Exome Sequencing Identifies Population-Specific Genetic Risk Factors for Progressive Supranuclear Palsy in Asia

Progressive supranuclear palsy (PSP) is a debilitating primary tauopathy. Although genome-wide association studies have identified risk loci in European populations, the genetic architecture of PSP in Asia remains largely undefined.

We aimed to identify population-specific genetic risk factors in Asian patients with PSP.

We performed whole-exome sequencing in 549 patients with PSP recruited across East and Southeast Asia. Variant frequencies were compared with 1492 whole-genome-sequenced controls from the Taiwan Biobank. Novel variants were functionally evaluated using cellular and Drosophila models.

Among 549 patients (mean age at onset 65.1 ± 7.4 years; 60.47% male), 29 (5.28%) carried heterozygous pathogenic or likely pathogenic variants, including 12 novel variants. Additionally, 127 patients (23.13%) harbored 144 rare variants of uncertain significance with minor allele frequency < 1%. Pathogenic variants were most frequently identified in ABCA7 (n = 6, 20.69%) and SMPD1 (n = 6, 20.69%), followed by BSN (n = 3, 10.34%) and MAPT (n = 2, 6.90%). Rare variant landscape analysis identified BSN as the most prominent contributor (38/173 total rare variants, 21.97%), followed by ABCA7 (13.29%), LRRK2 (10.40%), and MAPT (6.94%). Functional studies demonstrated that BSN variants enhance tau aggregation and neurodegeneration. Additionally, the common Asian LRRK2 variants were enriched in PSP, with p.G2385R significantly associated with PSP risk (odds ratio 2.75, 95% CI 1.77-4.32; P < 0.0001) and remained significant compared with Taiwan Biobank controls (P = 0.02), whereas the association for p.R1628P was attenuated.

Our findings delineate an ancestry-specific genetic architecture of PSP distinct from the MAPT-dominant pattern observed in European populations, providing mechanistic insights into disease biology. © 2026 International Parkinson and Movement Disorder Society.