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Osteoporosis: HELP
Articles by Frances M. K. Williams
Based on 8 articles published since 2008
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Between 2008 and 2019, F. M. Williams wrote the following 8 articles about Osteoporosis.
 
+ Citations + Abstracts
1 Article Association of interleukin-6 gene polymorphisms with hand osteoarthritis and hand osteoporosis. 2014

Blumenfeld, Orit / Williams, Frances M K / Valdes, Ana / Hart, Deborah J / Malkin, Ida / Spector, Timothy D / Livshits, Gregory. ·Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Twin Research and Genetic Epidemiology, King's College London St Thomas' Hospital Campus, London, UK. · Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Twin Research and Genetic Epidemiology, King's College London St Thomas' Hospital Campus, London, UK. Electronic address: gregl@post.tau.ac.il. ·Cytokine · Pubmed #25022967.

ABSTRACT: OBJECTIVE: Several genes, including IL-6 encoding pro-inflammatory cytokines, are involved in development of osteoarthritis and osteoporosis. The association of radiographic hand osteoarthritis (RHOA) and osteoporosis related phenotypes (RHOP) with polymorphisms in IL-6 has been reported inconsistently. The aim of this study was to examine the association, between RHOA and RHOP and IL-6 polymorphisms in two independent samples. METHODS: Two samples: UK females, including 1440 individuals assessed for RHOA and 3470 assessed for RHOP; Chuvash pedigree including 1499 females and males were assessed for RHOP and RHOA. SNPs were genotyped in the IL-6 genomic region, and used in association analysis with RHOA and RHOP phenotypes. RESULTS: RHOP phenotypes showed similar heritability estimates in both samples, ranging from 34.5 ± 5.5% to 61.0 ± 2.4%. RHOA in Chuvash had substantially lower heritability estimates compared to twins (e.g. OSP scores: 11.8 ± 2.3% vs. 39.2 ± 4.1%) with much higher prevalence and considerably stronger correlation with age (r = 0.811 vs. r = 0.505). RHOA in Chuvash sample may be traumatic in nature, caused by heavy and prolonged manual work related to their private farming. There were a number of statistically significant association results with both types of phenotypes. The most consistent result was obtained for JSN in both samples with SNP from the same haploblock. Their combined probability of no association was only p = 0.000003. Additionally, there were SNPs common for both RHOA and RHOP. CONCLUSIONS: We have shown polymorphisms in IL_6 are significantly associated with RHOA and hand RHOP in two samples having different ethnicity and lifestyle. Age × environment × genes interaction appears as an important factor of RHOA manifestation and progression.

2 Article Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment. 2014

Kemp, John P / Medina-Gomez, Carolina / Estrada, Karol / St Pourcain, Beate / Heppe, Denise H M / Warrington, Nicole M / Oei, Ling / Ring, Susan M / Kruithof, Claudia J / Timpson, Nicholas J / Wolber, Lisa E / Reppe, Sjur / Gautvik, Kaare / Grundberg, Elin / Ge, Bing / van der Eerden, Bram / van de Peppel, Jeroen / Hibbs, Matthew A / Ackert-Bicknell, Cheryl L / Choi, Kwangbom / Koller, Daniel L / Econs, Michael J / Williams, Frances M K / Foroud, Tatiana / Zillikens, M Carola / Ohlsson, Claes / Hofman, Albert / Uitterlinden, André G / Davey Smith, George / Jaddoe, Vincent W V / Tobias, Jonathan H / Rivadeneira, Fernando / Evans, David M. ·MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands. · Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America. · MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; School of Oral and Dental Sciences, University of Bristol, Bristol, United Kingdom; School of Experimental Psychology, University of Bristol, Bristol, United Kingdom. · The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Paediatrics, Erasmus University Medical Center, Rotterdam, The Netherlands. · University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands. · MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom. · The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom. · Department of Medical Biochemistry, Oslo University Hospital, Ullevaal, Oslo, Norway. · Department of Medical Biochemistry, Oslo University Hospital, Ullevaal, Oslo, Norway; Department of Medical Biochemistry, Oslo Deacon Hospital, Oslo, Norway. · Department of Human Genetics, McGill University, Montréal, Canada; McGill University and Genome Québec Innovation Centre, Montréal, Canada. · McGill University and Genome Québec Innovation Centre, Montréal, Canada. · Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Computer Science, Trinity University, San Antonio, Texas, United States of America; The Jackson Laboratory, Bar Harbor, Maine, United States of America. · The Jackson Laboratory, Bar Harbor, Maine, United States of America. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America. · Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands. · Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands. · School of Clinical Sciences, University of Bristol, Bristol, United Kingdom. ·PLoS Genet · Pubmed #24945404.

