Thesis defense Marieke Klein (Donder thesis series 365)

1 February 2019

Promotors: prof. dr. D. Norris, prof. dr. B. Franke

Co-promotors: dr. A. Arias Vásquez, dr. J. Bralten

From gene to disorder in ADHD: Mapping mechanisms at different levels of complexity

Attention-Deficit/Hyperactivity Disorder (ADHD), is a common neurodevelopmental disorder. While ADHD is diagnosed at the behavioral level, it is a neurobiological disorder that is most likely caused by a complex interplay between genetic and environmental risk factors. Despite its high heritability, gene identification has been challenging in ADHD. The aim of this thesis was (1) to discover genetic variants that contribute to the development of this disorder and (2) to identify the underlying (neuro)biological mechanisms. Understanding which genetic variants are relevant for the disorder can yield insights into the pathophysiology and potentially (in the long run) lead to novel treatment options. By applying various statistical genetics approaches, such as genome-wide association studies on common genetic variants or by combining linkage analyses with whole-exome sequencing in multigenerational families, we identified individual novel genetic risk factors for ADHD. Additionally, we obtained insights into the global genetic architecture of ADHD. The second part of the thesis focused on different approaches that can help to map the biological mechanisms from gene to the disorder. Neurobiological parameters, such as behavioral outcomes and brain volume measurements, were used both in animal models and in humans to link genetic variation to ADHD symptomatology. In ADHD, most brain imaging genetics studies focused on the investigation of single genetic variants. Among other findings, we were able to show that ADHD and the intracranial volume are significantly negatively correlated at the global genetic level, resembling earlier phenotypic observations.