Browsing by Author "Schlaeger, Thorsten M."

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    Genome sequencing unveils a regulatory landscape of platelet reactivity
    (Springer Nature, 2021-06-15) Keramati, Ali R.; Chen, Ming-Huei; Rodriguez, Benjamin A. T.; Yanek, Lisa R.; Bhan, Arunoday; Gaynor, Brady J.; Ryan, Kathleen; Brody, Jennifer A.; Zhong, Xue; Wei, Qiang; NHLBI Trans-Omics for Precision (TOPMed) Consortium; Kammers, Kai; Kanchan, Kanika; Iyer, Kruthika; Kowalski, Madeline H.; Pitsillides, Achilleas N.; Cupples, L. Adrienne; Li, Bingshan; Schlaeger, Thorsten M.; Shuldiner, Alan R.; O’Connell, Jeffrey R.; Ruczinski, Ingo; Mitchell, Braxton D.; Faraday, Nauder; Taub, Margaret A.; Becker, Lewis C.; Lewis, Joshua P.; Mathias, Rasika A.; Johnson, Andrew D.; Medicine, School of Medicine
    Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.
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    Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis
    (Elsevier, 2019-11-12) Huang, Kang-Chieh; Wang, Mong-Lien; Chen, Shih-Jen; Kuo, Jean-Cheng; Wang, Won-Jing; Nguyen, Phan Nguyen Nhi; Wahlin, Karl J.; Lu, Jyh-Feng; Tran, Audrey A.; Shi, Michael; Chien, Yueh; Yarmishyn, Aliaksandr A.; Tsai, Ping-Hsing; Yang, Tien-Chun; Jane, Wann-Neng; Chang, Chia-Ching; Peng, Chi-Hsien; Schlaeger, Thorsten M.; Chiou, Shih-Hwa; Biology, School of Science
    X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model.