RESUMEN
Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.
Asunto(s)
Adenosina Desaminasa/genética , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/genética , ARN Helicasas DEAD-box/genética , Exodesoxirribonucleasas/genética , Proteínas de Unión al GTP Monoméricas/genética , Mutación , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/genética , Fenotipo , Fosfoproteínas/genética , Ribonucleasa H/genética , Estudios de Asociación Genética , Genotipo , Humanos , Helicasa Inducida por Interferón IFIH1 , Interferones/sangre , Interferones/líquido cefalorraquídeo , Pterinas/líquido cefalorraquídeo , Proteína 1 que Contiene Dominios SAM y HDRESUMEN
The catechol-o-methyltransferase (COMT) gene has been extensively investigated in depression with somewhat contradictory results but the role of impulsivity, as a possible intermediate phenotype in this disorder, has not been considered yet. In our study, four tagging SNPs in the COMT gene (rs933271, rs740603, rs4680, rs4646316) were genotyped in two independent population cohorts: Manchester (n = 1267) and Budapest (n = 942). First, we investigated the association between COMT genotypes, impulsivity, neuroticism and depression using haplotype trend regression, and constructed a model using structural equation modeling to investigate the interaction between these factors. Secondly, we tested the effect of executive function on this model in a smaller interviewed sample (n = 207). Our results demonstrated that COMT haplotypes were significantly associated with impulsivity in the combined cohort, showing the same direction of effects in both populations. The COMT effect on depressive symptoms (in subjects without history of depression) and on executive function (interviewed sample) showed the opposite pattern to impulsivity. Structural equation models demonstrated that COMT and impulsivity acted, both together (through neuroticism) and independently, to increase the risk of depression. In addition, better executive function also operated as a risk factor for depression, possibly though reduced ability to flexibly disengage negative emotions. In conclusion, variations in the COMT gene exert complex effects on susceptibility to depression involving various intermediate phenotypes, such as impulsivity and executive function. These findings emphasise that modeling of disease pathways at phenotypic level are valuable for identifying genetic risk factors.
Asunto(s)
Catecol O-Metiltransferasa/genética , Trastorno Depresivo Mayor/genética , Función Ejecutiva , Conducta Impulsiva/genética , Adolescente , Adulto , Trastornos de Ansiedad/genética , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Mucosa Bucal/citología , Trastornos Neuróticos/genética , Neuroticismo , Polimorfismo de Nucleótido Simple , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Negative biases in emotional processing are well recognised in people who are currently depressed but are less well described in those with a history of depression, where such biases may contribute to vulnerability to relapse. AIMS: To compare accuracy, discrimination and bias in face emotion recognition in those with current and remitted depression. METHOD: The sample comprised a control group (n = 101), a currently depressed group (n = 30) and a remitted depression group (n = 99). Participants provided valid data after receiving a computerised face emotion recognition task following standardised assessment of diagnosis and mood symptoms. RESULTS: In the control group women were more accurate in recognising emotions than men owing to greater discrimination. Among participants with depression, those in remission correctly identified more emotions than controls owing to increased response bias, whereas those currently depressed recognised fewer emotions owing to decreased discrimination. These effects were most marked for anger, fear and sadness but there was no significant emotion × group interaction, and a similar pattern tended to be seen for happiness although not for surprise or disgust. These differences were confined to participants who were antidepressant-free, with those taking antidepressants having similar results to the control group. CONCLUSIONS: Abnormalities in face emotion recognition differ between people with current depression and those in remission. Reduced discrimination in depressed participants may reflect withdrawal from the emotions of others, whereas the increased bias in those with a history of depression could contribute to vulnerability to relapse. The normal face emotion recognition seen in those taking medication may relate to the known effects of antidepressants on emotional processing and could contribute to their ability to protect against depressive relapse.
