Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Farrell Kurt, Humphrey Jack, Chang Timothy, Zhao Yi, Leung Yuk Yee, Kuksa Pavel P, Patil Vishakha, Lee Wan-Ping, Kuzma Amanda B, Valladares Otto, Cantwell Laura B, Wang Hui, Ravi Ashvin, De Sanctis Claudia, Han Natalia, Christie Thomas D, Afzal Robina, Kandoi Shrishtee, Whitney Kristen, Krassner Margaret M, Ressler Hadley, Kim SoongHo, Dangoor Diana, Iida Megan A, Casella Alicia, Walker Ruth H, Nirenberg Melissa J, Renton Alan E, Babrowicz Bergan, Coppola Giovanni, Raj Towfique, Höglinger Günter U, Müller Ulrich, Golbe Lawrence I, Morris Huw R, Hardy John, Revesz Tamas, Warner Tom T, Jaunmuktane Zane, Mok Kin Y, Rademakers Rosa, Dickson Dennis W, Ross Owen A, Wang Li-San, Goate Alison, Schellenberg Gerard, Geschwind Daniel H, PSP Genetics Study Group, Crary John F, Naj Adam
Аннотация
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.