To investigate the degree of weight to put on the functional effect of rs950169, using data from a genome-wide association study examining the effects of approximately 550,000 SNPs on expression of 1.41 million exons in human frontal cortex tissue (Text S1), we looked to see what percentage of exons show association with a nearby (+/− 100 kb) SNP at or below the level of significance that rs950169 associates with the expression of the ADAMTSL3 exon 3605495 (https://www.affymetrix.com/analysis/netaffx/index.affx). We found that 84,840, or 6%, of exons showed a SNP association of this magnitude. This illustrates the importance of weighing functional evidence against an appropriate null hypothesis, and we note that in many cases arriving at a quantitative evaluation of this kind can be very difficult. This fact, along with the failed replication in the Italian, Icelandic and US data, suggests that evidence of functional effect for SNPs implicated in GWAS studies should not be considered an appropriate substitute for confirmation in replication datasets.