Asunto(s)
Trastorno Depresivo Mayor/psicología , Emociones , Expresión Facial , Reconocimiento en Psicología , Adolescente , Adulto , Análisis de Varianza , Antidepresivos/farmacología , Trastornos de Ansiedad/epidemiología , Estudios de Casos y Controles , Comorbilidad , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/epidemiología , Discriminación en Psicología , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Tiempo de Reacción , Recurrencia , Adulto JovenRESUMEN
Serotonin-1A (5-HT(1A)) receptors are known to play a role in impulsivity-related behavior. The C(-1019)G functional polymorphism (rs6295) has been suggested to regulate the 5-HT(1A) receptor gene (HTR(1A)) expression in presynaptic raphe neurons, namely, increased receptor concentration and reduced neuronal firing could be associated with the G allele. Previous studies indicate that this polymorphism is associated with aggression, suicide, and several psychiatric disorders, yet its association with impulsivity has rarely been investigated. We studied the relationship between impulsivity and the C(-1019)G polymorphism of the HTR(1A) in a population sample of 725 volunteers using the Impulsiveness subscale (IVE-I) of the Eysenck Impulsiveness, Venturesomeness, and Empathy scale and also the Barratt Impulsiveness Scale (BIS-11). Data were analyzed using analysis of variance with age and gender as covariates and Tukey's HSD post-hoc test. Post-hoc analysis revealed that the study had 0.958 power to detect 0.15 effect size. Significant differences between the C(-1019)G genotype groups (GG vs. GC vs. CC) were found. Subjects carrying GG genotype showed significantly higher impulsiveness scores compared to GC or CC carriers for the IVE-I scale (P = 0.014), for the Motor (P = 0.021), Cognitive Impulsiveness (P = 0.002), and for the BIS total score (P = 0.008) but not for the Nonplanning Impulsiveness (P = 0.520) subscale of the BIS-11. Our results suggest the involvement of the HTR(1A) in the continuum phenotype of impulsivity.
Asunto(s)
Conducta Impulsiva/genética , Polimorfismo Genético , Receptor de Serotonina 5-HT1A/genética , Adolescente , Adulto , Factores de Edad , Alelos , Cognición , Femenino , Genética Conductual , Genotipo , Humanos , Masculino , Neuronas/metabolismo , Factores SexualesRESUMEN
Two DNA polymorphisms in the XRCC1 gene, a microsatellite repeat region in the 3' un-translated region (3'UTR) of the gene and a G-->A substitution resulting in an Arg to Gln amino acid change in codon 399, were examined in 189 newborns who had previously been studied for glycophorin A (GPA) N0 and NN variant frequencies (Vfs) in cord blood erythrocytes. The GPA analysis had revealed that 14 of the 189 had extreme NN Vfs ranging from 40 x 10(-6) to 1787 x 10(-6). Mean Vfs for the remaining 175 were N0=(4.8+/-2.80)x10(-6) and NN=(2.62+/-2.01)x10(-6). Seven alleles of a polymorphic tandem [AC](n) region of the XRCC1 gene were identified. No association between [AC](n) genotype and either N0 or NN Vfs was found amongst the group of 175 nor was the distribution of genotypes unusual for the group of 14 with extreme NN Vfs. Analysis of the 399Gln polymorphism revealed that for the group of 175, 36.0% were Arg/Arg, 49.7% Arg/Gln and 14.3% Gln/Gln and genotype had no influence on N0 and NN Vfs. However, the distribution of genotypes was significantly different in the group of 14 with extreme NN Vfs, 14.3% being Arg/Arg, 42.8% Arg/Gln and 42.8% Gln/Gln. The 14 newborns with extreme NN Vfs may represent a sub-group with an unidentified genotoxic exposure and/or predisposition to gene-duplication mutations or alternatively the high values could have arisen by increased clonal expansion of haemopoietic precursor cells carrying NN mutations. Our results suggest that carriers of the Gln/Gln genotype are over represented in this group but the role that the genotype has in the derivation of high NN Vfs remains to be resolved.
