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

被引：55

作者：

Franceschini, Nora ^{[1
]}

van Rooij, Frank J. A. ^{[2
,3
,4
]}

Prins, Bram P. ^{[5
]}

Feitosa, Mary F. ^{[6
]}

Karakas, Mahir ^{[7
]}

Eckfeldt, John H. ^{[8
]}

Folsom, Aaron R. ^{[9
]}

Kopp, Jeffrey ^{[10
]}

Vaez, Ahmad ^{[5
]}

Andrews, Jeanette S. ^{[11
]}

Baumert, Jens ^{[12
]}

Boraska, Vesna ^{[13
]}

Broer, Linda ^{[2
,3
,4
]}

Hayward, Caroline ^{[14
]}

Ngwa, Julius S. ^{[15
]}

Okada, Yukinori ^{[16
,17
]}

Polasek, Ozren ^{[18
]}

Westra, Harm-Jan ^{[19
]}

Wang, Ying A. ^{[15
,20
]}

Del Greco M, Fabiola ^{[21
]}

Glazer, Nicole L. ^{[22
]}

Kapur, Karen ^{[23
,35
]}

Kema, Id P. ^{[24
]}

Lopez, Lorna M. ^{[25
,26
]}

Schillert, Arne ^{[27
]}

Smith, Albert V. ^{[28
,29
]}

Winkler, Cheryl A. ^{[30
]}

Zgaga, Lina ^{[31
,32
,33
]}

Bandinelli, Stefania ^{[34
]}

Bergmann, Sven ^{[23
,35
]}

Boban, Mladen ^{[36
]}

Bochud, Murielle ^{[37
]}

Chen, Y. D. ^{[38
,39
]}

Davies, Gail ^{[26
]}

Dehghan, Abbas ^{[2
,3
,4
]}

Ding, Jingzhong ^{[40
]}

Doering, Angela ^{[12
]}

Durda, J. Peter ^{[41
]}

Ferrucci, Luigi ^{[42
]}

Franco, Oscar H. ^{[2
,3
,4
]}

Franke, Lude ^{[19
]}

Gunjaca, Grog ^{[34
]}

Hofman, Albert ^{[2
,3
,4
]}

Hsu, Fang-Chi ^{[11
]}

Kolcic, Ivana ^{[18
]}

Kraja, Aldi ^{[6
]}

Kubo, Michiaki ^{[43
]}

Lackner, Karl J. ^{[44
]}

Launer, Lenore ^{[45
]}

Loehr, Laura R. ^{[1
]}

机构：

[1] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA

[2] Erasmus Univ, Med Ctr, ErasmusAGE, NL-3000 CA Rotterdam, Netherlands

[3] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands

[4] Netherlands Genom Initiat, Netherlands Consortium Hlth Aging, NL-2300 RC Leiden, Netherlands

[5] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands

[6] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA

[7] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89081 Ulm, Germany

[8] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[9] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA

[10] NIDDK, NIH, Bethesda, MD 20892 USA

[11] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA

[12] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany

[13] Univ Split, Sch Med, Dept Med Biol, Split 21000, Croatia

[14] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC,Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[15] Harvard Univ, Sch Publ Hlth, Boston Univ, Sch Publ Hlth,Dept Biostat, Boston, MA 02115 USA

[16] RIKEN, CGM, Lab Stat Anal, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan

[17] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Bunkyo Ku, Tokyo 1130033, Japan

[18] Univ Split, Sch Med, Dept Publ Hlth, Split 21000, Croatia

[19] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands

[20] Novartis Inst BioMed Res, Cambridge, MA 02139 USA

[21] Med Univ Lubeck, Affiliated Inst, Ctr Biomed, European Acad Bozen Bolzano EURAC, D-23562 Lubeck, Germany

[22] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA

[23] Univ Lausanne, Univ Hosp Ctr, Dept Med Genet, CH-1005 Lausanne, Switzerland

[24] Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, NL-9700 RB Groningen, Netherlands

[25] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland

[26] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9AD, Midlothian, Scotland

[27] Univ Hosp Schleswig Holstein, Inst Med Biometry & Stat, D-23538 Lubeck, Germany

[28] Iceland Heart Assoc, IS-201 Kopavogur, Iceland

[29] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

[30] NCI, Mol Genet Epidemiol Sect, NIH, Frederick Natl Lab, Ft Detrick, MD 21702 USA

[31] Univ Edinburgh, Queens Med Res Inst, Coll Med & Vet Med, Ctr Populat Hlth Sci, Edinburgh EH16 4TJ, Midlothian, Scotland

[32] Univ Edinburgh, Queens Med Res Inst, Coll Med & Vet Med, Inst Genet & Mol Med, Edinburgh EH16 4TJ, Midlothian, Scotland

[33] Univ Zagreb, Sch Med, Dept Med Stat Epidemiol & Med Informat, Zagreb 10000, Croatia

[34] Azienda Sanit Firenze, Geriatr Unit, I-50125 Florence, Italy

[35] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[36] Univ Split, Sch Med, Dept Pharmacol, Split 21000, Croatia

[37] Univ Inst Social & Prevent Med, Community Prevent Unit, CH-1005 Lausanne, Switzerland

[38] Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Los Angeles, CA 90048 USA

[39] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[40] Wake Forest Sch Med, Dept Internal Med, Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA

[41] Univ Vermont, Coll Med, Dept Pathol, Lab Clin Biochem Res, Burlington, VT 05405 USA

[42] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21225 USA

[43] RIKEN, CGM, Lab Genotyping Dev, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan

[44] Univ Med Ctr Mainz, Inst Clin Chem & Lab Med, D-55131 Mainz, Germany

[45] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA

[46] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA

[47] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Mol Med,Minato Ku, Tokyo 1088639, Japan

[48] Univ Ferrara, Dept Expt & Diagnost Med, I-44121 Ferrara, Italy

[49] Univ Edinburgh, Dept Psychol, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland

[50] Univ Hosp Split, Split 21000, Croatia

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2012年 / 91卷 / 04期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; BIOCHEMICAL TRAITS; SMOKING-BEHAVIOR; FC-RECEPTOR; ALBUMIN; DETERMINANTS; POPULATION; IDENTIFY; RISK; SNPS;

D O I：

10.1016/j.ajhg.2012.08.021

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：744 / 753

页数：10

共 25 条

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