Objective: To investigate the impact of four major risk genes, identified by genome-wide association studies (GWAS) in Indian patients with sporadic Progressive Supranuclear Palsy (PSP).

Background: PSP is the most common primary tauopathy characterized by predominant falls, vertical gaze palsy, cognitive decline. Though microtubule-associated protein tau (MAPT) gene has been identified as a major risk gene,  recent GWAS have identified several risk variants in genes like syntaxin 6 (STX6), myelin-associated oligodendrocyte basic protein (MOBP), eukaryotic translation initiation factor 2-α kinase 3 (Eif2AK3), etc. in various populations. However, the impact of these genes has so far not been explored in Indian patients with PSP.

Method: PSP patients (n= 80) fulfilling the MDS criteria and healthy subjects (n=88) were recruited during 2019-2022. Eight single nucleotide polymorphisms (SNPs) of MAPT  gene (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, rs7521, rs62063857, rs12185268), 2 SNPs of STX6 gene (rs1411478, rs3747957), 1 SNP of each MOBP (rs1768208), and Eif2AK3 gene(rs7571971) were genotyped in all the subjects using TaqMan Allelic Discrimination Assay. Besides, sequencing of Exon1, Exon10, and Exon 10 flanking intronic region of MAPT gene was carried out.

Results: Statistically significant differences were observed in the frequencies of the alleles and genotypes such as rs1467967, rs7521 SNPs, rs1411478, and rs7571971 (p<0.05 considered statistically significant). Besides, strong LD values were observed in MAPT between i) rs12185268 and rs62063857, and ii) rs1467967; rs62063857 with rs2471738 and rs1467967. (D’>0.8 considered strong LD).  Based on the SNPs, 16 different sub-haplotypes were observed in 1% or more in our cohorts of which H1h was found most common. We detected significant novel associations of two MAPT sub-haplotypes, such as H1b (p=0.04, OR=0.49) and H1m (p=0.01, OR=4.68) along with H1c (p=0.019, OR=3.28). Notably, strong synergistic gene-gene interactions between MAPT (rs1467967) and STX6 (rs1411478); MAPT (rs7521) and MOBP (rs1768208) (entropy score >1.8% considered strong synergistic interaction) were observed.

Conclusion: Significant associations of two MAPT sub-haplotypes suggest presence of novel MAPT haplotypes in Indian PSP patients. The present findings for the first time suggest strong epistatic interactions of MAPT gene with STX6 and MOBP gene in modulating the risk of PSP.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-insights-into-the-genetic-basis-of-indian-patients-with-progressive-supranuclear-palsy-psp/