Asunto(s)
Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Glicoforinas/genética , Mutación , Polimorfismo Genético , Secuencia de Bases , Cartilla de ADN , Genotipo , Humanos , Recién Nacido , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
BACKGROUND: Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. METHODS: In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. FINDINGS: 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. INTERPRETATION: AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. FUNDING: European Union's Seventh Framework Programme; European Research Council.
Asunto(s)
Adenosina Desaminasa/genética , Enfermedades Autoinmunes del Sistema Nervioso/metabolismo , Exodesoxirribonucleasas/genética , Regulación de la Expresión Génica , Interferón Tipo I/fisiología , Proteínas de Unión al GTP Monoméricas/genética , Malformaciones del Sistema Nervioso/metabolismo , Fosfoproteínas/genética , Ribonucleasa H/genética , Adolescente , Adulto , Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/genética , Biomarcadores , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Heterogeneidad Genética , Genotipo , Humanos , Lactante , Interferón Tipo I/sangre , Interferón Tipo I/líquido cefalorraquídeo , Interferón Tipo I/inmunología , Masculino , Mutación , Malformaciones del Sistema Nervioso/genética , Pruebas de Neutralización , Estudios Prospectivos , ARN Mensajero/biosíntesis , Proteínas de Unión al ARN , Proteína 1 que Contiene Dominios SAM y HD , Regulación hacia Arriba , Adulto JovenRESUMEN
OBJECTIVES: Hopelessness is one of the strongest risk factors for suicidal behavior but relevant genetic studies are poorly available. Tryptophan hydroxylase (TPH) is widely considered to be a good candidate for genetic association studies on depression and suicide, however, investigations on these complex, multifactorial phenotypes have resulted in conflicting data. We hypothesized that hopelessness could be a mediating phenotype between TPH2 gene, depression and suicidal behavior. METHODS: Depressive phenotype and suicidal risk were investigated of 760 individuals from general population by Zung Self Rating Depression Scale (ZDS), Beck's Hopelessness Scale (BHS) and a detailed background questionnaire. All participants' DNA samples were genotyped for 7 tag SNPs in TPH2 gene. Generalized linear models were performed for single marker association studies and p-values were corrected by Bonferroni criteria. In haplotype analyses score tests were used and permutated p-values were computed. RESULTS: Four SNPs of TPH2 gene showed association with hopelessness but only rs6582078 had a significant effect on the BHS scores after Bonferroni's correction; GG individuals had significantly higher BHS scores, while GT and TT had intermediate and lower BHS scores respectively (p=0.0047). Compared with other genotypes, homozygous GG individuals also had almost three times greater estimated suicidal risk, as did carriers of the AA genotype of rs6582078 (OR=2.87; p=0.005) and also of rs1352250 (OR=2.86; p=0.006). A risk and a protective haplotype of TPH2 gene were also identified in association with hopelessness. ZDS scores have not shown any association with TPH2 gene. CONCLUSIONS: We found that hopelessness, with its allied increased suicidal risk was strongly associated with TPH2 gene variants in multiple tests. These findings suggest that TPH2 gene confers risk for suicidal behavior while hopelessness can be a potential endophenotype for suicidal vulnerability.
