An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits

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dc.contributor.author Hsu, Yi-Hsiang en_US
dc.contributor.author Zillikens, M. Carola en_US
dc.contributor.author Wilson, Scott G. en_US
dc.contributor.author Farber, Charles R. en_US
dc.contributor.author Demissie, Serkalem en_US
dc.contributor.author Soranzo, Nicole en_US
dc.contributor.author Bianchi, Estelle N. en_US
dc.contributor.author Grundberg, Elin en_US
dc.contributor.author Liang, Liming en_US
dc.contributor.author Richards, J. Brent en_US
dc.contributor.author Estrada, Karol en_US
dc.contributor.author Zhou, Yanhua en_US
dc.contributor.author van Nas, Atila en_US
dc.contributor.author Moffatt, Miriam F. en_US
dc.contributor.author Zhai, Guangju en_US
dc.contributor.author Hofman, Albert en_US
dc.contributor.author van Meurs, Joyce B. en_US
dc.contributor.author Pols, Huibert A. P. en_US
dc.contributor.author Price, Roger I. en_US
dc.contributor.author Nilsson, Olle en_US
dc.contributor.author Pastinen, Tomi en_US
dc.contributor.author Cupples, L. Adrienne en_US
dc.contributor.author Lusis, Aldons J. en_US
dc.contributor.author Schadt, Eric E. en_US
dc.contributor.author Ferrari, Serge en_US
dc.contributor.author Uitterlinden, André G. en_US
dc.contributor.author Rivadeneira, Fernando en_US
dc.contributor.author Spector, Timothy D. en_US
dc.contributor.author Karasik, David en_US
dc.contributor.author Kiel, Douglas P. en_US
dc.date.accessioned 2012-01-11T16:09:04Z
dc.date.available 2012-01-11T16:09:04Z
dc.date.issued 2010-6-10 en_US
dc.identifier.citation Hsu, 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.issn 1553-7404 en_US
dc.identifier.uri http://hdl.handle.net/2144/3100
dc.description.abstract Osteoporosis 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.sponsorship US 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.iso en en_US
dc.publisher Public Library of Science en_US
dc.rights Hsu 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.title An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits en_US
dc.type article en_US
dc.identifier.doi 10.1371/journal.pgen.1000977 en_US
dc.identifier.pubmedid 20548944 en_US
dc.identifier.pmcid 2883588 en_US

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