Chasman, Daniel I. and Fuchsberger, Christian and Pattaro, Cristian and Teumer, Alexander and Boeger, Carsten A. and Endlich, Karlhans and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C. and O'Seaghdha, Conall M. and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V. and O'Connell, Jeffrey R. and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D. and Gierman, Hinco J. and Feitosa, Mary F. and Hwang, Shih-Jen and Atkinson, Elizabeth J. and Lohman, Kurt and Cornelis, Marilyn C. and Johansson, Asa and Toenjes, Anke and Dehghan, Abbas and Lambert, Jean-Charles and Holliday, Elizabeth G. and Sorice, Rossella and Kutalik, Zoltan and Lehtimaeki, Terho and Esko, Tonu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y. and Murgia, Federico and Trompet, Stella and Imboden, Medea and Coassin, Stefan and Pistis, Giorgio and Harris, Tamara B. and Launer, Lenore J. and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D. and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank and Demirkan, Ayse and Oostra, Ben A. and de Andrade, Mariza and Turner, Stephen T. and Ding, Jingzhong and Andrews, Jeanette S. and Freedman, Barry I. and Giulianini, Franco and Koenig, Wolfgang and Illig, Thomas and Meisinger, Christa and Gieger, Christian and Zgaga, Lina and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E. and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H. and Wright, Alan F. and Campbell, Harry and Ellinghaus, David and Noethlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K. and Nauck, Matthias and Stracke, Sylvia and Voelker, Uwe and Voelzke, Henry and Kovacs, Peter and Stumvoll, Michael and Maegi, Reedik and Hofman, Albert and Uitterlinden, Andre G. and Rivadeneira, Fernando and Aulchenko, Yurii S. and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Stengel, Benedicte and Ruggiero, Daniela and Bergmann, Sven and Kahonen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Kraemer, Bernhard K. and Portas, Laura and Ford, Ian and Buckley, Brendan M. and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K. and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J. Wouter and Probst-Hensch, Nicole M. and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R. and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S. and van Duijn, Cornelia M. and Borecki, Ingrid B. and Kardia, Sharon L. R. and Liu, Yongmei and Curhan, Gary C. and Rudan, Igor and Gyllensten, Ulf and Wilson, James F. and Franke, Andre and Pramstaller, Peter P. and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline and Hayward, Caroline and Ridker, Paul M. and Parsa, Afshin and Bochud, Murielle and Heid, Iris M. and Kao, W. H. Linda and Fox, Caroline S. and Koettgen, Anna (2012) Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. HUMAN MOLECULAR GENETICS, 21 (24). pp. 5329-5343. ISSN 0964-6906,
Full text not available from this repository. (Request a copy)Abstract
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological 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 the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) 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 the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(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 4.5 10(4)2.2 10(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 with 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GLOMERULAR-FILTRATION-RATE; COMMUNITY-BASED POPULATION; SERUM CREATININE; RENAL-FUNCTION; R PACKAGE; DISEASE; EXPRESSION; LOCI; TRAITS; SNPS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Epidemiologie und Präventivmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 May 2020 04:37 |
| Last Modified: | 04 May 2020 04:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/17595 |
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