From the exploratory analyses (Supplementary Material, Table S3), we identify a number of loci as having noteworthy association. One of the most appealing genes for risk for autism is ST8SIA2, coding for a protein expressed very highly throughout the mammalian brain (expression level or density >90 for 14 out of 17 brain regions assessed in the Allen Brain Atlas, http://www.brain-map.org/). Mice without polysialyltransferases ST8SiaII and ST8SiaIV, which modify neural cell adhesion molecule (NCAM1), show malformations of major brain axon tracts (40). Loss of either ST8 protein alone results in milder phenotypes. Inactivation of ST8SiaII in mice alters axonal targeting, involving hippocampal infrapyramidal mossy fibers, and the mice show increased exploration and diminished fear (40,41), behaviors of potential relevance to autism. Learning and memory, mediated through morphological synaptic plasticity, are also critically dependent on NCAM polysialylation status but in a complex way (42). Further studies are needed to determine the relevance of these neurodevelopmental results to the genetics of autism and identify the genetic variation affecting expression or function of ST8SIA2. With regard to genetic variation, in addition to the results found in our study, variation in ST8SIA2 has been associated with risk for schizophrenia in Asian populations (43,44).
