Putative identification of susceptibility genes for autism on 15q11-q13: Role of UBE3A and ATP10A

The etiology of autism is still largely unknown despite our current understanding from family and twin studies that genetics plays a substantial role in the etiology of the disorder. Moreover, integrating data from linkage studies and analyses of chromosomal abnormalities allow identifying 15q11-q13 as one of the regions of particular etiopathogenetic interest for autism and autism related disorders. In an effort to find the autism susceptibility genes potentially harbored in this chromosomal region we have screened a set of markers spanning two known imprinted, maternally expressed genes, UBE3A and ATP10A, selected because they are both positional and candidate genes. We replicated evidence of Linkage Disequilibrium at marker D15S122, located at the 5’ end of UBE3A and originally reported by Nurmi (2001). In addition, our analyses show also one significant haplotype that includes D15S122 at UBE3A and D15S1535 and SNP3 at ATP10A. These findings are of particular interest considering that the association of D15S122 has never been replicated until now and that UBE3A is the gene responsible for the Angelmann Syndrome, that shares neurological and behavioral abnormalities with the autism spectrum disorders. Despite the limited power to detect genes of minor effect with a low density SNPs, our data support a potential role of UBE3A in the complex pathogenic mechanisms of autism. To strengthen our findings, we are currently genotyping a denser set of SNPs across the region and using a larger sample, with the ultimate goal of identifying the specific polymorphism(s) responsible for the associatio

Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence.

In previous studies, we identified a locus for schizophrenia on 6q23.3 and proposed the Abelson helper integration site 1 (AHI1) as the candidate gene. AHI1 is expressed in the brain and plays a key role in neurodevelopment, is involved in Joubert syndrome, and has been recently associated with autism. The neurodevelopmental role of AHI1 fits with etiological hypotheses of schizophrenia. To definitively confirm our hypothesis, we searched for associations using a dense map of the region. Our strongest findings lay within the AHI1 gene: single-nucleotide polymorphisms rs11154801 and rs7759971 showed significant associations (P=6.23E-06; P=0.84E-06) and haplotypes gave P values in the 10E-8 to 10E-10 range. The second highest significant region maps close to AHI1 and includes the intergenic region between BC040979 and PDE7B (rs2038549 at P=9.70E-06 and rs1475069 at P=6.97E-06), and PDE7B and MAP7. Using a sample of Palestinian Arab families to confirm these findings, we found isolated signals. While these results did not retain their significance after correction for multiple testing, the joint analysis across the 2 samples supports the role of AHI1, despite the presence of heterogeneity. Given the hypothesis of positive selection of schizophrenia genes, we resequenced a 11 kb region within AHI1 in ethnically defined populations and found evidence for a selective sweep. Network analysis indicates 2 haplotype clades, with schizophrenia-susceptibility haplotypes clustering within the major clade. In conclusion, our data support the role of AHI1 as a susceptibility gene for schizophrenia and confirm it has been subjected to positive selection, also shedding light on new possible candidate genes, MAP7 and PDE7B.-Torri, F., Akelai, A., Lupoli, S., Sironi, M., Amann-Zalcenstein, D., Fumagalli, M., Dal Fiume, C., Ben-Asher, E., Kanyas, K., Cagliani, R., Cozzi, P., Trombetti, G., Lievers, L. S., Salvi, E., Orro, A., Beckmann, J. S., Lancet, D., Kohn, Y., Milanesi, L., Ebstein, R. B., Lerer, B., Macciardi, F. Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence