Year: 2015
Type: dissertation
Study design: Observational Study
Abstract: Autism spectrum disorder (ASD) is characterized by impairment in social interaction,\nlanguage impairment and repetitive behavior with varying degrees of severity. ASD\nrepresents the lower end on a continuously distributed measure of autistic-like traits\n(ALTs). Although a strong genetic component has repeatedly been identified in ASD,\nthe genetic cause of ASD is still unknown for the majority of ASD cases.\nOne of the main interests in this thesis is the neurobiology of melatonin, this\ninterest is based on findings indicating lower levels of melatonin in children with\nASD. In our investigations of rare mutations in melatonin related genes in subjects\nwith ASD, we identified a previously reported mutation that has been shown to\ndecrease the activity of one of the enzymes involved in the melatonin synthesis: the\nacetylserotonin O-methyltransferase (ASMT) (paper I). In the analysis of five common\nvariations in the ASMT gene in relation to ALTs in the general population we found\nassociation between a single nucleotide polymorphism and social interaction\nimpairment in girls (paper II).\nTo broaden the analysis of genetic influences on ALTs, we have performed\nassociation analyses between ALTs in the general population and common variation in\ngenes previously found to be associated with ASD (RELN, CNTNAP2, SHANK3 and\nCDH9/10 region) (paper III). Although these regions have previously been suggested\nto be strong ASD candidate regions, our results do not suggest a major influence of the\ninvestigated common variations on ALTs.\nIn the final paper, rare inherited genetic variations were investigated in a large\nfamily with autism and language disorders. In this study, we used several techniques,\nincluding whole exome sequencing and copy number variation analysis (paper IV). In\nthe family, several rare genetic variations which may partly explain the genetic etiology\nfor autism in this family were identified. We performed functional analyses for a\nmutation identified in the CYP11A1 gene, indicating a gain of function mutation. The\nCYP11A1 gene encodes the first enzyme in the steroid hormone biosynthesis, thus our\nresults may be in line with previous findings that have shown an elevated prenatal\nsteroidogenic activity in ASD.\nIn conclusion, we have identified both common and rare genetic variation that\nmay increase the genetic susceptibility for ASD. Our analyses have highlighted the\nimportance of taking both rare and common genetic susceptibility factors, as well as\ndifferent symptoms of the disorders, into account when elucidating the complex\ninheritance of ASDs.
Author: Lina Jönsson
Institution: University of Gothenburg
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W167248853