La esquizofrenia es un desorden mental severo, con una incidencia del 1% y una elevada heredabilidad (alrededor del 80%). Por ello, hay un enorme interés en conocer los factores genéticos implicados en la vulnerabilidad a padecer esquizofrenia. Sin embargo, esta enfermedad presenta una herencia poligénica y además un importante número de factores ambientales parecen influir en su aparición. Asimismo, la heterogeneidad clínica también es elevada y esto dificulta el tener un fenotipo bien definido para el estudio genético. Por ello, el estudio de fenotipos más recortados y mejor definidos puede ser de gran utilidad. En el presente trabajo, se han seleccionado nueve genes de interés. Nuestra hipótesis principal es que variaciones en estos genes modulan la vulnerabilidad a padecer esquizofrenia o alguno de sus rasgos característicos, particularmente las alucinaciones auditivas, el deterioro cognitivo y la disfunción emocional. Como objetivo, nos planteamos el estudio de polimorfismos genéticos en varias muestras caso-control y familiares de España, Alemania y Estados Unidos. Se realizaron análisis de asociación caso-control, basados en familias y estudios de asociación con diferentes escalas clínicas. Asimismo, se estudió el impacto de ciertos polimorfismos sobre fenotipos de neuroimagen estructural y funcional. Los resultados más interesantes fueron los siguientes: por una parte, diferentes genes del sistema serotoninérgico (principalmente los genes SLC6A4 y HTR2A) parecían influir en el estado emocional del paciente, así como en la respuesta emocional del paciente a las alucinaciones auditivas. Además, el gen ASPM se asoció con el riesgo de psicosis y con diferentes parámetros cognitivos y de neuroimagen. Otros genes como NOS1, STMN1, PDE4D y PLEKHB1 parecían influir sobre el riesgo de psicosis, así como sobre las puntuaciones obtenidas en diferentes escalas psicopatológicas, si bien en estos casos la significación fue menor. Todos estos resultados permiten proponer un modelo de vulnerabilidad, según el cual ciertos genes tendrían un mayor efecto sobre la vulnerabilidad a sufrir esquizofrenia, mientras que otros genes influirían sobre la severidad de ciertos síntomas. Además, nuestros resultados apoyan la existencia de una vulnerabilidad genética a respuestas emocionales aberrantes, que podría estar modulada por la variación en ciertos genes, tales como el transportador de serotonina.Schizophrenia is a severe psychotic mental disorder, with a prevalence of around 1% in general population. It is well known that this disease presents a high heritability (around 80%). For this reason, there is a great interest in discovering the genetic factors affecting the risk for schizophrenia. However, due to the polygenic inheritance of this disorder, it is particularly hard to discover schizophrenia-related genes. Moreover, it has been hypothesized that an important number of environmental factors of different nature may affect the vulnerability to schizophrenia. Furthermore, schizophrenia is a clinically heterogeneous disorder and it can be particularly difficult to have a well-defined phenotype for genetic studies. For all these reasons, we consider that it is important to study the neurobiology of schizophrenia as a global entity, but also to complement these studies with other approaches, for example through the use of other alternative phenotypes, such as cognitive impairment, electrophysiological responses or auditory hallucinations, for example. In the present study, different candidate genes were selected. Our main hypothesis is that variations in these nine genes modulate the vulnerability to schizophrenia and some of their most characteristic and important features, particularly auditory hallucinations, cognitive impairment and, finally, the emotional dysfunction associated to schizophrenia. To test this hypothesis, we focused the study on the analysis of genetic polymorphisms (mainly single nucleotide polymorphisms) in three case-control samples from Spain, Germany and United States and a family sample from the United States. All samples were of Caucasian origin. Different analysis were performed, namely case-control association analysis, family-based association analysis (in some cases) and association analysis with clinical measures that corresponded to different psychopathological scales (BPRS, KGV, PANSS and PSYRATS for auditory hallucinations and delusions). Moreover, we also assessed the impact of certain genetic polymorphisms on functional and structural neuroimaging phenotypes, which evaluated both cognitive and emotional aspects. The most interesting results were the following: first, several polymorphisms from serotonergic system genes (mainly SLC6A4 and HTR2A genes, but also TPH2 gene to a lesser extent) appeared to modulate the patient's emotional state, including the emotional response to auditory hallucinations, assessed with clinical scales and neuroimaging techniques. Moreover, the positive selection gene ASPM, involved in neurodevelopmental processes, was associated with the risk for psychosis and with different cognitive and neuroimaging measures in both the Spanish and the American sample. Other genes such as NOS1, STMN1, PDE4D and PLEKHB1 also appeared to influence the risk for psychosis and the scores in some psychopathological scales, although in these cases significance was weaker.All these findings allow us to propose a vulnerability model. According to this model, some genes would have a major effect on the vulnerability to schizophrenia, while other genes would have an effect on the severity to certain symptoms. Regarding the vulnerability to auditory hallucinations, our results also support the existence of a genetic vulnerability to aberrant emotional responses, which could be modulated by the variation in different genes, such as the serotonin transporter gene, among others.