An analysis of candidate autism loci on chromosome 2q24-q33: evidence for association to the STK39 gene.

A susceptibility locus for autism was identified to the chromosome 2q24-q33 region in independent cohorts of families, especially in subsets clinically defined with phrase speech delay (PSD). In the present work, we screened 84 linkage-informative SNPs covering this locus in a cohort of 334 families with autism and in subsets identified with PSD. We observed linkage to autism with the highest non-parametric linkage score (NPL) of 2.79 (P = 0.002) in the PSD subset with at least two affected subjects. In addition, using a set of 109 additional gene-oriented SNPs in this interval we observed that several SNPs encompassing the SLC25A12 gene provided the maximum evidence for linkage (NPL = 3.32, P = 0.0003). Using the transmission disequilibrium test to test for associations, we observed significant over-transmissions of rs2056202 (P = 0.006) within the SLC25A12 gene, rs1807984 (P = 0.007) within the STK39 gene, and rs2305586 (P = 0.009) within the ITGA4 gene. We also found evidence for association between autism and two other SNPs (rs1517342, P = 0.012 and rs971257, P = 0.030) or haplotypes (P = 0.003) of the STK39 gene. STK39 encodes a serine/threonine kinase (SPAK/PASK/STE20-SPS1 homolog) abundantly expressed in the brain with roles in cell differentiation, cell transformation and proliferation, and in regulation of ion transporters. In summary, we have observed further evidence for linkage and association between autism and loci within the 2q24-q33 region, including at STK39, a novel candidate gene for autism.