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dc.contributor.authorHsu, Yi-Hsiangen_US
dc.contributor.authorZillikens, M. Carolaen_US
dc.contributor.authorWilson, Scott G.en_US
dc.contributor.authorFarber, Charles R.en_US
dc.contributor.authorDemissie, Serkalemen_US
dc.contributor.authorSoranzo, Nicoleen_US
dc.contributor.authorBianchi, Estelle N.en_US
dc.contributor.authorGrundberg, Elinen_US
dc.contributor.authorLiang, Limingen_US
dc.contributor.authorRichards, J. Brenten_US
dc.contributor.authorEstrada, Karolen_US
dc.contributor.authorZhou, Yanhuaen_US
dc.contributor.authorvan Nas, Atilaen_US
dc.contributor.authorMoffatt, Miriam F.en_US
dc.contributor.authorZhai, Guangjuen_US
dc.contributor.authorHofman, Alberten_US
dc.contributor.authorvan Meurs, Joyce B.en_US
dc.contributor.authorPols, Huibert A. P.en_US
dc.contributor.authorPrice, Roger I.en_US
dc.contributor.authorNilsson, Olleen_US
dc.contributor.authorPastinen, Tomien_US
dc.contributor.authorCupples, L. Adrienneen_US
dc.contributor.authorLusis, Aldons J.en_US
dc.contributor.authorSchadt, Eric E.en_US
dc.contributor.authorFerrari, Sergeen_US
dc.contributor.authorUitterlinden, André G.en_US
dc.contributor.authorRivadeneira, Fernandoen_US
dc.contributor.authorSpector, Timothy D.en_US
dc.contributor.authorKarasik, Daviden_US
dc.contributor.authorKiel, Douglas P.en_US
dc.date.accessioned2012-01-11T16:09:04Z
dc.date.available2012-01-11T16:09:04Z
dc.date.issued2010-6-10en_US
dc.identifier.citationHsu, Yi-Hsiang, M. Carola Zillikens, Scott G. Wilson, Charles R. Farber, Serkalem Demissie, Nicole Soranzo, Estelle N. Bianchi, Elin Grundberg, Liming Liang, J. Brent Richards, Karol Estrada, Yanhua Zhou, Atila van Nas, Miriam F. Moffatt, Guangju Zhai, Albert Hofman, Joyce B. van Meurs, Huibert A. P. Pols, Roger I. Price, Olle Nilsson, Tomi Pastinen, L. Adrienne Cupples, Aldons J. Lusis, Eric E. Schadt, Serge Ferrari, André G. Uitterlinden, Fernando Rivadeneira, Timothy D. Spector, David Karasik, Douglas P. Kiel. "An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits" PLoS Genetics 6(6):e1000977. (2010)en_US
dc.identifier.issn1553-7404en_US
dc.identifier.urihttp://hdl.handle.net/2144/3100
dc.description.abstractOsteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6×10−8), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6×10−13; SOX6, p = 6.4×10−10) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation. Author Summary BMD and hip geometry are two major predictors of osteoporotic fractures, the most severe consequence of osteoporosis in elderly persons. We performed sex-specific genome-wide association studies (GWAS) for BMD at the lumbar spine and femor neck skeletal sites as well as hip geometric indices (NSA, NL, and NW) in the Framingham Osteoporosis Study and then replicated the top findings in two independent studies. Three novel loci were significant: in women, including chromosome 1p13.2 (RAP1A) for NW; in men, 2q11.2 (TBC1D8) for NSA and 18q11.2 (OSBPL1A) for NW. We confirmed a previously reported region on 8q24.12 (TNFRSF11B/OPG) for lumbar spine BMD in women. In addition, we integrated GWAS signals with eQTL in several tissues and publicly available expression signature profiling in cellular and whole-animal models, and prioritized 16 candidate genes/loci based on their potential involvement in skeletal metabolism. Among three prioritized loci (GPR177, SOX6, and CASR genes) associated with BMD in women, GPR177 and SOX6 have been successfully replicated later in a large-scale meta-analysis, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of using expression profiling to support the candidacy of suggestive GWAS signals that may contain important genes of interest.en_US
dc.description.sponsorshipUS National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR/AG 41398, R01 AR 050066, R01 AR 057118); National Heart, Lung, and Blood Institute (N01-HC-25195); Affymetrix (N02-HL-6-4278); Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03-012); Research Institute for Diseases in the Elderly (014-93-015; RIDE2) and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research project (050-060-810); Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education; Culture and Science; Ministry for Health; Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; National Institute of Aging and National Eye Institute; Genome Quebec; Genome Canada; Canada Institues of Health Research; National Osteoporosis Foundation; Osteoporosis Canada; Swedish Research Council; European Commission (HEALTH-F2-2008-201865-GEFOS)en_US
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsHsu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.titleAn Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traitsen_US
dc.typearticleen_US
dc.identifier.doi10.1371/journal.pgen.1000977en_US
dc.identifier.pubmedid20548944en_US
dc.identifier.pmcid2883588en_US


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