Abstract
Genetic variations at the Apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) loci have been implicated in multiple neurogenerative diseases, but their exact molecular mechanisms are unclear. In this study, we performed transcript level linear modelling using the blood whole transcriptome data and genotypes of the 570 subjects in the Parkinson’s Progression Markers Initiative (PPMI) cohort. ApoE, MAPT haplotypes and two SNPs at the SNCA locus (rs356181, rs3910105) were used to detect expression quantitative trait loci eQTLs associated with the transcriptome and differential usage of transcript isoforms. As a result, we identified 151 genes associated with the genotypic variations, 29 cis and 122 trans eQTL positions. Profound effect with genome-wide significance of ApoE e4 haplotype on the expression of TOMM40 transcripts was identified. This finding potentially explains in part the frequently established genetic association with the APOE e4 haplotypes in neurodegenerative diseases. Moreover, MAPT haplotypes had significant differential impact on 23 transcripts from the 17q21.31 and 17q24.1 loci. MAPT haplotypes had also the largest up-regulating (256) and the largest down-regulating (−178) effect sizes measured as β values on two different transcripts from the same gene (LRRC37A2). Intronic SNP in the SNCA gene, rs3910105, differentially induced expression of three SNCA isoforms. In conclusion, this study established clear association between well-known haplotypic variance and transcript specific regulation in the blood. APOE e4 and MAPT H1/H2 haplotypic variants are associated with the expression of several genes related to the neurodegeneration.
Highlights
Apolipoprotein E (ApoE) epsilon 4 haplotype (e4) is the major risk factor for the Alzheimer disease (AD) [1]
The increased risk for AD with ApoE e4 is evident in diverse populations and it is considered that all the genetic risk for AD in this region is accounted for by the ApoE e4 haplotype [4]
ApoE variants are involved in AD, but several studies report an association between ApoE e4 and Parkinson’s Disease (PD) [5]
Summary
Apolipoprotein E (ApoE) epsilon 4 haplotype (e4) is the major risk factor for the Alzheimer disease (AD) [1]. E4, e3 and e2, exist for ApoE and these are defined by the single nucleotide polymorphisms (SNPs) rs429358 and rs7412. The effect of e4 is dosage-dependent on the risk of AD and at the same time e2 variant of. ApoE exhibits protective effect for late onset AD [2]. This protective effect has been verified in the animal models overexpressing e4 or e3 variants of human ApoE genes [3]. ApoE variants are involved in AD, but several studies report an association between ApoE e4 and Parkinson’s Disease (PD) [5].
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