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. & 81 others 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

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)744-753
Number of pages10
JournalAmerican Journal of Human Genetics
Volume91
Issue number4
DOIs
StatePublished - Oct 5 2012
Externally publishedYes

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Serum Albumin
Meta-Analysis
Blood Proteins
Kidney Neoplasms
Genome-Wide Association Study
Linkage Disequilibrium
Kidney Diseases
Protein Biosynthesis
Ribosomes
Knockout Mice
Malnutrition
Genes
Proteins
Genome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Franceschini, N., Van Rooij, F. J. A., Prins, B. P., Feitosa, M. F., Karakas, M., Eckfeldt, J. H., ... 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

Discovery and fine mapping of serum protein loci through transethnic meta-analysis. / 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; Morris, Andrew P.

In: American Journal of Human Genetics, Vol. 91, No. 4, 05.10.2012, p. 744-753.

Research output: Contribution to journalArticle

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, HJ, Wang, YA, Del Greco M., F, Glazer, NL, Kapur, K, Kema, IP, Lopez, LM, Schillert, A, Smith, AV, Winkler, CA, Zgaga, L, 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, FC, 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 2012, 'Discovery and fine mapping of serum protein loci through transethnic meta-analysis', American Journal of Human Genetics, vol. 91, no. 4, pp. 744-753. https://doi.org/10.1016/j.ajhg.2012.08.021
Franceschini N, Van Rooij FJA, Prins BP, Feitosa MF, Karakas M, Eckfeldt JH et al. Discovery and fine mapping of serum protein loci through transethnic meta-analysis. American Journal of Human Genetics. 2012 Oct 5;91(4):744-753. https://doi.org/10.1016/j.ajhg.2012.08.021
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 ; Morris, Andrew P. / Discovery and fine mapping of serum protein loci through transethnic meta-analysis. In: American Journal of Human Genetics. 2012 ; Vol. 91, No. 4. pp. 744-753.
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TY - JOUR

T1 - Discovery and fine mapping of serum protein loci through transethnic meta-analysis

AU - Franceschini, Nora

AU - Van Rooij, Frank J A

AU - Prins, Bram P.

AU - Feitosa, Mary F.

AU - Karakas, Mahir

AU - Eckfeldt, John H.

AU - Folsom, Aaron R.

AU - Kopp, Jeffrey

AU - Vaez, Ahmad

AU - Andrews, Jeanette S.

AU - Baumert, Jens

AU - Boraska, Vesna

AU - Broer, Linda

AU - Hayward, Caroline

AU - Ngwa, Julius S.

AU - Okada, Yukinori

AU - Polasek, Ozren

AU - Westra, Harm Jan

AU - Wang, Ying A.

AU - Del Greco M., Fabiola

AU - Glazer, Nicole L.

AU - Kapur, Karen

AU - Kema, Ido P.

AU - Lopez, Lorna M.

AU - Schillert, Arne

AU - Smith, Albert V.

AU - Winkler, Cheryl A.

AU - Zgaga, Lina

AU - Bandinelli, Stefania

AU - Bergmann, Sven

AU - Boban, Mladen

AU - Bochud, Murielle

AU - Chen, Y. D.

AU - Davies, Gail

AU - Dehghan, Abbas

AU - Ding, Jingzhong

AU - Doering, Angela

AU - Durda, J. Peter

AU - Ferrucci, Luigi

AU - Franco, Oscar H.

AU - Franke, Lude

AU - Gunjaca, Grog

AU - Hofman, Albert

AU - Hsu, Fang Chi

AU - Kolcic, Ivana

AU - Kraja, Aldi

AU - Kubo, Michiaki

AU - Lackner, Karl J.

AU - Launer, Lenore

AU - Loehr, Laura R.

AU - Li, Guo

AU - Meisinger, Christa

AU - Nakamura, Yusuke

AU - Schwienbacher, Christine

AU - Starr, John M.

AU - Takahashi, Atsushi

AU - Torlak, Vesela

AU - Uitterlinden, André G.

AU - Vitart, Veronique

AU - Waldenberger, Melanie

AU - Wild, Philipp S.

AU - Kirin, Mirna

AU - Zeller, Tanja

AU - Zemunik, Tatijana

AU - Zhang, Qunyuan

AU - Ziegler, Andreas

AU - Blankenberg, Stefan

AU - Boerwinkle, Eric

AU - Borecki, Ingrid B.

AU - Campbell, Harry

AU - Deary, Ian J.

AU - Frayling, Timothy M.

AU - Gieger, Christian

AU - Harris, Tamara B.

AU - Hicks, Andrew A.

AU - Koenig, Wolfgang

AU - O'Donnell, Christopher J.

AU - Fox, Caroline S.

AU - Pramstaller, Peter P.

AU - Psaty, Bruce M.

AU - Reiner, Alex P.

AU - Rotter, Jerome I.

AU - Rudan, Igor

AU - Snieder, Harold

AU - Tanaka, Toshihiro

AU - Van Duijn, Cornelia M.

AU - Vollenweider, Peter

AU - Waeber, Gerard

AU - Wilson, James F.

AU - Witteman, Jacqueline C M

AU - Wolffenbuttel, Bruce H R

AU - Wright, Alan F.

AU - Wu, Qingyu

AU - Liu, Yongmei

AU - Jenny, Nancy S.

AU - North, Kari E.

AU - Felix, Janine F.

AU - Alizadeh, Behrooz Z.

AU - Cupples, L. Adrienne

AU - Perry, John R B

AU - Morris, Andrew P.

PY - 2012/10/5

Y1 - 2012/10/5

N2 - 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.

AB - 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.

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U2 - 10.1016/j.ajhg.2012.08.021

DO - 10.1016/j.ajhg.2012.08.021

M3 - Article

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EP - 753

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

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