ABSTRACT: Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼ 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ∼ 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

3 Article Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. 2014

Moayyeri, Alireza / Hsu, Yi-Hsiang / Karasik, David / Estrada, Karol / Xiao, Su-Mei / Nielson, Carrie / Srikanth, Priya / Giroux, Sylvie / Wilson, Scott G / Zheng, Hou-Feng / Smith, Albert V / Pye, Stephen R / Leo, Paul J / Teumer, Alexander / Hwang, Joo-Yeon / Ohlsson, Claes / McGuigan, Fiona / Minster, Ryan L / Hayward, Caroline / Olmos, José M / Lyytikäinen, Leo-Pekka / Lewis, Joshua R / Swart, Karin M A / Masi, Laura / Oldmeadow, Chris / Holliday, Elizabeth G / Cheng, Sulin / van Schoor, Natasja M / Harvey, Nicholas C / Kruk, Marcin / del Greco M, Fabiola / Igl, Wilmar / Trummer, Olivia / Grigoriou, Efi / Luben, Robert / Liu, Ching-Ti / Zhou, Yanhua / Oei, Ling / Medina-Gomez, Carolina / Zmuda, Joseph / Tranah, Greg / Brown, Suzanne J / Williams, Frances M / Soranzo, Nicole / Jakobsdottir, Johanna / Siggeirsdottir, Kristin / Holliday, Kate L / Hannemann, Anke / Go, Min Jin / Garcia, Melissa / Polasek, Ozren / Laaksonen, Marika / Zhu, Kun / Enneman, Anke W / McEvoy, Mark / Peel, Roseanne / Sham, Pak Chung / Jaworski, Maciej / Johansson, Åsa / Hicks, Andrew A / Pludowski, Pawel / Scott, Rodney / Dhonukshe-Rutten, Rosalie A M / van der Velde, Nathalie / Kähönen, Mika / Viikari, Jorma S / Sievänen, Harri / Raitakari, Olli T / González-Macías, Jesús / Hernández, Jose L / Mellström, Dan / Ljunggren, Osten / Cho, Yoon Shin / Völker, Uwe / Nauck, Matthias / Homuth, Georg / Völzke, Henry / Haring, Robin / Brown, Matthew A / McCloskey, Eugene / Nicholson, Geoffrey C / Eastell, Richard / Eisman, John A / Jones, Graeme / Reid, Ian R / Dennison, Elaine M / Wark, John / Boonen, Steven / Vanderschueren, Dirk / Wu, Frederick C W / Aspelund, Thor / Richards, J Brent / Bauer, Doug / Hofman, Albert / Khaw, Kay-Tee / Dedoussis, George / Obermayer-Pietsch, Barbara / Gyllensten, Ulf / Pramstaller, Peter P / Lorenc, Roman S / Cooper, Cyrus / Kung, Annie Wai Chee / Lips, Paul / Alen, Markku / Attia, John / Brandi, Maria Luisa / de Groot, Lisette C P G M / Lehtimäki, Terho / Riancho, José A / Campbell, Harry / Liu, Yongmei / Harris, Tamara B / Akesson, Kristina / Karlsson, Magnus / Lee, Jong-Young / Wallaschofski, Henri / Duncan, Emma L / O'Neill, Terence W / Gudnason, Vilmundur / Spector, Timothy D / Rousseau, François / Orwoll, Eric / Cummings, Steven R / Wareham, Nick J / Rivadeneira, Fernando / Uitterlinden, Andre G / Prince, Richard L / Kiel, Douglas P / Reeve, Jonathan / Kaptoge, Stephen K. ·Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ·Hum Mol Genet · Pubmed #24430505.

