Genetic and epigenetic signatures of attention-deficit/hyperactive disorder
- Autores: Paula Rovira Lorente
- Directores de la Tesis: Marta Ribases Haro (dir. tes.), María Soler Artigas (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2020
- Idioma: español
- Tribunal Calificador de la Tesis: Blanca Gutierrez Martinez (presid.), Araceli Rosa de la Cruz (secret.), Maria Teresa Ferrin Erdozain (voc.)
- Programa de doctorado: Programa de Doctorado en Genética por la Universidad de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental, complex and highly heritable disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that impair the daily functioning of patients. These symptoms typically initiate in childhood and persist over time in around two thirds of the diagnosed children. There is evidence that both common and rare genetic variants contribute to the risk for the disorder, with heritability estimates around 76% that seem to remain stable across the lifespan. However, the genetic variation associated with ADHD to date only explain a modest proportion of the phenotypic variance. In this context and taking into account that environmental factors also play a role into the disorder’s susceptibility, it has been proposed that epigenetic marks such as DNA methylation (DNAm) could be contributing as plausible mechanisms by which environmental influences lead to functional and/or structural brain alterations found in ADHD.
Given this background and bearing in mind that the genetic and epigenetic investigations conducted on ADHD have been mainly focused on its childhood presentation, the objectives of the present doctoral thesis have been to explore the contribution of common genetic variants to the risk for ADHD across the lifespan and to examine whether there are DNAm patterns specifically associated with ADHD in adults.
Firstly, to investigate the genetic basis of ADHD through a lifespan perspective, we have conducted the largest meta-analysis of genome-wide association studies (GWAS-MA) on persistent ADHD in adults to date, a GWAS-MA on ADHD in childhood, and a GWAS-MA on ADHD across the lifespan using data from children and adults in a total sample of 17,149 cases and 32,411 controls. Through this approach, we have identified nine new independent loci associated with ADHD across the lifespan and we have shown that the proportion of common genetic variation contributing to the disorder seems to be stable over time. Moreover, our results have revealed a high genetic overlap between ADHD in childhood and persistent ADHD in adults, driven by the whole group of children, and similar patterns of genetic correlation between ADHD and other ADHD-related phenotypes and different traits and disorders across the lifespan.
Secondly, by conducting the largest epigenome-wide association study (EWAS) of ADHD in adults to date, comprising 103 clinical samples of adults with ADHD and 100 controls, we have identified DNAm patterns associated with ADHD in adults. Our results have shown that these patterns are not driven by the individuals’ smoking status or polygenic risk burden for ADHD, neither by exposure to stressful life events in the group of cases. Moreover, the localization of these DNAm patterns in or near genes previously involved in cancer, and the enrichment found for epigenetic signatures of smoking behaviour and maternal smoking among our findings, have reinforced that smoking behaviour is a key factor to account for in this type of analyses. In addition, our enrichment analyses results have supported that genome-wide DNAm is developmental-stage specific and point to an overlap between genetic and epigenetic signatures in ADHD that needs to be further studied in larger samples.
In conclusion, the results of the present doctoral thesis provide new insights into the genetic basis of ADHD across the lifespan, support the hypothesis of the neurodevelopmental origin of persistent ADHD in adults, and shed light on the epigenetic signatures characterising ADHD in adults.
