Discovery and fine mapping of serum protein loci through transethnic meta-analysis.
Franceschini N., van Rooij FJA., Prins BP., Feitosa MF., Karakas M., Eckfeldt JH., Folsom AR., Kopp J., Vaez A., Andrews JS., Baumert J., Boraska V., Broer L., Hayward C., Ngwa JS., Okada Y., Polasek O., Westra H-J., Wang YA., Del Greco M F., Glazer NL., Kapur K., Kema IP., Lopez LM., Schillert A., Smith AV., Winkler CA., Zgaga L., LifeLines Cohort Study None., Bandinelli S., Bergmann S., Boban M., Bochud M., Chen YD., Davies G., Dehghan A., Ding J., Doering A., Durda JP., Ferrucci L., Franco OH., Franke L., Gunjaca G., Hofman A., Hsu F-C., Kolcic I., Kraja A., Kubo M., Lackner KJ., Launer L., Loehr LR., Li G., Meisinger C., Nakamura Y., Schwienbacher C., Starr JM., Takahashi A., Torlak V., Uitterlinden AG., Vitart V., Waldenberger M., Wild PS., Kirin M., Zeller T., Zemunik T., Zhang Q., Ziegler A., Blankenberg S., Boerwinkle E., Borecki IB., Campbell H., Deary IJ., Frayling TM., Gieger C., Harris TB., Hicks AA., Koenig W., O' Donnell CJ., Fox CS., Pramstaller PP., Psaty BM., Reiner AP., Rotter JI., Rudan I., Snieder H., Tanaka T., van Duijn CM., Vollenweider P., Waeber G., Wilson JF., Witteman JCM., Wolffenbuttel BHR., Wright AF., Wu Q., Liu Y., Jenny NS., North KE., Felix JF., Alizadeh BZ., Cupples LA., Perry JRB., Morris AP.
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.