo Familiar , Linaje , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
Several clinical and genetic studies have reported gender differences in obsessive-compulsive disorder (OCD). Previously, we conducted a linkage genome scan using multipoint allele-sharing methods to test for linkage in 219 families participating in the OCD Collaborative Genetics Study. When these families were stratified by proband's gender, suggestive linkage to chromosome 11p15 at marker D11S2362 (KAC(all) = 2.92, P = 0.00012) was detected in families with male probands, but not in the ones with female probands. We have since conducted fine mapping with a denser microsatellite marker panel in the region of 11p15, and detected a significant linkage signal at D11S4146 (KAC(all) = 5.08, P < 0.00001) in the families of male probands. Subsequently, 632 SNPs were genotyped spanning a 4.0 Mb region of the 1 LOD unit interval surrounding the linkage peak in the original families and an additional 165 families. Six SNPs were associated with OCD (P < 0.001): two SNPs were identified when all the families were included, and four SNPs only in male proband families. No SNP showed significant association with the OCD phenotype only in the families with a female proband. The results suggest a possible gender effect in the etiology of OCD.