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Tucker, Nathan

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Tucker

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Nathan

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Tucker, Nathan
Author's Publications: search.filters.isAuthorOfPublication.bf768722-0e22-49ce-834b-2c63bd92f8b4

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    PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance
    (Public Library of Science, 2016) Kiando, Soto Romuald; Tucker, Nathan; Castro-Vega, Luis-Jaime; Katz, Alexander; D’Escamard, Valentina; Tréard, Cyrielle; Fraher, Daniel; Albuisson, Juliette; Kadian-Dodov, Daniella; Ye, Zi; Austin, Erin; Yang, Min-Lee; Hunker, Kristina; Barlassina, Cristina; Cusi, Daniele; Galan, Pilar; Empana, Jean-Philippe; Jouven, Xavier; Gimenez-Roqueplo, Anne-Paule; Bruneval, Patrick; Hyun Kim, Esther Soo; Olin, Jeffrey W.; Gornik, Heather L.; Azizi, Michel; Plouin, Pierre-François; Ellinor, Patrick; Kullo, Iftikhar J.; Milan, David; Ganesh, Santhi K.; Boutouyrie, Pierre; Kovacic, Jason C.; Jeunemaitre, Xavier; Bouatia-Naji, Nabila
    Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10−4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10−10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10−4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.
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    Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures
    (eLife Sciences Publications, Ltd, 2016) Wang, Xinchen; Tucker, Nathan; Rizki, Gizem; Mills, Robert; Krijger, Peter HL; de Wit, Elzo; Subramanian, Vidya; Bartell, Eric; Nguyen, Xinh-Xinh; Ye, Jiangchuan; Leyton-Mange, Jordan Stewart; Dolmatova, Elena V; van der Harst, Pim; de Laat, Wouter; Ellinor, Patrick; Newton-Cheh, Christopher; Milan, David; Kellis, Manolis; Boyer, Laurie A
    Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits. DOI: http://dx.doi.org/10.7554/eLife.10557.001
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    Genetic association analyses highlight biological pathways underlying mitral valve prolapse
    (2016) Dina, Christian; Bouatia-Naji, Nabila; Tucker, Nathan; Delling, Francesca N.; Toomer, Katelynn; Durst, Ronen; Perrocheau, Maelle; Fernandez-Friera, Leticia; Solis, Jorge; Le Tourneau, Thierry; Chen, Ming-Huei; Probst, Vincent; Bosse, Yohan; Pibarot, Philippe; Zelenika, Diana; Lathrop, Mark; Hercberg, Serge; Roussel, Ronan; Benjamin, Emelia J.; Bonnet, Fabrice; Su Hao, LO; Dolmatova, Elena; Simonet, Floriane; Lecointe, Simon; Kyndt, Florence; Redon, Richard; Le Marec, Hervé; Froguel, Philippe; Ellinor, Patrick; Vasan, Ramachandran S.; Bruneval, Patrick; Norris, Russell A.; Milan, David; Slaugenhaupt, Susan; Levine, Robert; Schott, Jean-Jacques; Hagege, Albert A.; Jeunemaitre, Xavier
    Non-syndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown aetiology that predisposes to mitral regurgitation, heart failure and sudden death1. Previous family and pathophysiological studies suggest a complex pattern of inheritance2–5. We performed a meta-analysis of two genome-wide association studies in 1,442 cases and 2,439 controls. We identified and replicated in 1,422 cases and 6,779 controls six loci and provide functional evidence for candidate genes. We highlight LMCD1 encoding a transcription factor6, for which morpholino knockdown in zebrafish results in atrioventricular (AV) valve regurgitation. A similar zebrafish phenotype was obtained for tensin1 (TNS1), a focal adhesion protein involved in cytoskeleton organization. We also show the expression of tensin1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1−/− mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair7.