Genetic and Environmental Risk factors associated with Obsessive-Compulsive Disorder and its symptom dimensions: A twin study

Abstract

[spa] El trastorno obsesivo-compulsivo (TOC) es una enfermedad mental con una clara etiología multifactorial que engloba tanto componentes biológicos como psicosociales no del todo esclarecidos. Los estudios con gemelos son considerados una de las principales herramientas en la genética de conducta para identificar marcadores genéticos relevantes que subyacen a patologías complejas. En la presente tesis se pretende, mediante modelos de ecuaciones estructurales con gemelos, esclarecer los componentes biológicos del TOC al examinar los factores genéticos específicos y compartidos que existen entre las dimensiones de síntomas obsesivos (pensamientos prohibidos, comprobación, orden/simetría y contaminación/limpieza), síntomas de ansiedad (pánico, ansiedad generalizada y fobia social) y síntomas de otros trastornos del espectro obsesivo (trastorno dismórfico corporal y acumulación), en una muestra no-clínica de 2495 gemelos de entre 18 y 45 años. En segundo lugar estudiar el patrón de relaciones causales entre los síntomas TOC, del espectro ansioso y obsesivo, utilizando una nueva metodología de análisis con gemelos. Los resultados de esta tesis muestran por primera vez un patrón de heredabilidad diferente entre hombres y mujeres en los síntomas del espectro obsesivo (en concreto en el trastorno dismórfico corporal y de acumulación). Por otro lado, se demuestra una clara implicación del componente ansioso en la etiología del TOC, compartiendo tanto factores genéticos (especialmente en la dimensión de contaminación y pensamientos prohibidos) como ambientales (principalmente en orden/simetría y comprobación). Los síntomas del trastorno dismórfico corporal (TDC) también comparten genética con el TOC, especialmente con la dimensión obsesiva de comprobación. Los resultados demuestran que la genética asociada al TOC no se explica mejor con los trastornos del espectro obsesivo, sino que la ansiedad es un constructo esencial en su etiología. En la misma línea, la presencia de síntomas TOC aumenta la probabilidad de padecer síntomas de pánico y ansiedad generalizada; mientras que la presencia de síntomas de fobia social incrementa significativamente la probabilidad de desarrollar síntomas TOC. La presencia de síntomas obsesivos aumenta la posibilidad de que el mismo sujeto pueda presentar síntomas de acumulación a lo largo de la vida. Estos hallazgos ayudarán a futuros estudios a esclarecer qué factores genéticos, ambientales y/o epigenéticos específicos están asociados al TOC o son compartidos con otros trastornos relacionados.

[eng] There is an incomplete understanding of the heritability and the specific genetic bases of Obsessive-Compulsive Disorder (OCD). It has a complex multifactorial etiology comprising both biological as well as psychosocial components not clearly elucidated. Moreover, OCD is clinically heterogeneous and it is unknown whether this complex phenotypic reflects distinct or partially distinct etiology mechanisms. Until recently OCD was designated as an anxiety disorder (AD) due to the similarities in phenomenology, comorbidity and aggregation in families suffering from various ADs. In this context, it was implicitly understood that OCD was sharing common etiological factors with other ADs. However, the idea that disorders not classified in the anxiety group could also be associated with OCD has generated an intense and controversial debate about whether OCD is indeed and AD or, in fact, more closely related to other disorders, with the anxiety merely as a consequence of OCD symptoms. Twin studies are considered a key tool in behavioral genetics used to dissect the nature (genetic) versus the nurture (environmental) contributions to individual phenotypes. Also, twin studies are one of the best ways of identifying genetic markers relevant to understand the etiological factors that underlie complex psychopathologies. Unfortunately, there is a lack of empirical twin studies that have actually directly compared the OCD, obsessive-compulsive and related disorders (OCRDs) and ADs together. OBJECTIVES: To clarify biological components of OCD etiology by examining specific and shared genetic factors between Obsessive-Compulsive (OC) symptom dimensions (forbidden thoughts, checking, symmetry/ordering and washing) anxiety disorders (social phobia (SP), generalized anxiety disorder (GAD) and panic disorder (PD)) and OC spectrum disorders (body-dysmorphic disorder (BDD), hoarding disorder (HD) and hypochondriasis (HYP)). As a second aim this thesis would like to study the patter of causation relationships between OCD, the ADs and the OCRDs, using a new statistical approach to infer causation in twin data (ICE FALCON). A non-clinical sample of 2,495 male and female twins of 18 to 45 years old was used to address these objectives. The results of the present thesis show for the first time that the patterns of heritability of hypochondriasis, BDD and HD symptoms present genetic sex differences. Moreover, it shows that anxiety makes an essential contribution to the complex etiology of OCD. In the causation inference analysis it was demonstrated that OCD symptoms increase an individual’s probability to develop GAD, PD and HD symptoms, but not revers; and that social phobia increases an individual probability to develop OCD symptoms. Regarding OCD dimensions this thesis found that forbidden thoughts and washing show the highest association with the AD symptoms while symmetry/ordering shows the highest genetic specificity. On the other hand, checking dimension is genetically associated with other OCRDs (specifically BDD) and AD symptoms. Finally, only checking and symmetry/ordering dimensions share environmental factors with the ADs. In summary, this thesis answers questions of high clinical and diagnostic relevance for OCD, one of the most prevalent mental disorders (2-3%) and one of the largest generators of chronic suffering and cost in the current health programs. All the results from this thesis are related to the biological basis underlying the disorder and are aimed to elucidate more stable endophenotypes of analysis. This could have a large impact on both, improving patients’ quality of life and in the reduction of costs associated with the handling of a complex and heterogeneous disorder.