DISC1 y psicosis no afectiva: variaciones en endofenotipos y características clínicas en primeros episodios de psicosis
- Autores: Javier Vázquez Bourgon
- Directores de la Tesis: Benedicto Crespo Facorro (dir. tes.)
- Lectura: En la Universidad de Cantabria ( España ) en 2016
- Idioma: español
- Número de páginas: 169
- Títulos paralelos:
- DISC1 and non-affective psychosis: effect on endophenotypes and clinical characteristics in first episode psychosis
- Tribunal Calificador de la Tesis: Julio Sanjuán Arias (presid.), Álvaro Marcelino Díaz Martínez (secret.), Paolo Brambilla (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: UCrea
- Resumen
- español
Antecedentes La esquizofrenia es un trastorno psiquiátrico grave, resultante de la interacción conjunta de múltiples factores ambientales y genéticos. El gen Disrupted-in-Schizophrenia 1 (DISC1) destaca por su relevancia en el trastorno. Hay evidencia de su asociación tanto con la enfermedad, como con varios endofenotipos. Sin embargo, hay una falta de estudios sobre sus efectos longitudinalmente y en muestras de primeros episodios.
Métodos Doscientos veintiséis pacientes caucásicos con un primer episodio de psicosis fueron genotipados para rs821616, rs6675281 y rs1000731. La gravedad clínica, el funcionamiento neurocognitivo y la estructura cerebral (grosor cortical) se evaluaron al inicio y 3 años después de iniciar el tratamiento.
Resultados No encontramos asociación entre variaciones en el gen y riesgo de psicosis. Sin embargo, los pacientes homocigotos para el alelo Ser (Ser704Cys) presentaron síntomas positivos de mayor gravedad, en comparación con los portadores de Cys. Los pacientes que portan el alelo A (rs1000731) mostraron una mejora significativa en la memoria de trabajo y atención, y los homocigotos A (rs821616) una mejoría en la destreza motora. Aquellos pacientes homocigotos para el alelo Leu (rs6675281) tuvieron un descenso significativo en el grosor cortical tras 3 años, mientras que los portadores del alelo Phe presentaron un aumento del grosor. Por último, los pacientes homocigotos para el alelo G (rs1000731) fueron más frecuentemente no-respondedores al tratamiento.
Discusión Encontramos polimorfismos del gen DISC1 asociados con diferencias en endofenotipos y características clínicas relevantes, tanto al inicio de la enfermedad como tras 3 años de tratamiento, lo que sugiere que el gen DISC1 tiene un papel en la gravedad, curso y pronóstico de la psicosis.
- English
Background Schizophrenia is a severe psychiatric disorder, resulting from the joint interaction of multiple environmental and genetics factors of a small size effect. Disrupted-in-Schizophrenia 1 (DISC1) stands out due to its relevance in the disorder. Although, the biological function of the DISC1 is not completely understood, there is evidence of its involvement in neurodevelopment processes. Currently there is substantial data supporting DISC1 as one of the main candidate genes for schizophrenia, and there is mounting evidence of its association to several endophenotypes of the illness. However, there is a lack of studies on the effect of DISC1 on the longitudinal changes in these endophenotypes, and on first-episode samples.
Methods Two hundred and twenty-six Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys), rs6675281 (Leu607Phe) and rs1000731 SNPs. The clinical severity was assessed using BPRS, SAPS and SANS scales at baseline and after 6 weeks of initiating the treatment. Likewise, neurocognitive examinations and brain MRIs (cortical thickness ¿CT¬¿) were carried out at baseline and 3 years after initiating the treatment. Other clinical and socio-demographic variables were recorded to eliminate potential confounding effects. A control group of healthy subjects (n=303) was recruited by public advertising.
Results Our study failed to show an association between DISC1 polymorphisms and risk of psychosis. However, patients homozygous for the Ser allele of the Ser704Cys had significantly higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers. When examining the DISC1 effect on neurocognitive functioning, patients carrying the A allele of rs1000731 exhibited a significant improvement in Working Memory and Attention domains, and the homozygosity of the A allele of rs821616 showed a significant improvement in Motor Dexterity performance over 3 years of follow-up. When evaluating the relation between DISC1 gene and cortical thickness, we observed that the patients homozygous for the Leu allele of the rs6675281 SNP had a significant descend in CT over the 3-years period, while those carrying the Phe allele presented an increase in CT. When combining the two SNPs we found a synergic effect on CT progression, presenting those patients homozygous for Leu607 +Ser704 a more pronounced cortical thinning. Finally, when studying the possible effect of DISC1 polymorphisms on treatment response we found that those patients homozygous for the G allele of rs1000731 were more frequently non-responders, measured with SANS after 6 weeks of treatment. When analyzing the clinical improvement longitudinally, we observed that those patients carrying the A allele for the rs1000731 presented a greater improvement in positive symptoms dimension.
Discussion We found DISC1 gene polymorphisms associated with differences in relevant clinical characteristics and endophenotypes, both at baseline and after 3 years of treatment, suggesting that DISC1 gene has a role in the severity, course and prognosis of the psychosis.
- español
