Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis

N Franceschini; FJA van Rooij; BP Prins; MF Feitosa; M Karakas; JH Eckfeldt; AR Folsom; J Kopp; A Vaez; JS Andrews; J Baumert; V Boraska; Linda Broer; C Hayward; JS Ngwa; Y Okada; O Polasek; HJ Westra; YA Wang; F Del Greco; NL Glazer; K Kapur; P Id; LM Lopez; A Schillert; AV Smith; CA Winkler; L Zgaga; S Bandinelli; S Bergmann; M Boban; M Bochud; YD Chen; G Davies; Abbas Dehghan; JZ (Jing Zhong) Ding; A Doering; JP Durda; L Ferrucci; OH Franco Duran; L Franke; G Gunjaca; Bert Hofman; FC Hsu; I Kolcic; A Kraja; M Kubo; KJ Lackner; L Launer; LR Loehr; G (Guo) Li; C Meisinger; Y Nakamura; C Schwienbacher; JM Starr; A Takahashi; V Torlak; André Uitterlinden; V Vitart; M Waldenberger; PS Wild; M Kirin; T Zeller; T Zemunik; QY Zhang; A Ziegler; S Blankenberg; E Boerwinkle; IB Borecki; H Campbell; IJ Deary; TM Frayling; C Gieger; TB Harris; AA Hicks; W Koenig; CJ O'Donnell; CS Fox; PP Pramstaller; BM Psaty; AP Reiner; JI Rotter; I Rudan; H Snieder; T Tanaka; Cornelia Duijn; P Vollenweider; G Waeber; JF Wilson; JCM Witteman; BHR Wolffenbuttel; AF Wright; QY Wu; YM Liu; NS Jenny; KE North; Janine Felix; BZ Alizadeh; LA Cupples; JRB Perry; AP Morris

doi:10.1016/j.ajhg.2012.08.021

Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis

N Franceschini, FJA van Rooij, BP Prins, MF Feitosa, M Karakas, JH Eckfeldt, AR Folsom, J Kopp, A Vaez, JS Andrews, J Baumert, V Boraska, Linda Broer, C Hayward, JS Ngwa, Y Okada, O Polasek, HJ Westra, YA Wang, F Del GrecoNL Glazer, K Kapur, P Id, LM Lopez, A Schillert, AV Smith, CA Winkler, L Zgaga, S Bandinelli, S Bergmann, M Boban, M Bochud, YD Chen, G Davies, Abbas Dehghan, JZ (Jing Zhong) Ding, A Doering, JP Durda, L Ferrucci, OH Franco Duran, L Franke, G Gunjaca, Bert Hofman, FC Hsu, I Kolcic, A Kraja, M Kubo, KJ Lackner, L Launer, LR Loehr, G (Guo) Li, C Meisinger, Y Nakamura, C Schwienbacher, JM Starr, A Takahashi, V Torlak, André Uitterlinden, V Vitart, M Waldenberger, PS Wild, M Kirin, T Zeller, T Zemunik, QY Zhang, A Ziegler, S Blankenberg, E Boerwinkle, IB Borecki, H Campbell, IJ Deary, TM Frayling, C Gieger, TB Harris, AA Hicks, W Koenig, CJ O'Donnell, CS Fox, PP Pramstaller, BM Psaty, AP Reiner, JI Rotter, I Rudan, H Snieder, T Tanaka, Cornelia Duijn, P Vollenweider, G Waeber, JF Wilson, JCM Witteman, BHR Wolffenbuttel, AF Wright, QY Wu, YM Liu, NS Jenny, KE North, Janine Felix, BZ Alizadeh, LA Cupples, JRB Perry, AP Morris

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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 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.

Original language	Undefined/Unknown
Pages (from-to)	744-753
Number of pages	10
Journal	American Journal of Human Genetics
Volume	91
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2012.08.021
Publication status	Published - 2012

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EMC NIHES-01-64-01
EMC NIHES-01-64-02

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Cite this

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., ... Morris, AP. (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

@article{6930a0d8c86f4dfeaa8d3f17f4af5851,

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 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.",