ABSTRACT: Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

4 Article Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. 2012

Estrada, Karol / Styrkarsdottir, Unnur / Evangelou, Evangelos / Hsu, Yi-Hsiang / Duncan, Emma L / Ntzani, Evangelia E / Oei, Ling / Albagha, Omar M E / Amin, Najaf / Kemp, John P / Koller, Daniel L / Li, Guo / Liu, Ching-Ti / Minster, Ryan L / Moayyeri, Alireza / Vandenput, Liesbeth / Willner, Dana / Xiao, Su-Mei / Yerges-Armstrong, Laura M / Zheng, Hou-Feng / Alonso, Nerea / Eriksson, Joel / Kammerer, Candace M / Kaptoge, Stephen K / Leo, Paul J / Thorleifsson, Gudmar / Wilson, Scott G / Wilson, James F / Aalto, Ville / Alen, Markku / Aragaki, Aaron K / Aspelund, Thor / Center, Jacqueline R / Dailiana, Zoe / Duggan, David J / Garcia, Melissa / Garcia-Giralt, Natàlia / Giroux, Sylvie / Hallmans, Göran / Hocking, Lynne J / Husted, Lise Bjerre / Jameson, Karen A / Khusainova, Rita / Kim, Ghi Su / Kooperberg, Charles / Koromila, Theodora / Kruk, Marcin / Laaksonen, Marika / Lacroix, Andrea Z / Lee, Seung Hun / Leung, Ping C / Lewis, Joshua R / Masi, Laura / Mencej-Bedrac, Simona / Nguyen, Tuan V / Nogues, Xavier / Patel, Millan S / Prezelj, Janez / Rose, Lynda M / Scollen, Serena / Siggeirsdottir, Kristin / Smith, Albert V / Svensson, Olle / Trompet, Stella / Trummer, Olivia / van Schoor, Natasja M / Woo, Jean / Zhu, Kun / Balcells, Susana / Brandi, Maria Luisa / Buckley, Brendan M / Cheng, Sulin / Christiansen, Claus / Cooper, Cyrus / Dedoussis, George / Ford, Ian / Frost, Morten / Goltzman, David / González-Macías, Jesús / Kähönen, Mika / Karlsson, Magnus / Khusnutdinova, Elza / Koh, Jung-Min / Kollia, Panagoula / Langdahl, Bente Lomholt / Leslie, William D / Lips, Paul / Ljunggren, Östen / Lorenc, Roman S / Marc, Janja / Mellström, Dan / Obermayer-Pietsch, Barbara / Olmos, José M / Pettersson-Kymmer, Ulrika / Reid, David M / Riancho, José A / Ridker, Paul M / Rousseau, François / Slagboom, P Eline / Tang, Nelson L S / Urreizti, Roser / Van Hul, Wim / Viikari, Jorma / Zarrabeitia, María T / Aulchenko, Yurii S / Castano-Betancourt, Martha / Grundberg, Elin / Herrera, Lizbeth / Ingvarsson, Thorvaldur / Johannsdottir, Hrefna / Kwan, Tony / Li, Rui / Luben, Robert / Medina-Gómez, Carolina / Palsson, Stefan Th / Reppe, Sjur / Rotter, Jerome I / Sigurdsson, Gunnar / van Meurs, Joyce B J / Verlaan, Dominique / Williams, Frances M K / Wood, Andrew R / Zhou, Yanhua / Gautvik, Kaare M / Pastinen, Tomi / Raychaudhuri, Soumya / Cauley, Jane A / Chasman, Daniel I / Clark, Graeme R / Cummings, Steven R / Danoy, Patrick / Dennison, Elaine M / Eastell, Richard / Eisman, John A / Gudnason, Vilmundur / Hofman, Albert / Jackson, Rebecca D / Jones, Graeme / Jukema, J Wouter / Khaw, Kay-Tee / Lehtimäki, Terho / Liu, Yongmei / Lorentzon, Mattias / McCloskey, Eugene / Mitchell, Braxton D / Nandakumar, Kannabiran / Nicholson, Geoffrey C / Oostra, Ben A / Peacock, Munro / Pols, Huibert A P / Prince, Richard L / Raitakari, Olli / Reid, Ian R / Robbins, John / Sambrook, Philip N / Sham, Pak Chung / Shuldiner, Alan R / Tylavsky, Frances A / van Duijn, Cornelia M / Wareham, Nick J / Cupples, L Adrienne / Econs, Michael J / Evans, David M / Harris, Tamara B / Kung, Annie Wai Chee / Psaty, Bruce M / Reeve, Jonathan / Spector, Timothy D / Streeten, Elizabeth A / Zillikens, M Carola / Thorsteinsdottir, Unnur / Ohlsson, Claes / Karasik, David / Richards, J Brent / Brown, Matthew A / Stefansson, Kari / Uitterlinden, André G / Ralston, Stuart H / Ioannidis, John P A / Kiel, Douglas P / Rivadeneira, Fernando. ·Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·Nat Genet · Pubmed #22504420.

