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    Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis


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    Franceschini, Nora, van Rooij, Frank J.A., Prins, Bram P., Feitosa, Mary F., Karakas, Mahir, Eckfeldt, John H., Folsom, Aaron R., Kopp, Jeffrey, Vaez, Ahmad, Andrews, Jeanette S., Baumert, Jens, Boraska, Vesna, Broer, Linda, Hayward, Caroline, Ngwa, Julius S., Okada, Yukinori, Polasek, Ozren, Westra, Harm-Jan, Wang, Ying A., Del Greco M., Fabiola, Glazer, Nicole L., Kapur, Karen, Kema, Ido P., Lopez, Lorna M., Schillert, Arne, Smith, Albert V., Winkler, Cheryl A., Zgaga, Lina, Bandinelli, Stefania, Bergmann, Sven, Boban, Mladen, Bochud, Murielle, Chen, Y.D., Davies, Gail, Dehghan, Abbas, Ding, Jingzhong, Doering, Angela, Durda, J. Peter, Ferrucci, Luigi, Franco, Oscar H., Franke, Lude, Gunjaca, Grog, Hofman, Albert, Hsu, Fang-Chi, Kolcic, Ivana, Kraja, Aldi, Kubo, Michiaki, Lackner, Karl J., Launer, Lenore, Loehr, Laura R., Li, Guo, Meisinger, Christa, Nakamura, Yusuke, Schwienbacher, Christine, Starr, John M., Takahashi, Atsushi, Torlak, Vesela, Uitterlinden, André G., Vitart, Veronique, Waldenberger, Melanie, Wild, Philipp S., Kirin, Mirna, Zeller, Tanja, Zemunik, Tatijana, Zhang, Qunyuan, Ziegler, Andreas, Blankenberg, Stefan, Boerwinkle, Eric, Borecki, Ingrid B., Campbell, Harry, Deary, Ian J., Frayling, Timothy M., Gieger, Christian, Harris, Tamara B., Hicks, Andrew A., Koenig, Wolfgang, O’Donnell, Christopher J., Fox, Caroline S., Pramstaller, Peter P., Psaty, Bruce M., Reiner, Alex P., Rotter, Jerome I., Rudan, Igor, Snieder, Harold, Tanaka, Toshihiro, van Duijn, Cornelia M., Vollenweider, Peter, Waeber, Gerard, Wilson, James F., Witteman, Jacqueline C.M., Wolffenbuttel, Bruce H.R., Wright, Alan F., Wu, Qingyu, Liu, Yongmei, Jenny, Nancy S., North, Kari E., Felix, Janine F., Alizadeh, Behrooz Z., Cupples, L. Adrienne, Perry, John R.B. and Morris, Andrew P. (2012) Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis. The American Journal of Human Genetics, 91 (4). pp. 744-753. ISSN 00029297

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    Abstract

    Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.
    Item Type: Article
    Keywords: Discovery; Fine Mapping; Serum Protein Loci; Transethnic; Meta-analysis;
    Academic Unit: Faculty of Science and Engineering > Biology
    Faculty of Science and Engineering > Research Institutes > Human Health Institute
    Item ID: 17396
    Identification Number: 10.1016/j.ajhg.2012.08.021
    Depositing User: Lorna Lopez
    Date Deposited: 10 Jul 2023 15:15
    Journal or Publication Title: The American Journal of Human Genetics
    Publisher: Cell Press
    Refereed: Yes
    Related URLs:
    URI: https://mural.maynoothuniversity.ie/id/eprint/17396
    Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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