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, Jahrgang 91, Nr. 4, 05.10.2012, S. 744-753.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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
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 -