Complex Models of Genetic and Environmental Influences on Human Cognition. Implications for Functional Psychoses / Modelos complejos de las influencias genéticas y ambientales en la cognición humana. Implicaciones para las psicosis funcionales

Abstract

The general construct of human cognition implies a series of mental processes by means of which human interpret and consequently act on the world that surrounds them (Sternberg y Mio, 2009). During the last decades, the recognition of human diversity and psychological variability among individuals has encouraged challenging questions addressing inter-individual differences that make each subject unique in terms of their cognitive performance (Baddeley, 2003; Botvinick, 2008). In particular, quantitative genetic studies show that both genetic variability and environmental factors are involved in the phenotypic expression of cognitive functions (Plomin, 2011). However, the mechanisms by which genes and exposure to environmental influences may contribute to the observed variability are not yet clear.

The study of the origins of inter-individual differences in cognition is strongly associated with the ontogenic development of the human brain (Tau, 2010). As a consequence, cognitive alterations are considered a central trait in those mental disorders where neurodevelopmental alterations are assumed to exist, such as schizophrenia. This disease, which affects around 1% of the world’s population, is one of the main causes of years lost due to disability (WHO, 2004), while cognitive alterations in these patients explain about 20%-60% of the variance in measures of outcome (Green, 2004).

The aetiological model of neurodevelopment in schizophrenia proposes that this disease might be the expression of neurobiological compromise that could begin early in the lifespan, even before the onset of the clinical symptoms (van Os, 2009). However, and despite the scientific efforts invested in the elucidation of its aetiological underpinnings, the heterogeneous presentation of the disease has prevented a deeper comprehension of these mechanisms.

Are all cognitive domains heritable? Are there long-term consequences on cognition for the early exposure to environmental impact? What is the association between genetic variability and cognitive vulnerability? Can we identify specific neurobiological pathways in the expression of the cognitive alterations of patients with schizophrenia? These questions are explored in the present thesis through the analyses of twins- and family-based samples, which constitute powerful designs to study the effects of genetic and environmental variability on human cognition.

In the six chapters of results that are the body of this thesis, complex models are proposed that aim at representing the mechanisms involved in the origin of cognitive variability at the population level. The findings included indicate that this variability could be the result of the relative contribution of genetic determination and environmental modelling, which could vary in different cognitive functions following ontogenic mechanisms of neurodevelopment. Specifically, results are reported on the influences of childhood maltreatment and socioeconomic status as environmental stressors, as well as Val158Met functional polymorphism of COMT gene as a genetic factor.

The aetiological implications of the study of these processes are extended to the field of mental disorders, as the results may indicate that the cognitive variability present among patients with schizophrenia could support a model of developmental compromise in this disease. Accordingly, the effects of genetic and environmental influences on behaviour may underlie the heterogeneous expression of this highly disabling mental disorder.

To sum up, the phenotypic diversity of schizophrenia and human cognition, far from representing an obstacle, lays the foundations for complex models of these traits that may feed an increasing understanding of their aetiology (Belsky, 2011). These findings highlight the putative role of neurobiological liability traits in crucial aspects of clinical practice. Risk factors might be identified that could be included as potential guidelines in the assessment and management of need-adapted treatments (Leiftker, 2009). Moreover, liability traits might operate as markers in preventive interventions for targeting individuals at risk of developing particular forms of the disease (Keshavan, 2011).

El constructo general de cognición humana involucra una serie de procesos mentales por medio de los cuales los individuos perciben, interpretan y, en consecuencia, actúan sobre la realidad que los rodea y sobre sus pares (Sternberg y Mio, 2009). En los últimos años, el reconocimiento de la diversidad humana y la variabilidad de los rasgos psicológicos entre los individuos ha promovido preguntas acerca de las diferencias inter-individuales que hacen a cada sujeto único en términos de cognición (Baddeley, 2003; Botvinick, 2008). En particular, los estudios de genética cuantitativa demuestran que tanto la variabilidad genética como los factores ambientales podrían estar involucrados en la expresión fenotípica de las funciones cognitivas (Plomin, 2011). Sin embargo, aún no son claros los mecanismos específicos por medio de los cuales los genes y el ambiente contribuyen a esta variabilidad.

Las alteraciones cognitivas son un rasgo central en enfermedades mentales donde se presume que existen alteraciones del neurodesarrollo, como lo es la esquizofrenia. El modelo etiológico del neurodesarrollo de la esquizofrenia propone que esta enfermedad se expresaría como consecuencia de alteraciones neurobiológicas que iniciarían en una época temprana de la vida, incluso antes del desencadenamiento de los síntomas clínicos (van Os, 2009). No obstante, la presentación heterogénea de la enfermedad ha dificultado una comprensión más clara de los mecanismos involucrados en su manifestación.

¿Son todas las funciones cognitivas igualmente heredables? ¿Tienen los factores ambientales tempranos consecuencias a largo plazo sobre la cognición? ¿Cuál es la relación entre variabilidad genética y vulnerabilidad cognitiva? ¿Existen vías neurobiológicas específicas para la manifestación de las alteraciones cognitivas en pacientes con esquizofrenia? Estas preguntas se exploran en la presente tesis a partir de análisis basados en muestras de gemelos y en grupos familiares, que constituyen una manera metodológicamente potente de estudiar los efectos de la variabilidad genética y ambiental sobre la cognición humana.

En este sentido, la diversidad fenotípica de la esquizofrenia y la cognición humana, lejos de representar un obstáculo para la investigación de su etiología, sienta las bases de modelos complejos que podrían fomentar una comprensión cada vez más completa de los mecanismos de vulnerabilidad y resiliencia posiblemente involucrados en su origen (Belsky, 2011).