We sought support for the results obtained from the primary analyses by two approaches. First, we analyze independent ASD families from the Autism Genetics Resource Exchange (AGRE) database, combining AGP trios with AGRE simplex/multiplex families to perform a ‘mega-analysis’ in 2179 families for the four primary analyses. This ‘mega-analysis’, performed on all markers, did not add much additional support (Table 2), in terms of more significant association signals identified at the discovery phase, and no new loci emerged for their association with ASD (see Supplementary Material). For example, at rs4141463 (in MACROD2), the estimated odds ratio changed from 0.56 to 0.65 for the strict diagnosis (Table 2), European ancestry, resulting in a P-value of 4.7 × 10−8. An observation merits consideration for this and related results. Although the common allele is over-transmitted in both the original and AGRE data sets, the differential transmission as measured by the odds ratio is notably smaller for the latter, a result that is consistent with the winner's curse (22). Thus, if rs4141463 truly confers risk, the estimate from the AGRE data is a more realistic estimate of risk.
