After testing ∼1 million SNPs for association with ASD, we identified in one of our set of four primary analyses one SNP, rs4141463, in MACROD2 crossing a preset threshold of P < 5 × 10−8. Three other SNPs crossed this threshold in the context of exploratory analyses, making their interpretation more difficult due to multiple testing. All of these results spring from a relatively small sample size for GWA studies (n ≤ 1369 families), limiting both our power to detect association and the certainty of the associations detected. Unbiased estimates of odds ratios detected by GWA studies are typically in the range of 1.1–1.3; to have good power to detect such effect sizes requires many thousands of samples, which is beyond the reach of the autism genetics community at the moment. This issue could at least partially explain why most genomic regions with prior evidence of SNP associations for ASD risk garner little support from our data (Supplementary Material, Table S6). Moreover, the winner's curse and shrinkage to the mean (22,25,26) could explain the smaller odds ratios that we estimated from the replication data (Table 2).
