Genetics and Neurobiology of Autism and Related Neuropsychiatric Conditions

Jonas Melke

The ultimate aim of this project is to identify genes and neurobiological pathways involved in autism. Autism is a neurodevelopmental disorder characterized by problems in social communication and by repetitive behavior. The disorder is highly genetic, but for the majority of cases we still do not know which genes that are involved. In our work we use two major strategies. The first is an open-ended approach where the initial results will determine how the project will proceed, whereas the second is more defined and concerns further investigations of candidate genes already known through our (and other’s) previous studies. In the first part of our project, we carry out genome-wide screens for chromosomal rearrangements, i.e., deleted or duplicated parts of the chromosomes, in autism patients using state-of-the-art Affymetrix single nucleotide polymorphism (SNP) arrays. The next step will be to exactly identify the genes that are affected by such rearrangements. We will then screen these genes search for causative mutations and association of common variants in large populations of autism-related disorders. As candidate susceptibility variants and genes are identified, our goal is to determine their role in the pathophysiology of the disease by functional studies in cultured cells and animal models. In the second part of the project, candidate genes already known through our previous studies will be further investigated in new patient populations and in functional studies. We have previously shown that low melatonin levels is a common trait in autism and that this almost entirely is due to low activity of ASMT, the last enzyme in the melatonin synthesis pathway. The gene encoding ASMT has now been extensively investigated in autism patients throughout the world, revealing several novel variants associated with autism. Recently, we have also identified interesting variants in other genes involved in melatonin metabolism. To clarify the role of the identified variants in melatonin-related genes in autism etiology, we investigate the functional role of these in cultured cells using quantitative PCR, enzyme activity assays and receptor binding.