Disentangling the genetic causes of autism

By suspecting that the scarce results obtained by several genome wide association studies, even in highly heritable diseases, could be due to wrong assumptions inferred from reference genomes but not true in affected individuals, we re-analyzed data from the Autism Genome Project (AGP) Consortium starting from the genotype calling phase and trying to made the minimum assumptions possible, and identified patterns of individual raw genotypes associated to the disease, mainly lack of hybridization and cross hybridization. In light of it, we re-designed the polygenic model of individual risk and were able to explain most of the variance – AUC larger than 0.9 - in an independent dataset of whole exome sequencing provided by the Autism Sequencing Consortium. The outstanding analytical results pointed out to several highly significant positions, most of them having the autistic individuals as the group with the unknown variants. By performing functional annotation clustering, the most significant cluster (5.6 enrichment score) put together three categories related to the nuclear pore complex (NPC) interacting protein. We also analyzed sequenced genotypes of Aspergers individuals and found out that they are much closer to individuals with typical development than to strict autistic ones.