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Author: Katrin Horn2
Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.
LIFE Adult, Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for … rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Authors: M. Gorski, B. Jung, Y. Li, P. R. Matias-Garcia, M. Wuttke, S. Coassin, C. H. L. Thio, M. E. Kleber, T. W. Winkler, V. Wanner, J. F. Chai, A. Y. Chu, M. Cocca, M. F. Feitosa, S. Ghasemi, A. Hoppmann, K. Horn, M. Li, T. Nutile, M. Scholz, K. B. Sieber, A. Teumer, A. Tin, J. Wang, B. O. Tayo, T. S. Ahluwalia, P. Almgren, S. J. L. Bakker, B. Banas, N. Bansal, M. L. Biggs, E. Boerwinkle, E. P. Bottinger, H. Brenner, R. J. Carroll, J. Chalmers, M. L. Chee, M. L. Chee, C. Y. Cheng, J. Coresh, M. H. de Borst, F. Degenhardt, K. U. Eckardt, K. Endlich, A. Franke, S. Freitag-Wolf, P. Gampawar, R. T. Gansevoort, M. Ghanbari, C. Gieger, P. Hamet, K. Ho, E. Hofer, B. Holleczek, V. H. Xian Foo, N. Hutri-Kahonen, S. J. Hwang, M. A. Ikram, N. S. Josyula, M. Kahonen, C. C. Khor, W. Koenig, H. Kramer, B. K. Kramer, B. Kuhnel, L. A. Lange, T. Lehtimaki, W. Lieb, R. J. F. Loos, M. A. Lukas, L. P. Lyytikainen, C. Meisinger, T. Meitinger, O. Melander, Y. Milaneschi, P. P. Mishra, N. Mononen, J. C. Mychaleckyj, G. N. Nadkarni, M. Nauck, K. Nikus, B. Ning, I. M. Nolte, M. L. O'Donoghue, M. Orho-Melander, S. A. Pendergrass, B. W. J. H. Penninx, M. H. Preuss, B. M. Psaty, L. M. Raffield, O. T. Raitakari, R. Rettig, M. Rheinberger, K. M. Rice, A. R. Rosenkranz, P. Rossing, J. I. Rotter, C. Sabanayagam, H. Schmidt, R. Schmidt, B. Schottker, C. A. Schulz, S. Sedaghat, C. M. Shaffer, K. Strauch, S. Szymczak, K. D. Taylor, J. Tremblay, L. Chaker, P. van der Harst, P. J. van der Most, N. Verweij, U. Volker, M. Waldenberger, L. Wallentin, D. M. Waterworth, H. D. White, J. G. Wilson, T. Y. Wong, M. Woodward, Q. Yang, M. Yasuda, L. M. Yerges-Armstrong, Y. Zhang, H. Snieder, C. Wanner, C. A. Boger, A. Kottgen, F. Kronenberg, C. Pattaro, I. M. Heid

Date Published: 30th Oct 2020

Publication Type: Journal article

Genome-wide association analysis of actigraphic sleep phenotypes in the LIFE Adult Study.
LIFE Adult, Genetical Statistics and Systems Biology

Abstract (Expand)

The genetic basis of sleep is still poorly understood. Despite the moderate to high heritability of sleep-related phenotypes, known genetic variants explain only a small proportion of the phenotypical … variance. However, most previous studies were based solely upon self-report measures. The present study aimed to conduct the first genome-wide association (GWA) of actigraphic sleep phenotypes. The analyses included 956 middle- to older-aged subjects (40-79 years) from the LIFE Adult Study. The SenseWear Pro 3 Armband was used to collect 11 actigraphic parameters of night- and daytime sleep and three parameters of rest (lying down). The parameters comprised measures of sleep timing, quantity and quality. A total of 7 141 204 single nucleotide polymorphisms (SNPs) were analysed after imputation and quality control. We identified several variants below the significance threshold of P </= 5x 10(-8) (not corrected for analysis of multiple traits). The most significant was a hit near UFL1 associated with sleep efficiency on weekdays (P = 1.39 x 10(-8) ). Further SNPs were close to significance, including an association between sleep latency and a variant in CSNK2A1 (P = 8.20 x 10(-8) ), a gene known to be involved in the regulation of circadian rhythm. In summary, our GWAS identified novel candidate genes with biological plausibility being promising candidates for replication and further follow-up studies.

Authors: J. Spada, M. Scholz, H. Kirsten, T. Hensch, K. Horn, P. Jawinski, C. Ulke, R. Burkhardt, K. Wirkner, M. Loeffler, U. Hegerl, C. Sander

Date Published: 30th Apr 2016

Publication Type: Journal article

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