Thesis defense Janita Bralten (Donders Series 176)

12 February 2015

Promotors: Prof.dr. J. Buitelaar, Prof.dr. B. Franke

Genetic factors and the brain in ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a common and complex neurodevelopmental disorder characterized by developmentally inappropriate inattentiveness, and/or increased impulsivity and hyperactivity. The underlying etiology of ADHD remains largely unknown. Two types of evidence about the nature of ADHD are the starting points of this thesis. First, ADHD is considered to be a disorder of brain development. Widespread alterations in brain structure and brain function are reported on a group level for participants with ADHD compared to controls. However, findings on brain volumetric differences in ADHD are inconsistent and mostly studied in small samples. Second, ADHD is highly heritable, with heritability estimates of 76%. ADHD is (in most affected individuals) a multifactorial disorder in which multiple genetic factors and environmental factors play a role. Most of the genetic factors have a small effect size and are thought to interact with each other and with environmental factors, making the identification of these factors difficult. Although some ADHD-related genetic risk factors are identified, finding additional ones remains challenging. As ADHD runs in families, it can be of interest to investigate familiality. Familial means that a trait is more common within families than between families (i.e. due to shared genetic and/or shared environmental factors).

My overall aim in this research project is to gain further insight into the genetic underpinnings and brain correlates of ADHD, the latter serving as a possible link between genetic risk factors and the clinical phenotype. My thesis can be divided in three parts. In the first part we investigate the ADHD brain. We find structural brain differences between participants with ADHD and controls and we show that these differences can also be found in unaffected siblings of participants with ADHD (they are familial). In the second part we investigate ADHD genetics. We show that age is important in genetic association analyses in ADHD and we show that aggregation of phenotypes and aggregation of genetic variants (pathway-based analyses) can help to find genetic associations in ADHD. In the third part of this thesis we investigate brain imaging genetics in ADHD. After performing a multivariate analysis technique we find a structural brain pattern that differs between participants with ADHD and participants without ADHD.

Overall, this thesis provides new insights on volumetric brain alterations in ADHD, genetic risk variants linked to ADHD traits and provides innovative analysis methods for combining brain and genetic analyses in terms of brain imaging genetics of ADHD.