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

Genes play an important role in the risk of Progressive Supranuclear Palsy (PSP). Some of the major risk genes identified for PSP include <i>MAPT</i>, <i>STX6</i>, <i>MOBP</i>, and <i>EIF2AK3</i> 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 <i>MAPT</i> gene (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, rs7521, rs12185268, and rs62063857, and two SNPs of <i>STX6</i> gene (rs3747957 and rs1411478), one SNP each from <i>MOBP</i> (rs1768208) and <i>EIF2AK3</i> (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 <i>MAPT</i> gene (rs1467967, rs242557, rs3785883), along with <i>STX6</i> (rs1411478) and <i>MOBP</i> (rs1768208), appeared to be the best five-locus model (<i>p</i> &lt; 0.001), suggesting strong interactions among <i>MAPT</i>, <i>STX6</i> and <i>MOBP</i> genes in modulating the risk of PSP. Strong synergistic interactions were observed within <i>MAPT</i> gene (rs1467967, rs244557, rs3785883, rs7521, and rs2471738), and between <i>MAPT</i> (rs7521) and <i>MOBP</i> (rs1768208). Additionally, moderately strong synergistic interactions were found between (i) <i>MOBP</i> (rs1768208) and <i>STX6</i> (rs1411478), and (ii) <i>MOBP</i> (rs1768208) and <i>MAPT</i> (rs3785883) genes. The findings of this study suggest significant impact of gene-gene interactions amongst <i>MAPT</i>, <i>STX6</i>, and <i>MOBP</i> genes in modulating the risk of PSP. This implies that epistatic interactions might constitute an important mechanism in delineating the genetic basis of PSP.