MAPT Locus in Parkinson's Disease Patients of Ashkenazi Origin: A Stratified Analysis

Abstract

Introduction: MAPT locus is associated with Parkinson's disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods: LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results: The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2-G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes (MAPT and SPPL2C); structural deletions and segmental duplication (KANSL1); and variants affecting gene expression and intron excision ratio in brain tissues (LRRC37A/2). Conclusions: Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy.

Keywords: GBA1; H2 haplotype; KANSL1; LRRK2; MAPT; Parkinson’s disease.

Figure 1

Schematic representation of the MAPT locus and the linkage disequilibrium (LD) region in Ashkenazi Jews (AJs). The upper panel presents the genes in chr17:45,306,351-46,866,206 from the hg38 UCSC genome browser GENCODE V43 annotation track. Variants are represented by black lines, while boxes filled with transparent grey diagonal lines indicate regions with low WGS coverage. Black-colored genes represent coding genes, and grey-colored genes indicate pseudogenes. In the lower panel, the specific genotypes of 10 H2/H2 AJ-PD carriers and 47 AJ-PD H1/H1 carriers are depicted schematically and not drawn to scale. Three H2/H2 individuals (PD8, PD9, and PD10) carry recombinant alleles marked as R1, R2, and R3. These three reduce the LD region to a 1.2 Mb interval.