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Background  Genome wide association studies have identified microtubule associated protein tau ( MAPT ) H1 haplotype single nucleotide polymorphisms (SNPs) as leading common risk variants for Parkinson’s disease, progressive supranuclear palsy and corticobasal degeneration. The  MAPT  risk variants fall within a large 1.8 Mb region of high linkage disequilibrium, making it difficult to discern the functionally important risk variants. Here, we leverage the strong haplotype-specific expression of  MAPT  exon 3 to investigate the functionality of SNPs that fall within this H1 haplotype region of linkage disequilibrium.    Methods  In this study, we dissect the molecular mechanisms by which haplotype-specific SNPs confer allele-specific effects on the alternative splicing of  MAPT  exon 3. Firstly, we use haplotype-hybrid whole-locus genomic  MAPT  vectors studies to identify functional SNPs. Next, we characterise the RNA-protein interactions at two loci by mass spectrometry. Lastly, we knockdown candidate splice factors to determine their effect on  MAPT  exon 3 using a novel allele-specific qPCR assay.    Results  Using whole-locus genomic DNA expression vectors to express  MAPT  haplotype variants, we demonstrate that rs17651213 regulates exon 3 inclusion in a haplotype-specific manner. We further investigated the functionality of this region using RNA-electrophoretic mobility shift assays to show differential RNA-protein complex formation at the H1 and H2 sequence variants of SNP rs17651213 and rs1800547 and subsequently identified candidate trans-acting splicing factors interacting with these functional SNPs sequences by RNA-protein pull-down experiment and mass spectrometry. Finally, gene knockdown of candidate splice factors identified by mass spectrometry demonstrate a role for hnRNP F and hnRNP Q in the haplotype-specific regulation of exon 3 inclusion.    Conclusions  We identified common splice factors hnRNP F and hnRNP Q regulating the haplotype-specific splicing of  MAPT  exon 3 through intronic variants rs1800547 and rs17651213. This work demonstrates an integrated approach to characterise the functionality of risk variants in large regions of linkage disequilibrium.    Electronic supplementary material  The online version of this article (10.1186/s13024-017-0224-6) contains supplementary material, which is available to authorized users.

Haplotype-specific MAPT exon 3 expression regulated by common intronic polymorphisms associated with Parkinsonian disorders