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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
This article derives from two interdisciplinary research projects funded by the UK Arts and Humanities Research Council, involving the application of psychological experimental techniques to the study of poetic form and reader response. It discusses the semantic and expressive effects of space and pattern in innovative forms of contemporary British and American poetry. After referring to some historical and theoretical contexts for these issues, the article analyses the results of experiments using eye-tracking, manipulations of text, memory tests and readers' recorded responses and interpretations. The first group of poems studied were lineated, with extended spaces within lines and displacement of lines from the left margin. Referring to a poem from Geoffrey Hill'sCanaan(1996), the authors show that such use of space may serve to articulate syntactical structures, but may also promote richer interpretation by encouraging cross-linear semantic connections. The second technique studied was the break from linear into postlinear poetry, as an initially lineated sequence shifts to pages of dispersed text. In readings of Susan Howe'sPythagorean Silence(fromThe Europe of Trusts, 1990), the authors detected more radical effects of space, shape and pattern, with associated consequences for interpretative strategies and aesthetic responses. Finally, the article discusses the potential for both mutual support and heuristic challenge between an empirical study of reader response, and a historical-theoretical approach as exemplified by Jerome McGann's interpretation ofPythagorean Silence.