Genome-Wide Association Analyses Identify SPOCK as a Key Novel Gene Underlying Age at Menarche 英文参考文献.docVIP

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Genome-Wide Association Analyses Identify SPOCK as a Key Novel Gene Underlying Age at Menarche 英文参考文献.doc

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Genome-Wide Association Analyses Identify SPOCK as a Key Novel Gene Underlying Age at Menarche 英文参考文献

Genome-WideAssociationAnalysesIdentifySPOCKasa KeyNovelGeneUnderlyingAgeatMenarche Yao-ZhongLiu1,Yan-FangGuo1,2,LiangWang1,2,Li-JunTan3,Xiao-GangLiu1,2,Yu-FangPei1 ,Han Yan1,2,Dong-HaiXiong4,Fei-YanDeng1,NaYu1,Yin-PingZhang1,2,LeiZhang1,2,Shu-FengLei1 ,Xiang- DingChen3,Hong-BinLiu1,Xue-ZhenZhu2,ShawnLevy5,ChristopherJ.Papasian1,BettyM.Drees1, JamesJ.Hamilton1,RobertR.Recker4,Hong-WenDeng1,2,3* 1School of Medicine, University ofMissouri Kansas City, Kansas City, Missouri, United States ofAmerica, 2Institute of Molecular Genetics, School ofLife Science and Technology, Xi’an Jiaotong University, Xi’an, People’s Republic of China, 3Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University,Changsha,Hunan,People’sRepublicofChina,4OsteoporosisResearchCenter,CreightonUniversity,Omaha,Nebraska,UnitedStatesofAmerica,5Vanderbilt MicroarraySharedResource,VanderbiltUniversity,Nashville,Tennessee,UnitedStatesofAmerica Abstract For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largelyunknown.ToidentifygeneticfactorsunderlyingAAMvariation,agenome-wideassociationstudy(GWAS)examining about380,000SNPswasconductedin477Caucasianwomen.Afollow-upreplicationstudywasperformedtovalidateour majorGWASfindingsusingtwoindependentCaucasiancohortswith854siblingsand762unrelatedsubjects,respectively, and one Chinese cohort of 1,387 unrelated subjects—all females. Our GWAS identified a novel gene, SPOCK (Sparc/ Osteonectin,CWCV,andKazal-likedomainsproteoglycan),whichhadsevenSNPsassociatedwithAAMwithgenome-wide falsediscoveryrate(FDR)q,0.05.SixmostsignificantSNPsofthegenewereselectedforvalidationinthreeindependent replicationcohorts.AllofthesixSNPswerereplicatedinatleastonecohort.Inparticular,SNPsrndrs1859345 were replicated both within and across different ethnic grou