Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Chasman, D. I. and Fuchsberger, C. and Pattaro, C. and Teumer, A. and Boger, C. A. and Endlich, K. and Olden, M. and Chen, M. H. and Tin, A. and Taliun, D. and Li, M. and Gao, X. and Gorski, M. and Yang, Q. and Hundertmark, C. and Foster, M. C. and O'Seaghdha, C. M. and Glazer, N. and Isaacs, A. and Liu, C. T. and Smith, A. V. and O'Connell, J. R. and Struchalin, M. and Tanaka, T. and Li, G. and Johnson, A. D. and Gierman, H. J. and Feitosa, M. F. and Hwang, S. J. and Atkinson, E. J. and Lohman, K. and Cornelis, M. C. and Johansson, A. and Tonjes, A. and Dehghan, A. and Lambert, J. C. and Holliday, E. G. and Sorice, R. and Kutalik, Z. and Lehtimaki, T. and Esko, T. and Deshmukh, H. and Ulivi, S. and Chu, A. Y. and Murgia, F. and Trompet, S. and Imboden, M. and Coassin, S. and Pistis, G. and Harris, T. B. and Launer, L. J. and Aspelund, T. and Eiriksdottir, G. and Mitchell, B. D. and Boerwinkle, E. and Schmidt, H. and Cavalieri, M. and Rao, M. and Hu, F. and Demirkan, A. and Oostra, B. A. and de, A. M. and Turner, S. T. and Ding, J. and Andrews, J. S. and Freedman, B. I. and Giulianini, F. and Koenig, W. and Illig, T. and Meisinger, C. and Gieger, C. and Zgaga, L. and Zemunik, T. and Boban, M. and Minelli, C. and Wheeler, H. E. and Igl, W. and Zaboli, G. and Wild, S. H. and Wright, A. F. and Campbell, H. and Ellinghaus, D. and Nothlings, U. and Jacobs, G. and Biffar, R. and Ernst, F. and Homuth, G. and Kroemer, H. K. and Nauck, M. and Stracke, S. and Volker, U. and Volzke, H. and Kovacs, P. and Stumvoll, M. and Magi, R. and Hofman, A. and Uitterlinden, A. G. and Rivadeneira, F. and Aulchenko, Y. S. and Polasek, O. and Hastie, N. and Vitart, V. and Helmer, C. and Wang, J. J. and Stengel, B. and Ruggiero, D. and Bergmann, S. and Kahonen, M. and Viikari, J. and Nikopensius, T. and Province, M. and Ketkar, S. and Colhoun, H. and Doney, A. and Robino, A. and Kramer, B. K. and Portas, L. and Ford, I. and Buckley, B. M. and Adam, M. and Thun, G. A. and Paulweber, B. and Haun, M. and Sala, C. and Mitchell, P. and Ciullo, M. and Kim, S. K. and Vollenweider, P. and Raitakari, O. and Metspalu, A. and Palmer, C. and Gasparini, P. and Pirastu, M. and Jukema, J. W. and Probst-Hensch, N. M. and Kronenberg, F. and Toniolo, D. and Gudnason, V. and Shuldiner, A. R. and Coresh, J. and Schmidt, R. and Ferrucci, L. and Siscovick, D. S. and van Duijn, C. M. and Borecki, I. B. and Kardia, S. L. and Liu, Y. and Curhan, G. C. and Rudan, I. and Gyllensten, U. and Wilson, J. F. and Franke, A. and Pramstaller, P. P. and Rettig, R. and Prokopenko, I. and Witteman, J. and Hayward, C. and Ridker, P. M. and Parsa, A. and Bochud, M. and Heid, I. M. and Kao, W. L. and Fox, C. S. and Kottgen, A.. (2012) Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. Human molecular genetics, Vol. 21, H. 24. pp. 5329-5343.

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Official URL: http://edoc.unibas.ch/dok/A6094247

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Abstract

In conducting genome-wide association studies (GWAS), analytic approaches leveraging biologic information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on SNPs in genes that are connected by functional evidence, determined by literature mining and gene ontology hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (p=5.6x10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2, and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall p-values of 4.5x10(-4)-2.2x10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection to the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general

Faculties and Departments:	09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Chronic Disease Epidemiology
UniBasel Contributors:	Imboden, Medea
Item Type:	Article, refereed
Article Subtype:	Research Article
Publisher:	Oxford Univ. Press
ISSN:	0964-6906
Note:	Publication type according to Uni Basel Research Database: Journal article
Related URLs:	Document Document
Identification Number:	pmid: 22962313 doi: 10.1093/hmg/dds369
Last Modified:	19 Jul 2013 07:43
Deposited On:	19 Jul 2013 07:40

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