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RESEARCH PRODUCT
Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis
Bruce M. PsatyBruce M. PsatyChristine SchwienbacherChristine SchwienbacherJens BaumertPhilipp S. WildJeanette S. AndrewsM. Fabiola Del GrecoAtsushi TakahashiEric BoerwinkleVeronique VitartGuo LiChrista MeisingerPeter VollenweiderLaura R. LoehrLinda BroerJames F. WilsonIngrid B. BoreckiMahir KarakasAldi T. KrajaCaroline S. FoxOscar H. FrancoYongmei LiuIgor RudanL. Adrienne CupplesL. Adrienne CupplesJohn H. EckfeldtAndreas ZieglerNora FranceschiniVesela TorlakAlan F. WrightYusuke NakamuraChristopher J. O'donnellChristopher J. O'donnellKari E. NorthJulius S. NgwaMary F. FeitosaAhmad VaezQingyu WuAlbert HofmanPeter P. PramstallerOzren PolasekAlexander P. ReinerJeffrey B. KoppIdo P. KemaArne SchillertJerome I. RotterMurielle BochudAndrew A. HicksYukinori OkadaJohn R. B. PerryTamara B. HarrisQunyuan ZhangYing A. WangYing A. WangJingzhong DingNancy S. JennyTimothy M. FraylingHarold SniederGérard WaeberMladen BobanJohn M. StarrBehrooz Z. AlizadehLina ZgagaLina ZgagaLina ZgagaMichiaki KuboStefania BandinelliAaron R. FolsomHarm-jan WestraMirna KirinAbbas DehghanMelanie WaldenbergerWolfgang KoenigKarl J. LacknerAngela DoeringLorna M. LopezCornelia M. Van DuijnBram PrinsTatijana ZemunikCaroline HaywardJacqueline C.m. WittemanGrog GunjacaKaren KapurKaren KapurHarry CampbellIan J. DearySven BergmannSven BergmannFrank J. A. Van RooijCheryl A. WinklerLude FrankeStefan BlankenbergIvana KolcicLenore J. LaunerTanja ZellerLuigi FerrucciY. D. ChenChristian GiegerVesna BoraskaJanine F. FelixJ. Peter DurdaGail DaviesBruce H. R. WolffenbuttelFang-chi HsuAlbert V. SmithToshihiro TanakaNicole L. GlazerAndré G. UitterlindenAndrew P. Morrissubject
MaleLinkage disequilibriumGenome-wide association studyDETERMINANTSLinkage DisequilibriumMiceGenetics(clinical)POPULATIONGenetics (clinical)SNPSRISKGeneticseducation.field_of_studybiologyChromosome MappingBlood ProteinsIDENTIFYMiddle AgedFemaleAdultPopulationSerum albuminserum protein; albumin; GWASSingle-nucleotide polymorphismLocus (genetics)ALBUMINWhite PeopleAsian PeopleGene mappingSDG 3 - Good Health and Well-beingReportBIOCHEMICAL TRAITSFC-RECEPTORGeneticsAnimalsHumansGenetic Predisposition to DiseaseSMOKING-BEHAVIORddc:610GENOME-WIDE ASSOCIATIONeducationAllelesSerum AlbuminAgedGenetic associationGenetic LociProtein BiosynthesisProteolysisbiology.proteinRibosomesGenome-Wide Association Studydescription
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 −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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-10-01 | The American Journal of Human Genetics |