Discovering genetic risk factors for neuropsychiatric disorders and their consequences using dogs, humans and mice
Childhood neuropsychiatric disorders such as obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) account for significant morbidity in childhood and long-term developmental consequences (including depression and substance use disorders) as children grow into adulthood. We know that these disorders are highly heritable and that they involve dysfunction of cortico-striatal-thalamic circuits. Yet genetic studies to date have not accounted for a high proportion of the genetic variance in these disorders, and the mechanisms by which the effects of genetic variants are mediated by neural circuits is largely unknown. One approach to elucidate the etiology and biological mechanisms of childhood neuropsychiatric disorders is to exploit the fact that many of the basic behaviours underlying these disorders (such as compulsive traits, impulsivity and hyperactivity) can be observed across species. To adopt this approach we have formed the Comparative Behavioural Genomics Consortium (CBGC), which takes advantage of the strengths of our three research groups and a considerable amount of data already collected. Our plan for the next three years has three main aims (Fig. 1). First, we will use genome-wide approaches to map behavioural traits in dogs and humans (Gene discovery). Second, we will apply a novel statistical approach (hypothesis-driven GWAS or GWAS-HD) to prioritize genetic analyses of human genetic traits using information derived from our canine models (Gene validation). Finally, we will examine the functional consequences of genetic variants identified in dogs and humans on neural circuits in mice (Functional validation). A theme that cuts across all three aims is the use of measures across species of the constituent traits of ADHD and OCD (compulsive, impulsive and hyperactive traits). The novel, comparative genetics approach that guides the Consortium will elucidate the genetic contributions to compulsive behaviours, hyperactivity and impulsivity in humans, dogs and mice By identifying the genetic determinants of these traits which In turn confer risk for childhoood neuropsychiatric disorders, our findings will and provide new insights into early detection and the biological mechanisms of these disorders.
Gene targeting in the brain, Electrophisiological approaches, Behavioural methodologies, (epi)genetic approaches, "omics" approaches, anxiety disorders, aetiology, Electrical and magnetic brain stimulation, dog, mouse, human, genetic, association, linkage, pedigree, replication, risk, variant, mutation, fine mapping, neuropsychiatric, adhd, ocd, add
2014 - 2018
Hannes Lohi (Coordinator)