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

BACKGROUND: 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. OBJECTIVES: We aimed to identify population-specific genetic risk factors in Asian patients with PSP. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Authors

Institutions

Publication Details

Journal
Movement Disorders
Published
2026-11-01
DOI
https://doi.org/10.1002/mds.70595
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Wan‐Ping Lee, Ichiro Yabe, Pin‐Shiuan Chen, Gerard Saranza et al.
2 links
Movement Disorders
Parkinson's Disease Mechanisms and Treatments
article

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

Wan‐Ping Lee, Ichiro Yabe, Pin‐Shiuan Chen, Gerard Saranza, Min‐Yu Lan, Rung‐Juen Lin, Yi Jayne Tan, Han‐Lin Chiang, Chin‐Hsien Lin, Xiaosheng Zheng, Tzi Shin Toh, Adeline Su Lyn Ng, Eng‐King Tan, Hsiu-Chen Chang, Ni‐Chung Lee, Chih‐Chiang Chan, Hiroaki Yaguchi, Shen‐Yang Lim, Yuen Kang Chia, Yih‐Ru Wu, Yi Wen Tay, Joshua Chin Ern Ooi, Chun‐Hwei Tai, T.-S. Lee, Ai Huey Tan, Lie Cheng, Huan‐Yun Chen, Sung‐Pin Fan, Jung Hwan Shin, Han‐Joon Kim, Miao‐Zi Hung, Chuan‐Jen Hsu, Wei Feng Luo, Azlina Ahmad‐Annuar, Chun‐Yu Chen, Jee‐Young Lee, Shu‐Yi Huang, Cheng‐Hsuan Li, Taichi Nomura, Anis Nadhirah Khairul Anuar, Chin‐Song Lu, Yang‐Yee Chang
article en

Abstract

BACKGROUND: 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. OBJECTIVES: We aimed to identify population-specific genetic risk factors in Asian patients with PSP. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Movement Disorders
Seoul National University (KR), National Taiwan University (TW), Hokkaido University (JP), Taipei Veterans General Hospital (TW), University of Malaya (MY), Kaohsiung Chang Gung Memorial Hospital (TW), Linkou Chang Gung Memorial Hospital (TW), Duke-NUS Medical School (SG), National Neuroscience Institute (SG), National Taiwan University Hospital (TW), Second Affiliated Hospital of Zhejiang University (CN), National Cheng Kung University Hospital (TW), Queen Elizabeth Hospital (MY), Chong Hua Hospital (PH), Zhejiang University (CN), University of Pennsylvania (US), National Cheng Kung University (TW)
Ministry of Health, Labour and Welfare, Universiti Malaya, National Taiwan University Hospital, National Science and Technology Council, National Medical Research Council, Japan Society for the Promotion of Science, Science and Technology Program of Zhejiang Province, Key Research and Development Program of Zhejiang Province
Good health and well-being
Openalex Percentile: Top 14%
Parkinson's Disease Mechanisms and Treatments
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.

Laika access coming soon