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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.J. ; Boraska, V.* ; Broer, L.* ; Hayward, C.* ; Ngwa, J.S.* ; Okada, Y.* ; Polasek, O.* ; Westra, H.J.* ; Wang, Y.A.* ; Del Greco, F.* ; Glazer, N.L.* ; Kapur, K.* ; Id, P.* ; Lopez, L.M.* ; Schillert, A.* ; Smith, A.V.* ; Winkler, C.A.* ; Zgaga, L.* ; Bandinelli, S.* ; Bergmann, S.* ; Boban, M.* ; Bochud, M.* ; Chen, Y.D.* ; Davies, G.* ; Dehghan, A.* ; Ding, J.Z.* ; Döring, A. ; Durda, J.P.* ; Ferrucci, L.* ; Franco, O.H.* ; Franke, L.* ; Gunjaca, G.* ; Hofman, A.* ; Hsu, F.C.* ; Kolcic, I.* ; Kraja, A.* ; Kubo, M.* ; Lackner, K.J.* ; Launer, L.* ; Loehr, L.R.* ; Li, G.* ; Meisinger, C. ; Nakamura, Y.* ; Schwienbacher, C.* ; Starr, J.M.* ; Takahashi, A.* ; Torlak, V.* ; Uitterlinden, A.G.* ; Vitart, V.* ; Waldenberger, M. ; Wild, P.S.* ; Kirin, M.* ; Zeller, T.* ; Zemunik, T.* ; Zhang, Q.Y.* ; Ziegler, A.* ; Blankenberg, S.* ; Boerwinkle, E.* ; Borecki, I.B.* ; Campbell, H.* ; Deary, I.J.* ; Frayling, T.M.* ; Gieger, C. ; Harris, T.B.* ; Hicks, A.A.* ; Koenig, W.* ; O'Donnell, C.J.* ; Fox, C.S.* ; Pramstaller, P.P.* ; Psaty, B.M.* ; Reiner, A.P.* ; Rotter, J.I.* ; Rudan, I.* ; Snieder, H.* ; Tanaka, T.* ; van Duijn, C.M.* ; Vollenweider, P.* ; Waeber, G.* ; Wilson, J.F.* ; Witteman, J.C.M.* ; Wolffenbuttel, B.H.R.* ; Wright, A.F.* ; Wu, Q.Y.* ; Liu, Y.M.* ; Jenny, N.S.* ; North, K.E.* ; Felix, J.F.* ; Alizadeh, B.Z.* ; Cupples, L.A.* ; Perry, J.R.B.* ; Morris, A.P.*

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

Am. J. Hum. Genet. 91, 744-753 (2012)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 x 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMDS-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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords GENOME-WIDE ASSOCIATION; BIOCHEMICAL TRAITS; SMOKING-BEHAVIOR; FC-RECEPTOR; ALBUMIN; DETERMINANTS; POPULATION; IDENTIFY; RISK; SNPS
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 91, Issue: 4, Pages: 744-753 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
Research Unit Molecular Epidemiology (AME)