Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes,Nature Communications

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Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes
Nature Communications ( IF 14.7 ) Pub Date : 2024-09-09 , DOI: 10.1038/s41467-024-52025-x
Kurt Farrell _{1,

2,

3,

4,

5,

6} , Jack Humphrey _{3,

4,

5,

7} , Timothy Chang ₈ , Yi Zhao _{9,

10} , Yuk Yee Leung _{9,

10,

11} , Pavel P Kuksa _{9,

10,

11} , Vishakha Patil ₈ , Wan-Ping Lee _{9,

10,

11} , Amanda B Kuzma _{9,

10} , Otto Valladares _{9,

10} , Laura B Cantwell _{9,

10} , Hui Wang _{9,

10,

11} , Ashvin Ravi _{3,

4,

5,

7} , Claudia De Sanctis _{1,

2,

3,

4,

5,

6} , Natalia Han _{1,

2,

3,

4,

5,

6} , Thomas D Christie _{1,

2,

3,

4,

5,

6} , Robina Afzal _{1,

2,

3,

4,

5,

6} , Shrishtee Kandoi _{1,

2,

3,

4,

5,

6} , Kristen Whitney _{1,

2,

3,

4,

5,

6} , Margaret M Krassner _{1,

2,

3,

4,

5,

6} , Hadley Ressler _{1,

2,

3,

4,

5,

6} , SoongHo Kim _{1,

2,

3,

4,

5,

6} , Diana Dangoor _{1,

2,

3,

4,

5,

6} , Megan A Iida _{1,

2,

3,

4,

5,

6} , Alicia Casella _{1,

2,

3,

4,

5,

6} , Ruth H Walker _{12,

13} , Melissa J Nirenberg _{12,

13} , Alan E Renton _{3,

4,

5,

7} , Bergan Babrowicz _{1,

2,

3,

4,

5,

6} , Giovanni Coppola ₈ , Towfique Raj _{3,

4,

5,

7} , Günter U Höglinger _{14,

15,

16} , Ulrich Müller ₁₇ , Lawrence I Golbe _{18,

19} , Huw R Morris _{20,

21} , John Hardy _{21,

22} , Tamas Revesz _{21,

23} , Tom T Warner _{20,

21,

23} , Zane Jaunmuktane _{20,

21,

23} , Kin Y Mok _{21,

22} , Rosa Rademakers _{24,

25,

26} , Dennis W Dickson ₂₆ , Owen A Ross ₂₆ , Li-San Wang _{9,

10,

11} , Alison Goate _{3,

4,

5,

7} , Gerard Schellenberg _{9,

10} , Daniel H Geschwind _{8,

27,

28,

29,

30} , , John F Crary _{1,

2,

3,

4,

5,

6} , Adam Naj _{9,

10,

31}

Affiliation

Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics & Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Institute for Precision Health, University of California, Los Angeles, CA, USA.
Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Neurology, Ludwig-Maximilians-Universität Hospital, Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Institute of Human Genetics, Justus-Liebig University, Giessen, Germany.
Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
CurePSP, Inc., New York, NY, USA.
Department of Clinical and Movement Neurosciences, University College London, London, UK.
Queen Square Institute of Neurology, University College London, London, UK.
Dementia Research Institute, University College London, London, UK.
Queen Square Brain Bank for Neurological Disorders, University College London, London, UK.
VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Center for Autism Research and Treatment Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10⁻⁸) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson’s disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.

中文翻译：

进行性核上性麻痹的遗传学、转录组学、组织学和生化分析涉及神经胶质细胞活化和新风险基因

进行性核上性麻痹（PSP）是一种罕见的帕金森病，其特征是运动、平衡和认知问题。PSP 与阿尔茨海默病（AD）和其他疾病不同，通过神经元和神经胶质细胞病理学显示异常的微管相关蛋白 tau。遗传贡献者可能介导这些差异;然而，PSP 的遗传学仍未得到充分探索。在这里，我们进行了最大的 PSP 全基因组关联研究（GWAS），其中包括 2779 例（2595 例神经病理学证实）和 5584 例对照，并确定了六个独立的 PSP 易感基因位点与全基因组显着性（P < 5 × ^10-8）关联，包括 5 个已知（MAPT、MOBP、STX6、RUNX2、SLCO1A2）和 1 个新基因座（C4A).与细胞类型特异性表观基因组注释的整合揭示了少突胶质细胞特征，这可能在后续研究中区分 PSP 与 AD 和帕金森病。使用表达数量性状基因座（eQTL）对候选 PSP 风险基因进行优先级排序，可识别少突胶质细胞对全基因组重要基因座中一半基因表达的特异性影响，以及与脑组织中 C4A 表达的关联，这可能是由 C4A 拷贝数增加驱动的。最后，组织学研究表明 tau 聚集体存在于少突胶质细胞中，与 C4（补体）沉积共定位。将 GWAS 与功能研究、表观基因组和 eQTL 分析相结合，我们确定了 PSP 发病机制中 MOBP 、 STX6 、 RUNX2 、 SLCO1A2 和 C4A 变异的潜在因果作用。

更新日期：2024-09-10

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