Search for Susceptibility Genes in Autism Spectrum Disorders

Autism (MIM 209850) is a severe neurodevelopmental disorder characterized by abnormalities in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities, which are evident by the age of three years. Autism is the most severe form of a broad group of disorders known as pervasive developmental disorders (PDD) or autism spectrum disorders (ASD), which include also milder conditions such as Asperger syndrome (AS), disintegrative disorder, and atypical forms of autism. The population prevalence for autism is 10-20 per 10 000, whereas the total prevalence for all autism spectrum disorders is close to 10-60 per 10 000. Twin and family studies have repeatedly and unequivocally indicated a strong genetic component in ASDs, but the underlying genetic mechanisms are still largely unknown. To analyze the genetic factors underlying autism, we have carried out two genome-wide scans in well characterized Finnish ASD families. First, we analyzed 38 families having diagnoses of autism, AS and developmental dysphasia, and identified a susceptibility locus at 3q25-27 with a maximum multipoint LOD score of 4.81. Also, other putative linkage findings were observed at 1q21-23 and Xq13. The second genome-wide scan was performed in a sample of 17 extended families with AS. The most solid linkage finding was observed at 3p14-24 with the highest multipoint NPLall score of 3.32. Other suggestive findings were identified at 1q21-23 and 13q31-33. Next, we analyzed the data from genome-wide scans performed in the US and Finnish autism samples combined, in order to reveal shared susceptibility loci for these two samples. The most promising shared locus was identified at 3p24-26 (NPLall=2.20) in the vicinity of the earlier finding in the AS-sample. Two members of the neuroligin gene family, NLGN3 and NLGN4, have been shown to be mutated in individuals with autism, AS and mental retardation. Two neuroligin genes, NLGN1 at 3q26 and NLGN3 at Xq13, are located within the putative susceptibility loci identified in the first genome scan of this study. However, no evidence for functional mutations or significant allelic association was observed at NLGN1, NLGN3 or NLGN4 in the Finnish sample. Recently, DYX1C1 was identified as a candidate for developmental dyslexia in a Finnish study sample. It has been suggested that variants at this gene might confer susceptibility also for other disorders involving language development or acquiring specific competences. Therefore, we wanted to test whether the effect is present also in autism, which is an extreme example of such a disorder. No evidence for association or deviated allelic diversity in the haplotype analyses was observed, and thus, at least a presence of a major effect was excluded. Taken together, the present study has involved the identification of potential susceptibility loci for ASDs at 1q21-23, 3p14-26, 3q25-27, 13q31-33, and Xq13. As the initial follow-up of the genome-wide scans, the most relevant candidates were analyzed but with no indication of etiological significance. The original articles included in this thesis represent the first step towards identification of susceptibility genes for ASDs in the Finnish population and this data provides a strong foundation for future fine-scale mapping of the identified loci.