From genes to phenotypes of neurodevelopmental disorders in children, impact of environmental factors and epistasis.

Causes of Autism Spectrum Disorders (ASD) are complex. ASD has a high heredity and has therefore long sought for genetic risk factors for the disease. A number of genetic risk factors for ASD have been identified, but this still explains less than 15% of cases. The BUPgen project has discovered several genetic risk factors for ASD through studies of genes and how genes affect multiple diseases and traits. The BUP now participates in a worldwide weekend throughout the description of the ASD group, where several genetic variants associated with ASD have been discovered. The BUPgen project has cleared this through data collection and blood / saliva samples from several hundred children and adults with ASD in Norway. In addition to using this information in the effort to find reasons for ASD, the database and the biobank are used to map the clinical image in national collaborative projects. Work has been done to reveal to what extent the social difficulties that define ASD are due to specific cognitive outcomes. Furthermore, EEG-based measurements have been performed that have mapped how individuals with ASD process social information. We have also found that immunological conditions can affect the symptoms of mental disorders. The BUP researchers have also been involved in a project investigating the hormone oxytocin and social cognition. The BUPgen project has also gathered information from around 1500 parents to people with ASD and their opinions on genetic testing. Furthermore, a questionnaire survey was conducted about their experience of the Norwegian service offering. The results of this study show a generally very positive attitude towards the use of genetic engineering among Norwegian parents to persons with ASD. The participants in the survey emphasize the importance of confidentiality in this type of research and express the desire to be kept up to date in what results appear in the studies they participate in. Clinical use of genetic tests, the participants are also very positive to, only 8% of the respondents are generally against gene testing in this group. Those who oppose testing are skeptical about the benefits of this more than they are worried about the disadvantages of repetition. The BUPgen project started several projects that look at ASD in combination with known genetic syndromes. Several genetic syndromes have a markedly elevated risk of ASD and the BUP study will study the variation in such syndrome by searching for mechanisms that may be relevant to specific characteristics of ASD or comorbidity. In addition, we have found genetic overlap with other BUP diseases, including ADHD.

Neurodevelopmental disorders include a variety of clinical phenotypes characterized by social, motor, communication and learning dysfunctions, and constitute a range of diagnosis from the general type (i.e. autism spectrum disorders) to the specific types (i.e. learning disabilities, motor skills- and communication disorders etc.). These are often severe disorders and major public health problems with high heritability, but unknown pathophysiology. There are indications of abnormalities in specific brain regions, and cognitive dysfunction is prevalent. Disease genes have been identified, but most genes remain undiscovered, and there is a large degree of pleiotropy; the same risk gene can lead to a range of phenotypes. The health care system can vary betwe en regions, and the attitudes towards genetic testing in families are unknown. We will recruit a large sample (n=600) of neurodevelopmental disorders with a focus on autism, based on our network of clinical sites. Clinical data will come from standardized routine clinical assessments, to reduce the burden of the participant, and will include diagnostic procedure, symptom assessments and cognitive profiling, and DNA, and brain MRI (in subsample) acquired with high quality protocol. Also, information from b irth and patients registries will be obtained, and state-of-the-art genotyping will be done. This will give us a unique opportunity to identify new genetic variants and determine the association to phenotype characteristics, examine how environmental and genetic factors interact. We will also describe experience with the health care system and attitudes towards genetic testing in families. The project integrates international collaboration (Copenhagen, San Diego and Reykjavik), focuses on research educati on and aims to improve the quality of the participating hospitals. The results will provide novel knowledge about the pathophysiological mechanisms which may be used for preventive measures in the future.