Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy,Molecular Neurodegeneration

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Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2024-08-16 , DOI: 10.1186/s13024-024-00747-3
Hui Wang _{1,

2} , Timothy S Chang ₃ , Beth A Dombroski _{1,

2} , Po-Liang Cheng _{1,

2} , Vishakha Patil ₃ , Leopoldo Valiente-Banuet ₃ , Kurt Farrell ₄ , Catriona Mclean ₅ , Laura Molina-Porcel _{6,

7} , Alex Rajput ₈ , Peter Paul De Deyn _{9,

10} , Nathalie Le Bastard ₁₁ , Marla Gearing ₁₂ , Laura Donker Kaat ₁₃ , John C Van Swieten ₁₃ , Elise Dopper ₁₃ , Bernardino F Ghetti ₁₄ , Kathy L Newell ₁₄ , Claire Troakes ₁₅ , Justo G de Yébenes ₁₆ , Alberto Rábano-Gutierrez ₁₇ , Tina Meller ₁₈ , Wolfgang H Oertel ₁₈ , Gesine Respondek ₁₉ , Maria Stamelou _{20,

21} , Thomas Arzberger _{22,

23} , Sigrun Roeber ₂₄ , Ulrich Müller ₂₄ , Franziska Hopfner ₂₅ , Pau Pastor _{26,

27} , Alexis Brice ₂₈ , Alexandra Durr ₂₈ , Isabelle Le Ber ₂₈ , Thomas G Beach ₂₉ , Geidy E Serrano ₂₉ , Lili-Naz Hazrati ₃₀ , Irene Litvan ₃₁ , Rosa Rademakers _{32,

33} , Owen A Ross ₃₃ , Douglas Galasko ₃₁ , Adam L Boxer ₃₄ , Bruce L Miller ₃₄ , Willian W Seeley ₃₄ , Vivanna M Van Deerlin ₁ , Edward B Lee _{1,

35} , Charles L White ₃₆ , Huw Morris ₃₇ , Rohan de Silva ₃₈ , John F Crary ₄ , Alison M Goate ₃₉ , Jeffrey S Friedman ₄₀ , Yuk Yee Leung _{1,

2} , Giovanni Coppola _{3,

41} , Adam C Naj _{1,

2,

42} , Li-San Wang _{1,

2} , , Clifton Dalgard ₄₃ , Dennis W Dickson ₃₃ , Günter U Höglinger ₂₅ , Gerard D Schellenberg _{1,

2} , Daniel H Geschwind _{3,

44,

45} , Wan-Ping Lee _{1,

2}

Affiliation

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Pathology, Department of Artificial Intelligence & Human Health, Nash Family, Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain, Institute, Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.
Alzheimer's Disease and Other Cognitive Disorders Unit. Neurology Service, Hospital Clínic, Fundació Recerca Clínic Barcelona (FRCB). Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, SK, Canada.
Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk (Antwerp), Belgium.
Department of Neurology, University Medical Center Groningen, NL-9713 AV, Groningen, Netherlands.
Fujirebio Europe NV, Technologiepark 6, 9052, Ghent, Belgium.
Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Netherlands Brain Bank and Erasmus University, Rotterdam, Netherlands.
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
Autonomous University of Madrid, Madrid, Spain.
Fundación CIEN (Centro de Investigación de Enfermedades Neurológicas) - Centro Alzheimer Fundación Reina Sofía, Madrid, Spain.
Department of Neurology, Philipps-Universität, Marburg, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Parkinson's Disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.
European University of Cyprus, Nicosia, Cyprus.
Department of Psychiatry and Psychotherapy, University Hospital Munich, Ludwig-Maximilians-University Munich, Munich, Germany.
Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
German Brain Bank, Neurobiobank Munich, Munich, Germany.
Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität (LMU) München; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias I Pujol, Badalona, Barcelona, Spain.
Neurosciences, The Germans Trias I Pujol Research Institute (IGTP) Badalona, Badalona, Spain.
Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
Banner Sun Health Research Institute, Sun City, AZ, USA.
University McGill, Montreal, QC, Canada.
Department of Neuroscience, University of California, San Diego, CA, USA.
VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA.
Memory and Aging Center, University of California, San Francisco, CA, USA.
Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
University of Texas Southwestern Medical Center, Dallas, TX, USA.
Departmento of Clinical and Movement Neuroscience, University College of London, London, UK.
Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
Department of Genetics and Genomic Sciences, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Bioventure, Inc., Del Mar, CA, USA.
Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Anatomy Physiology and Genetics, the American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USA.

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. 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. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. 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 enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

中文翻译：

全基因组测序分析揭示了与进行性核上性麻痹相关的新易感基因位点和结构变异

进行性核上性麻痹（PSP）是一种罕见的神经退行性疾病，其特征是聚集的 tau 蛋白在星形胶质细胞、神经元和少突胶质细胞中积累。以前的 PSP 全基因组关联研究是基于基因型阵列的，因此不足以分析罕见变异以及较大的突变，例如小插入/缺失（indel）和结构变异（SV）。在这项研究中，我们在 1,718 例病例和 2,944 例欧洲血统对照的队列中进行了全基因组测序（WGS）并对单核苷酸变异（SNV）、插入缺失和 SVs 进行了关联分析。在 1,718 名 PSP 个体中，1,441 名经尸检证实，277 名被临床诊断。我们对常见 SNV 和插入缺失的分析证实了 MAPT 、 MOBP 、 STX6 、 SLCO1A2 、 DUSP10 和 SP1 的已知遗传位点，并进一步发现了 APOE 、 FCHO1/MAP1S 、 KIF13A 、 TRIM24 、 TNXB 和 ELOVL1 中的新信号。值得注意的是，与阿尔茨海默病（AD）相比，我们观察到 APOE ε2 等位基因是 PSP 中的风险等位基因。对稀有 SNV 和插入缺失的分析确定了 ZNF592 中的显著相关性，进一步的基因网络分析确定了 PSP 中神经元基因失调的一个模块。此外，在 H1/H2 单倍型区域（17q21.31）和其他基因座中观察到 7 个与 PSP 相关的常见 SV，包括 IGH 、 PCMT1 、 CYP2A13 和 SMCP。在 H1/H2 单倍型区域，PSP 中存在罕见缺失和重复的负担（P = 6.73 × 10-3）。通过 WGS，我们显著增强了对 PSP 遗传基础的理解，为探索疾病机制和治疗干预提供了新的靶点。

更新日期：2024-08-17

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