M2 - ANALYZING THE ROLE OF COMMON EXOMIC VARIANTS ON MODULATING ADHD BEHAVIORS USING A BEHAVIORAL DYNAMIC APPROACH

Abstract

Background Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common behavioural disorder in school-aged children (3–6%). ADHD is characterized by developmentally inappropriate levels of attention, motor hyperactivity/impulsivity, or both. ADHD is a multifactorial highly heritable disorder, but its genetic underpinnings remain very difficult to unravel. This is mainly due to its multilayered phenotypic presentations (combination of several cognitive, emotional and motor traits), multiple environmental determinants and its complex genetic architecture. Our research group has been dissecting these various dimensions through a pharmaco-behavioural genetic study of ADHD while systematically collecting highly relevant environmental factors. Methods This unbiased and systematic approach will be deployed in two phases. First, we are using 179 children diagnosed with ADHD aged between 6–12 years and their parents to identify common exomic SNPs that are associated with ADHD or behavioural traits that are relevant for ADHD. This genotyping has already been completed through collaboration with the international ADHD genetic consortium. Preliminary results of this genotyping and its quality control indicate that there are over 20 000 eligible SNPs that can be analysed. In the second phase, 100 SNPs were selected according to a specific algorithm being developed (including criteria such as consistent association with ADHD across various behavioural relevant traits, functional relevance based on the role of the SNP in gene function or expression, the role of the gene in functional neural networks…) to be replicated in an independent sample of over 500 patients and their parents which are currently available in our laboratory. Results Preliminary results of this genotyping and its quality control indicate that there are over 20,000 eligible SNPs that can be analysed. In the second phase, 100 SNPs were selected according to a specific algorithm being developed (including criteria such as consistent association with ADHD across various behavioural relevant traits, functional relevance based on the role of the SNP in gene function or expression, the role of the gene in functional neural networks…). Discussion To our knowledge, this is the largest study attempting to unravel the genetic architecture of ADHD combining highly enriched behavioural dimensions of ADHD, pharmacological probes and a two-pronged whole exomic exploratory and a confirmatory steps. It is expected that this highly sophisticated approach will enable us to better understand the genetic of ADHD and its phenotypic variability.