We further investigated whether the observed genetic overlap between AD and PD was polygenic and generalizable across a number of loci or non-polygenic and driven by the MAPT locus alone. Using recently developed statistical methods to evaluate pleiotropic effects 19–22, we investigated relative ‘enrichment’ of pleiotropic SNPs in AD (APOE, age and sex co-varied summary statistic p-values from ADGC) as a function of significance in PD (summary statistic p-values from IPDGC) (for additional details see Supplemental Methods). Removing the MAPT-associated genetic signal, consisting of all SNPs in r2 > 0.2 (based on 1000 Genomes Project LD structure) within 1 Mb of MAPT variants, resulted in considerable attenuation of genetic enrichment (Supplemental Figured 1a–d) indicating that the observed pleiotropy between AD and PD was non-polygenic and likely confined to the MAPT region. Similarly, after ‘pruning’ (removing SNPs in r2 > 0.2) all available ADGC SNPs, we found a single pleiotropic locus on chromosome 17 between AD and PD that was in r2 = 1.0 with MAPT. Though some genetic enrichment was still present after removing the MAPT-associated SNPs, we found a similar pattern in PD SNP enrichment conditioned on AD (Supplementary Figure 2).
