Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. We performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), small insertions/deletions (indels), and structural variants (SVs) in a cohort of 1,718 individuals with PSP and 2,944 control subjects. Analysis of common SNVs and indels confirmed known genetic loci at MAPT , MOBP , S TX6 , SLCO1A2 , DUSP10 , and SP1 , and also uncovered novel signals in APOE , FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1 . In contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele and the ε4 allele to be protective, a pattern similar to the association pattern observed in age-related macular degeneration (AMD) but the opposite observed for Alzheimer's disease (AD). Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. We also observed seven common SVs associated with PSP on the H1/H2 haplotype region (17q21.31) and in a few other loci: IGH , PCMT1 , CYP2A13 , and SMCP . Particularly, in the H1/H2 haplotype region, there is a burden of rare deletions and duplications ( P = 6.73×10 -3 ) in PSP. Through WGS, we significantly refine our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.