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. 2023 Oct 30;14(11):2023.
doi: 10.3390/genes14112023.

Navigating the ALS Genetic Labyrinth: The Role of MAPT Haplotypes

Ivan Tourtourikov  1   2 , Kristiyan Dabchev  2   3 , Tihomir Todorov  2 , Teodor Angelov  4 , Teodora Chamova  4 , Ivailo Tournev  5   6 , Tanya Kadiyska  2   7 , Vanyo Mitev  1 , Albena Todorova  1   2
Affiliations

Navigating the ALS Genetic Labyrinth: The Role of MAPT Haplotypes

Ivan Tourtourikov et al. Genes (Basel). .

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by wide clinical and biological heterogeneity, with a large proportion of ALS patients also exhibiting frontotemporal dementia (FTD) spectrum symptoms. This project aimed to characterize risk subtypes of the H1 haplotype within the MAPT (microtubule-associated protein tau) gene, according to their possible effect as a risk factor and as a modifying factor in relation to the age of disease onset. One hundred patients from Bulgaria with sporadic ALS were genotyped for the variants rs1467967, rs242557, rs1800547, rs3785883, rs2471738, and rs7521. Haploview 4.2 and SHEsisPlus were used to reconstruct haplotype frequencies using genotyping data from the 1000 Genomes project as controls. Genotype-phenotype correlation was investigated in the context of age of disease onset and risk of disease development. While the individual variants of the subtypes do not influence the age of onset of the disease, a correlation was found between the specific haplotype GGAGCA (H1b) and the risk of developing sALS, with results showing that individuals harboring this haplotype have a nearly two-fold increased risk of developing sALS compared to other H1 subtypes. The results from this study suggest that fine transcriptional regulation at the MAPT locus can influence the risk of ALS.

Keywords: ALS; H1 haplotype; MAPT; neurodegenerative disorders.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Tau protein gene structure, showing the tagging SNPs used to discriminate MAPT subhaplotypes and the different isoforms expressed in the human brain.
Figure 2
Figure 2
Regression scatterplot for the additive effect of the SNP’s minor allele on the age of onset.
Figure 3
Figure 3
Linkage disequilibrium scores for the control group and the ALS group: white (weak LD)—D’ < 1, LOD < 2; shaded pink/red (stronger LD)—D’ < 1, LOD ≥ 2; bright red (almost complete LD)—D’ = 1, LOD ≥ 2. Numbers in the squares depict D’ values, where D’ = 1.0 when no number is given.
See this image and copyright information in PMC

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