Discovery and fine mapping of serum protein loci through transethnic meta-analysis

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

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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.

Original languageEnglish
Pages (from-to)744-753
Number of pages10
JournalAmerican Journal of Human Genetics
Volume91
Issue number4
DOIs
Publication statusPublished - 05-10-2012

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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    Franceschini, N., Van Rooij, F. J. A., Prins, B. P., Feitosa, M. F., Karakas, M., Eckfeldt, J. H., Folsom, A. R., Kopp, J., Vaez, A., Andrews, J. S., Baumert, J., Boraska, V., Broer, L., Hayward, C., Ngwa, J. S., Okada, Y., Polasek, O., Westra, H. J., Wang, Y. A., ... Morris, A. P. (2012). Discovery and fine mapping of serum protein loci through transethnic meta-analysis. American Journal of Human Genetics, 91(4), 744-753. https://doi.org/10.1016/j.ajhg.2012.08.021