Genetic Architecture of MAPT Gene Region in Parkinson Disease Subtypes

Abstract

The microtubule-associated protein tau (MAPT) region has been conceptualized as a model of the interaction between genetics and functional disease outcomes in neurodegenerative disorders, such as Parkinson disease (PD). Indeed, haplotype-specific differences in expression and alternative splicing of MAPT transcripts affect cellular functions at different levels, increasing susceptibility to a range of neurodegenerative processes. In order to evaluate a possible link between MAPT variants, PD risk and PD motor phenotype, we analyzed the genetic architecture of MAPT in a cohort of PD patients. We observed a statistically significant association between the H1 haplotype and PD risk (79.5 vs 69.5%; χ2 = 9.9; OR, 1.7; 95% CI, 1.2–2.4; p = 0.002). The effect was more evident in non tremor dominant (TD) PD subjects (NTD-PD) (82 vs 69.5%; χ2 = 13.6; OR, 2.03; 95% CI, 1.4–3; p = 0.0003), while no difference emerged between PD subgroup of tremor dominant patients (TD-PD) and control subjects. Examination of specific intra-H1 variations showed that the H1h subhaplotype was overrepresented in NTD-PD patients compared with controls (p = 0.007; OR, 2.9; 95% CI, 1.3–6.3). Although we cannot exclude that MAPT variation may be associated with ethnicity, our results may support the hypothesis that MAPT H1 clade and a specific H1 subhaplotype influence the risk of PD and modulate the clinical expression of the disease, including motor phenotype.

Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

“…The MAPT locus is present within a large 1.8-Mb LD block and manifests as two distinct haplotypes, H1 and H2, which differ genetically in two primary ways: (i) more than 2000 SNPs differ across the two haplotypes, and (ii) an approximately 1-Mb inversion that includes the MAPT gene 51, 52 (Figure 6a). Previous reports have nominated multiple explanations for how these alterations are associated with PD, including increased MAPT expression in the H1 haplotype 53, 54 (Figure 6b), different ratios of splice isoforms 55–57 , and the use of alternative promoters 58 . We created a haplotype-specific map of chromatin accessibility and 3D chromatin interactions at the MAPT locus (Figure 6c).…”

Association of MAPT subhaplotypes with clinical and demographic features in Parkinson’s disease

“…We did not observe any associations between MAPT haplotypes and PD subtype. In a previous study of 46 tremor dominant (TD) and 135 non‐TD PD patients, 24 the H1h subhaplotype occurred at a significantly higher frequency in the non‐TD PD patients compared to controls (7.4% vs2.6%) when compared with controls, whereas the difference between TD patients and controls was not statistically significant (5.3% vs2.6%). However, the lack of significance for the latter comparison may be due to limited power, and indeed the 7.4% and 5.3% frequencies for the TD and non‐TD patients are fairly similar, pointing toward a lack of association with PD subtype as found in our study.…”

“…In addition to studies estimating the increased risk of PD that is associated with MAPT H1, some studies have assessed associations between MAPT H1/H2 haplotypes and selected features, mainly cognitive function, 14‐19 age at onset (AAO), 20‐22 PD subtype, 23,24 and progression 25 . Therefore, the aim of this study was to assess the associations of specific MAPT subhaplotypes with detailed clinical features of PD in a large patient cohort collected and characterized at the Mayo Clinic Florida.…”

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

“…Genomic screen of 1056 individuals from 235 families yielded significant evidence of association for allelic and haplotype association with tau [193]. The involvement of MAPT in PD pathogenesis has been confirmed so far in GWAS studies [194] with more evident association between the H1 haplotype and PD risk in non tremor dominant patients [195].…”