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1.
PLoS Genet ; 9(10): e1003864, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24204291

RESUMEN

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.


Asunto(s)
Trastorno Obsesivo Compulsivo/genética , Carácter Cuantitativo Heredable , Síndrome de Tourette/genética , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Humanos , Trastorno Obsesivo Compulsivo/patología , Fenotipo , Polimorfismo de Nucleótido Simple , Síndrome de Tourette/patología
2.
Elife ; 122023 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-37254842

RESUMEN

Resident macrophages are distributed across all tissues and are highly heterogeneous due to adaptation to different tissue-specific environments. The resident macrophages of the sensory ganglia (sensory neuron-associated macrophages, sNAMs) are in close contact with the cell body of primary sensory neurons and might play physiological and pathophysiological roles. After peripheral nerve injury, there is an increase in the population of macrophages in the sensory ganglia, which have been implicated in different conditions, including neuropathic pain development. However, it is still under debate whether macrophage accumulation in the sensory ganglia after peripheral nerve injury is due to the local proliferation of resident macrophages or a result of blood monocyte infiltration. Here, we confirmed that the number of macrophages increased in the sensory ganglia after the spared nerve injury (SNI) model in mice. Using different approaches, we found that the increase in the number of macrophages in the sensory ganglia after SNI is a consequence of the proliferation of resident CX3CR1+ macrophages, which participate in the development of neuropathic pain, but not due to infiltration of peripheral blood monocytes. These proliferating macrophages are the source of pro-inflammatory cytokines such as TNF and IL-1b. In addition, we found that CX3CR1 signaling is involved in the sNAMs proliferation and neuropathic pain development after peripheral nerve injury. In summary, these results indicated that peripheral nerve injury leads to sNAMs proliferation in the sensory ganglia in a CX3CR1-dependent manner accounting for neuropathic pain development. In conclusion, sNAMs proliferation could be modulated to change pathophysiological conditions such as chronic neuropathic pain.


Asunto(s)
Neuralgia , Traumatismos de los Nervios Periféricos , Ratones , Animales , Traumatismos de los Nervios Periféricos/complicaciones , Ganglios Espinales , Macrófagos , Ganglios Sensoriales , Células Receptoras Sensoriales , Proliferación Celular , Hiperalgesia
3.
Pain ; 161(8): 1730-1743, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32701834

RESUMEN

The inflammatory/immune response at the site of peripheral nerve injury participates in the pathophysiology of neuropathic pain. Nevertheless, little is known about the local regulatory mechanisms underlying peripheral nerve injury that counteracts the development of pain. Here, we investigated the contribution of regulatory T (Treg) cells to the development of neuropathic pain by using a partial sciatic nerve ligation model in mice. We showed that Treg cells infiltrate and proliferate in the site of peripheral nerve injury. Local Treg cells suppressed the development of neuropathic pain mainly through the inhibition of the CD4 Th1 response. Treg cells also indirectly reduced neuronal damage and neuroinflammation at the level of the sensory ganglia. Finally, we identified IL-10 signaling as an intrinsic mechanism by which Treg cells counteract neuropathic pain development. These results revealed Treg cells as important inhibitory modulators of the immune response at the site of peripheral nerve injury that restrains the development of neuropathic pain. In conclusion, the boosting of Treg cell function/activity might be explored as a possible interventional approach to reduce neuropathic pain development after peripheral nerve damage.


Asunto(s)
Neuralgia , Traumatismos de los Nervios Periféricos , Linfocitos T Reguladores , Animales , Hiperalgesia , Ratones , Ratones Endogámicos C57BL , Traumatismos de los Nervios Periféricos/complicaciones , Nervio Ciático , Células TH1
4.
Front Integr Neurosci ; 11: 39, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29311861

RESUMEN

The sense of agency (SoA) is a multifaceted construct, which can be defined as the ability to understand the causal relationships between our actions and sensory events. Obsessive-Compulsive Disorder (OCD) patients with checking compulsions often report a "lack of action completion" sensations, which has been conceptualized in the so-called "Not Just Right Experiences" construct. An intriguing explanation of this phenomenon comes from Belayachi and Van der Linden (2009, 2010), who suggest that OCD-checking patients are more prone to specify their action in a relatively molecular and inflexible way. Currently, there are no studies in literature which address this issue in OCD patients, except for the one of Gentsch et al. (2012), who suggested an altered SoA in these patients. Here we exploited a novel construct, gaze agency, to evaluate causal attribution capabilities in a group of 21 OCD patients (checkers) and matched healthy controls (HCs). Basically, two tasks targeted observers' capability to identify their own eye movements as the cause of concurrently presented beeps, which allowed us to measure agency sensitivity as well as subtle agency alterations in an ecological setting. We found a poorer performance in OCD patients as compared to HCs in many parameters of our tasks, suggesting a difficulty with causal attribution possibly due to both a reduced cognitive flexibility and a less functional gaze agency in OCD patients.

5.
Am J Psychiatry ; 172(1): 82-93, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25158072

RESUMEN

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. METHOD: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. RESULTS: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). CONCLUSIONS: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.


Asunto(s)
Trastorno Obsesivo Compulsivo/genética , Síndrome de Tourette/genética , Adulto , Comorbilidad , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/epidemiología , Polimorfismo de Nucleótido Simple , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Síndrome de Tourette/diagnóstico , Síndrome de Tourette/epidemiología
6.
J Am Acad Child Adolesc Psychiatry ; 53(8): 910-9, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25062598

RESUMEN

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. METHOD: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. RESULTS: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). CONCLUSION: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.


Asunto(s)
Variaciones en el Número de Copia de ADN , Trastorno Obsesivo Compulsivo/genética , Síndrome de Tourette/genética , Adolescente , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Trastorno Obsesivo Compulsivo/diagnóstico , Polimorfismo de Nucleótido Simple , Síndrome de Tourette/diagnóstico
7.
Obes Facts ; 5(3): 408-19, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22797368

RESUMEN

OBJECTIVE: The common single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity-associated gene (FTO) is associated with obesity. As genetic variants associated with weight regulation might also be implicated in the etiology of eating disorders, we evaluated whether SNP rs9939609 is associated with bulimia nervosa (BN) and anorexia nervosa (AN). METHODS: Association of rs9939609 with BN and AN was assessed in 689 patients with AN, 477 patients with BN, 984 healthy non-population-based controls, and 3,951 population-based controls (KORA-S4). Based on the familial and premorbid occurrence of obesity in patients with BN, we hypothesized an association of the obesity risk A-allele with BN. RESULTS: In accordance with our hypothesis, we observed evidence for association of the rs9939609 A-allele with BN when compared to the non-population-based controls (unadjusted odds ratio (OR) = 1.142, one-sided 95% confidence interval (CI) 1.001-∞; one-sided p = 0.049) and a trend in the population-based controls (OR = 1.124, one-sided 95% CI 0.932-∞; one-sided p = 0.056). Interestingly, compared to both control groups, we further detected a nominal association of the rs9939609 A-allele to AN (OR = 1.181, 95% CI 1.027-1.359, two-sided p = 0.020 or OR = 1.673, 95% CI 1.101-2.541, two-sided p = 0.015,). CONCLUSION: Our data suggest that the obesity-predisposing FTO allele might be relevant in both AN and BN.


Asunto(s)
Alelos , Anorexia Nerviosa/genética , Bulimia Nerviosa/genética , Genotipo , Obesidad/genética , Polimorfismo de Nucleótido Simple , Proteínas/genética , Adolescente , Adulto , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Niño , Intervalos de Confianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Riesgo , Adulto Joven
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