author = "N Franceschini and {van Rooij}, FJA and BP Prins and MF Feitosa and M Karakas and JH Eckfeldt and AR Folsom and J Kopp and A Vaez and JS Andrews and J Baumert and V Boraska and Linda Broer and C Hayward and JS Ngwa and Y Okada and O Polasek and HJ Westra and YA Wang and {Del Greco}, F and NL Glazer and K Kapur and P Id and LM Lopez and A Schillert and AV Smith and CA Winkler and L Zgaga and S Bandinelli and S Bergmann and M Boban and M Bochud and YD Chen and G Davies and Abbas Dehghan and Ding, {JZ (Jing Zhong)} and A Doering and JP Durda and L Ferrucci and {Franco Duran}, OH and L Franke and G Gunjaca and Bert Hofman and FC Hsu and I Kolcic and A Kraja and M Kubo and KJ Lackner and L Launer and LR Loehr and Li, {G (Guo)} and C Meisinger and Y Nakamura and C Schwienbacher and JM Starr and A Takahashi and V Torlak and Andr{\'e} Uitterlinden and V Vitart and M Waldenberger and PS Wild and M Kirin and T Zeller and T Zemunik and QY Zhang and A Ziegler and S Blankenberg and E Boerwinkle and IB Borecki and H Campbell and IJ Deary and TM Frayling and C Gieger and TB Harris and AA Hicks and W Koenig and CJ O'Donnell and CS Fox and PP Pramstaller and BM Psaty and AP Reiner and JI Rotter and I Rudan and H Snieder and T Tanaka and Cornelia Duijn and P Vollenweider and G Waeber and JF Wilson and JCM Witteman and BHR Wolffenbuttel and AF Wright and QY Wu and YM Liu and NS Jenny and KE North and Janine Felix and BZ Alizadeh and LA Cupples and JRB Perry and AP Morris",

year = "2012",

doi = "10.1016/j.ajhg.2012.08.021",

language = "Undefined/Unknown",

volume = "91",

pages = "744--753",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

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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, F, Glazer, NL, Kapur, K, Id, P, 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, JZ, Doering, A, Durda, JP, Ferrucci, L, Franco Duran, OH, Franke, L, Gunjaca, G, Hofman, B, 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, A, Vitart, V, Waldenberger, M, Wild, PS, Kirin, M, Zeller, T, Zemunik, T, Zhang, QY, 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, Duijn, C, Vollenweider, P, Waeber, G, Wilson, JF, Witteman, JCM, Wolffenbuttel, BHR, Wright, AF, Wu, QY, Liu, YM, Jenny, NS, North, KE, Felix, J, 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

TY - JOUR

T1 - Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis

AU - Franceschini, N

AU - van Rooij, FJA

AU - Prins, BP

AU - Feitosa, MF

AU - Karakas, M

AU - Eckfeldt, JH

AU - Folsom, AR

AU - Kopp, J

AU - Vaez, A

AU - Andrews, JS

AU - Baumert, J

AU - Boraska, V

AU - Broer, Linda

AU - Hayward, C

AU - Ngwa, JS

AU - Okada, Y

AU - Polasek, O

AU - Westra, HJ

AU - Wang, YA

AU - Del Greco, F

AU - Glazer, NL

AU - Kapur, K

AU - Id, P

AU - Lopez, LM

AU - Schillert, A

AU - Smith, AV

AU - Winkler, CA

AU - Zgaga, L

AU - Bandinelli, S

AU - Bergmann, S

AU - Boban, M

AU - Bochud, M

AU - Chen, YD

AU - Davies, G

AU - Dehghan, Abbas

AU - Ding, JZ (Jing Zhong)

AU - Doering, A

AU - Durda, JP

AU - Ferrucci, L

AU - Franco Duran, OH

AU - Franke, L

AU - Gunjaca, G

AU - Hofman, Bert

AU - Hsu, FC

AU - Kolcic, I

AU - Kraja, A

AU - Kubo, M

AU - Lackner, KJ

AU - Launer, L

AU - Loehr, LR

AU - Li, G (Guo)

AU - Meisinger, C

AU - Nakamura, Y

AU - Schwienbacher, C

AU - Starr, JM

AU - Takahashi, A

AU - Torlak, V

AU - Uitterlinden, André

AU - Vitart, V

AU - Waldenberger, M

AU - Wild, PS

AU - Kirin, M

AU - Zeller, T

AU - Zemunik, T

AU - Zhang, QY

AU - Ziegler, A

AU - Blankenberg, S

AU - Boerwinkle, E

AU - Borecki, IB

AU - Campbell, H

AU - Deary, IJ

AU - Frayling, TM

AU - Gieger, C

AU - Harris, TB

AU - Hicks, AA

AU - Koenig, W

AU - O'Donnell, CJ

AU - Fox, CS

AU - Pramstaller, PP

AU - Psaty, BM

AU - Reiner, AP

AU - Rotter, JI

AU - Rudan, I

AU - Snieder, H

AU - Tanaka, T

AU - Duijn, Cornelia

AU - Vollenweider, P

AU - Waeber, G

AU - Wilson, JF

AU - Witteman, JCM

AU - Wolffenbuttel, BHR

AU - Wright, AF

AU - Wu, QY

AU - Liu, YM

AU - Jenny, NS

AU - North, KE

AU - Felix, Janine

AU - Alizadeh, BZ

AU - Cupples, LA

AU - Perry, JRB

AU - Morris, AP

PY - 2012

Y1 - 2012

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 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.

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 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.

U2 - 10.1016/j.ajhg.2012.08.021

DO - 10.1016/j.ajhg.2012.08.021

M3 - Article

C2 - 23022100

SN - 0002-9297

VL - 91

SP - 744

EP - 753

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -