Impact of gene-gene interactions in Progressive Supranuclear Palsy: new genetic perspectives in the Asian-Indian population.

Abstract

Genes play an important role in the risk of Progressive Supranuclear Palsy (PSP). Some of the major risk genes identified for PSP include MAPT, STX6, MOBP, and EIF2AK3 in several ethnic groups. However, the interactions among these genes have not been explored in PSP. Therefore, this prospective case-control study aimed to explore the impact of gene-gene interactions in patients with PSP (n = 106) and healthy subjects (n = 109) of Indian ethnicity. Eight single nucleotide polymorphisms (SNPs) of MAPT gene (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, rs7521, rs12185268, and rs62063857, and two SNPs of STX6 gene (rs3747957 and rs1411478), one SNP each from MOBP (rs1768208) and EIF2AK3 (rs7571971) genes were genotyped by TaqMan Alleleic Discrimination Assay in all the study participants. Gene-gene interactions among these 12 SNPs were performed using the multi-dimensionality reduction (MDR) test. The combination of SNPs from the MAPT gene (rs1467967, rs242557, rs3785883), along with STX6 (rs1411478) and MOBP (rs1768208), appeared to be the best five-locus model (p < 0.001), suggesting strong interactions among MAPT, STX6 and MOBP genes in modulating the risk of PSP. Strong synergistic interactions were observed within MAPT gene (rs1467967, rs244557, rs3785883, rs7521, and rs2471738), and between MAPT (rs7521) and MOBP (rs1768208). Additionally, moderately strong synergistic interactions were found between (i) MOBP (rs1768208) and STX6 (rs1411478), and (ii) MOBP (rs1768208) and MAPT (rs3785883) genes. The findings of this study suggest significant impact of gene-gene interactions amongst MAPT, STX6, and MOBP genes in modulating the risk of PSP. This implies that epistatic interactions might constitute an important mechanism in delineating the genetic basis of PSP.