A Spanish-Portuguese GWAS of progressive supranuclear palsy reveals a novel risk locus in NFASC

Abstract

Progressive supranuclear palsy (PSP) is a rare 4-repeat tauopathy that causes behavioural, movement and cognitive abnormalities. We genotyped all available clinical and histopathological PSP cases in Spain and Portugal (N = 522), and conducted the largest PSP GWAS of the Iberian population to date. Genetic burden analysis revealed reduced diagnostic specificity in clinically diagnosed atypical PSP cases—when applying the 2017 MDS criteria—compared to Richardson’s syndrome cases. We independently replicated eight PSP risk variants in seven known loci (MAPT, MOBP, EIF2AK3, STX6, SLCO1A2, DUSP10 and APOE), and identified a novel locus in NFASC/CNTN2 (rs12744678 C: OR[95%CI] = 0.83[0.78–0.89]; p = 4.15·10−08) after meta-analysis with a newly available Dutch cohort and publicly available summary statistics (3,099 PSP; 11,482 controls). Enrichment analysis and protein expression profiling highlighted oligodendrocyte function and myelination as likely contributors to PSP pathogenesis. Our findings broaden the genetic landscape of PSP and suggest potential therapeutic avenues focused on modulating neuron–oligodendrocyte interactions.