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

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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; LifeLines Cohort Study.

In: AM J HUM GENET, Vol. 91, No. 4, 05.10.2012, p. 744-753.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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, 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 & LifeLines Cohort Study 2012, 'Discovery and fine mapping of serum protein loci through transethnic meta-analysis', AM J HUM GENET, vol. 91, no. 4, pp. 744-753. https://doi.org/10.1016/j.ajhg.2012.08.021

APA

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., ... LifeLines Cohort Study (2012). Discovery and fine mapping of serum protein loci through transethnic meta-analysis. AM J HUM GENET, 91(4), 744-753. https://doi.org/10.1016/j.ajhg.2012.08.021

Vancouver

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. AM J HUM GENET. 2012 Oct 5;91(4):744-753. https://doi.org/10.1016/j.ajhg.2012.08.021

Bibtex

@article{f7f766ec77964f4ea24237e9c1c39d83,
title = "Discovery and fine mapping of serum protein loci through transethnic meta-analysis",
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.",
keywords = "Adult, Aged, Alleles, Animals, Asian Continental Ancestry Group/genetics, Blood Proteins/genetics, Chromosome Mapping/methods, European Continental Ancestry Group/genetics, Female, Genetic Loci, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Humans, Linkage Disequilibrium/genetics, Male, Mice, Middle Aged, Protein Biosynthesis/genetics, Proteolysis, Ribosomes/genetics, Serum Albumin/genetics",
author = "Nora Franceschini and {van Rooij}, {Frank J A} and Prins, {Bram P} and Feitosa, {Mary F} and Mahir Karakas and Eckfeldt, {John H} and Folsom, {Aaron R} and Jeffrey Kopp and Ahmad Vaez and Andrews, {Jeanette S} and Jens Baumert and Vesna Boraska and Linda Broer and Caroline Hayward and Ngwa, {Julius S} and Yukinori Okada and Ozren Polasek and Harm-Jan Westra and Wang, {Ying A} and {Del Greco M}, Fabiola and Glazer, {Nicole L} and Karen Kapur and Kema, {Ido P} and Lopez, {Lorna M} and Arne Schillert and Smith, {Albert V} and Winkler, {Cheryl A} and Lina Zgaga and Stefania Bandinelli and Sven Bergmann and Mladen Boban and Murielle Bochud and Chen, {Y D} and Gail Davies and Abbas Dehghan and Jingzhong Ding and Angela Doering and Durda, {J Peter} and Luigi Ferrucci and Franco, {Oscar H} and Lude Franke and Grog Gunjaca and Albert Hofman and Fang-Chi Hsu and Ivana Kolcic and Aldi Kraja and Michiaki Kubo and Lackner, {Karl J} and Lenore Launer and Loehr, {Laura R} and Guo Li and Christa Meisinger and Yusuke Nakamura and Christine Schwienbacher and Starr, {John M} and Atsushi Takahashi and Vesela Torlak and Uitterlinden, {Andr{\'e} G} and Veronique Vitart and Melanie Waldenberger and Wild, {Philipp S} and Mirna Kirin and Tanja Zeller and Tatijana Zemunik and Qunyuan Zhang and Andreas Ziegler and Stefan Blankenberg and Eric Boerwinkle and Borecki, {Ingrid B} and Harry Campbell and Deary, {Ian J} and Frayling, {Timothy M} and Christian Gieger and Harris, {Tamara B} and Hicks, {Andrew A} and Wolfgang Koenig 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 Igor Rudan and Harold Snieder and Toshihiro Tanaka and {van Duijn}, {Cornelia M} and Peter Vollenweider and Gerard Waeber and Wilson, {James F} and Witteman, {Jacqueline C M} and Wolffenbuttel, {Bruce H R} and Wright, {Alan F} and Qingyu Wu and Yongmei Liu 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} and {LifeLines Cohort Study}",
note = "Copyright {\textcopyright} 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2012",
month = oct,
day = "5",
doi = "10.1016/j.ajhg.2012.08.021",
language = "English",
volume = "91",
pages = "744--753",
journal = "AM J HUM GENET",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

RIS

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

AU - LifeLines Cohort Study

N1 - Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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.

KW - Adult

KW - Aged

KW - Alleles

KW - Animals

KW - Asian Continental Ancestry Group/genetics

KW - Blood Proteins/genetics

KW - Chromosome Mapping/methods

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Linkage Disequilibrium/genetics

KW - Male

KW - Mice

KW - Middle Aged

KW - Protein Biosynthesis/genetics

KW - Proteolysis

KW - Ribosomes/genetics

KW - Serum Albumin/genetics

U2 - 10.1016/j.ajhg.2012.08.021

DO - 10.1016/j.ajhg.2012.08.021

M3 - SCORING: Journal article

C2 - 23022100

VL - 91

SP - 744

EP - 753

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 4

ER -