Asunto(s)
Emociones/fisiología , Endofenotipos , Variación Genética/genética , Ideación Suicida , Triptófano Hidroxilasa/genética , Adulto , Femenino , Humanos , Masculino , Factores de Riesgo , Suicidio/psicología , Adulto JovenRESUMEN
BACKGROUND: The neuroplastic pathway, which includes cyclic adenosine monophosphate response element-binding protein 1 (CREB1), brain-derived neurotrophic factor (BDNF), and its receptor (neurotrophic tyrosine kinase receptor, type 2 [NTRK2]), plays a crucial role in the adaptation of brain to stress, and thus variations of these genes are plausible risk factors for depression. METHODS: A population-based sample was recruited, subsets of which were interviewed and underwent functional magnetic resonance imaging. We investigated the association of nine polymorphisms throughout the CREB1-BDNF-NTRK2 pathway with lifetime depression, rumination, current depression severity, negative life events, and sad face emotion processing in a three-level design. RESULTS: In the population study, BDNF-rs6265 and CREB1-rs2253206 major alleles were significantly associated with rumination and through rumination with current depression severity. However, childhood adversity increased the risk of lifetime depression in the minor allele carriers of BDNF-rs6265 and CREB1-rs2253206 and in alleles of six other single nucleotide polymorphisms (SNPs). We validated our findings in the interviewed subjects using structural equation modeling. Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF-rs6265 and CREB1-rs2253206. CONCLUSIONS: Genetic variation associated with reduced function in the CREB1-BDNF-NTRK2 pathway has multiple, sometimes opposing, influences on risk mechanisms of depression, but almost all the SNPs studied amplified the effect of childhood adversity. The use of cognitive and neural intermediate phenotypes together with a molecular pathway approach may be critical to understanding how genes influence risk of depression.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Trastorno Depresivo/genética , Polimorfismo de Nucleótido Simple , Receptor trkB/genética , Adolescente , Adulto , Alelos , Encéfalo/fisiopatología , Mapeo Encefálico , Trastorno Depresivo/fisiopatología , Femenino , Regulación de la Expresión Génica , Estudios de Asociación Genética , Variación Genética , Genotipo , Haplotipos , Humanos , Procesamiento de Imagen Asistido por Computador , Acontecimientos que Cambian la Vida , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
The serotonergic system has been widely implicated in stress related psychiatric disorders such as depression and anxiety. We investigated the possible association between depression and anxiety scores and SNPs within the HTR1A and HTR1B genes in a population sample (n=1387). There was no direct SNP-phenotype association, but in interaction with recent stressful life events rs6295 G, rs878567 T alleles and rs6296 C alleles were associated with significantly higher symptom scores. A subset of control subjects (n=101) took part in a computerised face emotion processing task. Healthy rs6295 GG carriers did not show an affective bias to perceive more negative emotions but reacted more quickly to fearful faces. Thus we conclude that the serotonin-1A receptor conveys vulnerability to these psychiatric disorders by modulating threat-related information processing. Our results extend previous findings of an interaction between stressful life events and the serotonin transporter gene to two other genes in the serotonergic pathway and emphasise the possible role of increased threat-related information processing as an intermediate phenotype.
Asunto(s)
Ansiedad/genética , Cognición , Depresión/genética , Acontecimientos que Cambian la Vida , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT1B/genética , Estrés Psicológico/genética , Adulto , Alelos , Ansiedad/psicología , Estudios de Cohortes , ADN/análisis , ADN/genética , Depresión/psicología , Emociones , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Escalas de Valoración Psiquiátrica , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Estrés Psicológico/psicología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Decision making, choosing the best option from the possible outcomes, is impaired in many psychiatric conditions including affective disorders. We tested the hypothesis that variations in serotonergic genes (TPH2, TPH1, SLC6A4, HTR1A), which influence serotonin availability, affect choice behavior in a probabilistic gambling task. A population cohort (N=1035) completed a paper-and-pencil gambling task, filled out personality and symptom questionnaires and gave consent for the use of their DNA in a genetic association study. A subgroup of subjects (N=69) also completed a computer version of the task. The gambling task was designed to estimate an individual's tendency to take a risk when choosing between a smaller but more certain 'win' and a larger, less probable one. We genotyped seven haplotype tagging SNPs in the TPH2 gene, and previously reported functional polymorphisms from the other genes (rs1800532, 5HTTLPR, and rs6295). Carriers of the more prevalent TPH2 haplotype, which was previously associated with less active enzyme variant, showed reduced risk taking on both tasks compared with subjects not carrying the common haplotype. The effect of TPH2 haplotypes on risk-taking was independent of current depression and anxiety symptoms, neuroticism and impulsiveness scores. We did not find an association between functional polymorphisms in the TPH1, SLC6A4, HTR1A genes and risk-taking behavior. In conclusion, our study demonstrates the role of the TPH2 gene and the serotonin system in risk taking and suggests that TPH2 gene may contribute to the expression of psychiatric phenotypes through altered decision making.
