The most associated polymorphism (rs2135551) is in the 3′UTR of exon 30 of ADAMTSL3. To investigate a possible functional mechanism for this SNP, we tested for association with alternative splicing events in the associated region (exons 28, 29, and 30) using brain tissue. We found that the associated SNPs rs950169 and rs2135551 showed a highly significant correlation with the use of an alternative splice acceptor site, resulting in a truncated PLAC (protease and lacunin) domain in the ADAMTSL3 protein (p<0.0001, Figure S2). We then confirmed a causal relationship between rs950169 and the observed splicing pattern using a MINIGENE system (Text S1), and showed an association between rs950169 genotype and the splice form of ADAMTSL3 in brain tissue from both healthy controls and Alzheimer's disease patients (Figure S3). Finally, we showed that ADAMTSL3 is particularly strongly expressed in hippocampal pyramidal cells (Figure S4).
