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