Asunto(s)
Juego de Azar , Polimorfismo de Nucleótido Simple , Asunción de Riesgos , Triptófano Hidroxilasa/genética , Adulto , Estudios de Cohortes , Toma de Decisiones , Femenino , Estudios de Asociación Genética , Haplotipos , Heterocigoto , Humanos , Masculino , Trastornos Mentales/genética , Pruebas de Personalidad , Fenotipo , Receptor de Serotonina 5-HT1A/genética , Análisis de Secuencia de ADN , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Encuestas y CuestionariosRESUMEN
Cannabinoid receptor 1 (CB1) gene (CNR1) knockout mice are prone to develop anhedonic and helpless behavior after chronic mild stress. In humans, the CB1 antagonist rimonabant increases the risk of depressed mood disorders and anxiety. These studies suggest the hypothesis that genetic variation in CB1 receptor function influences the risk of depression in humans in response to stressful life events. In a population sample (n=1269), we obtained questionnaire measures of personality (Big Five Inventory), depression and anxiety (Brief Symptom Inventory), and life events. The CNR1 gene was covered by 10 SNPs located throughout the gene to determine haplotypic association. Variations in the CNR1 gene were significantly associated with a high neuroticism and low agreeableness phenotype (explained variance 1.5 and 2.5%, respectively). Epistasis analysis of the SNPs showed that the previously reported functional 5' end of the CNR1 gene significantly interacts with the 3' end in these phenotypes. Furthermore, current depression scores significantly associated with CNR1 haplotypes but this effect diminished after covariation for recent life events, suggesting a gene x environment interaction. Indeed, rs7766029 showed highly significant interaction between recent negative life events and depression scores. The results represent the first evidence in humans that the CNR1 gene is a risk factor for depression--and probably also for co-morbid psychiatric conditions such as substance use disorders--through a high neuroticism and low agreeableness phenotype. This study also suggests that the CNR1 gene influences vulnerability to recent psychosocial adversity to produce current symptoms of depression.
Asunto(s)
Química Encefálica/genética , Trastorno Depresivo/genética , Predisposición Genética a la Enfermedad/genética , Trastornos Neuróticos/genética , Personalidad/genética , Receptor Cannabinoide CB1/genética , Adaptación Psicológica/fisiología , Adolescente , Adulto , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/psicología , Análisis Mutacional de ADN , Trastorno Depresivo/metabolismo , Trastorno Depresivo/psicología , Ambiente , Femenino , Pruebas Genéticas , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Trastornos Neuróticos/metabolismo , Trastornos Neuróticos/fisiopatología , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Encuestas y Cuestionarios , Adulto JovenRESUMEN
In animal models endogenous cannabinoids have an inhibitory effect on trigeminovascular activation through the cannabinoid receptor 1 (CB1), although there is no evidence of the potential role of CB1 in human migraine. In this study we applied single marker association and haplotypic trend regression analysis to investigate the relationship between the CB1 gene (CNR1) and headache with migraine symptoms (nausea, photophobia and disability, measured by the ID-migraine questionnaire). We identified our controls (CO=684) as those who have not reported ID-migraine symptoms at all and defined migraine headache sufferers (M=195) as those who reported all three symptoms. The CNR1 was covered by 10 SNPs located throughout the gene based on haplotype tagging (htSNP) and previous literature. Our results demonstrated a significant haplotypic effect of CNR1 on migraine headaches (p=0.008, after permutation p=0.017). This effect was independent of reported depression or drug/alcohol abuse although using neuroticism in the analysis as covariant slightly decreased this association (p=0.027, permutated p=0.052). These results suggest a significant effect of CNR1 on migraine headaches that might be related to the alteration of peripheral trigeminovascular activation. In addition, this is the first study to demonstrate the effectiveness of using trait components combinations to define extreme phenotypes with haplotype analysis in genetic association studies for migraine. However, further studies are needed to elucidate the role of CNR1 and the cannabinoid system in migraine.