ABSTRACT: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

5 Article Significant differences in UK and US female bone density reference ranges. 2010

Noon, E / Singh, S / Cuzick, J / Spector, T D / Williams, F M K / Frost, M L / Howell, A / Harvie, M / Eastell, R / Coleman, R E / Fogelman, I / Blake, G M / Anonymous400648. ·Osteoporosis Research Unit, Division of Imaging Sciences, King's College London, London, UK. ·Osteoporos Int · Pubmed #20063090.

ABSTRACT: INTRODUCTION: Dual energy X-ray absorptiometry (DXA) is widely used for the diagnosis of osteoporosis and to investigate the effect of pharmacological treatments on BMD. In both routine and research settings, it is important that DXA results are correctly interpreted. METHODS: T- and Z-scores for the first 650 UK Caucasian women enrolled in the IBIS-II study were compared with data from two independent studies of unrelated, unselected UK Caucasian women: (1) 2,382 women aged 18 to 79 recruited to the Twins UK Adult Twin Registry; (2) 431 women aged 21 to 84 with no risk factors for osteoporosis recruited at Guy's Hospital. All DXA measurements were performed on Hologic densitometers. Subjects were divided into six age bands, and T- and Z-scores were calculated using the manufacturer's US reference range for the spine and the National Health and Nutrition Examination Survey III reference range for the femoral neck and total hip. RESULTS: The overall mean Z-scores for the IBIS-II, Twin, and Guy's groups were: spine: +0.61, +0.29, +0.33; femoral neck: +0.42, +0.36, +0.45; total hip: +0.65, +0.38, +0.39 (all p<0.001 compared with the expected value of 0). The mean body weight of subjects in the three studies was 74.4, 65.5, and 65.4 kg, respectively. Analysis revealed a highly significant relationship between Z-score and weight at each BMD site with a slope of 0.03 kg(-1). CONCLUSIONS: In general, US spine and hip reference ranges are not suitable for the calculation of Z-scores in UK women. For some research study designs, the differences may significantly influence the pattern of subject recruitment.

6 Article Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. 2009

Richards, J Brent / Kavvoura, Fotini K / Rivadeneira, Fernando / Styrkársdóttir, Unnur / Estrada, Karol / Halldórsson, Bjarni V / Hsu, Yi-Hsiang / Zillikens, M Carola / Wilson, Scott G / Mullin, Benjamin H / Amin, Najaf / Aulchenko, Yurii S / Cupples, L Adrienne / Deloukas, Panagiotis / Demissie, Serkalem / Hofman, Albert / Kong, Augustine / Karasik, David / van Meurs, Joyce B / Oostra, Ben A / Pols, Huibert A P / Sigurdsson, Gunnar / Thorsteinsdottir, Unnur / Soranzo, Nicole / Williams, Frances M K / Zhou, Yanhua / Ralston, Stuart H / Thorleifsson, Gudmar / van Duijn, Cornelia M / Kiel, Douglas P / Stefansson, Kari / Uitterlinden, André G / Ioannidis, John P A / Spector, Tim D / Anonymous860641. ·McGill University, Montreal, Quebec, Canada. ·Ann Intern Med · Pubmed #19841454.

ABSTRACT: BACKGROUND: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. OBJECTIVE: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. DESIGN: Large-scale meta-analysis of genome-wide association data. SETTING: 5 international, multicenter, population-based studies. PARTICIPANTS: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. MEASUREMENTS: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. RESULTS: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. LIMITATION: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. CONCLUSION: In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.

7 Article Loci at chromosomes 13, 19 and 20 influence age at natural menopause. 2009

Stolk, Lisette / Zhai, Guangju / van Meurs, Joyce B J / Verbiest, Michael M P J / Visser, Jenny A / Estrada, Karol / Rivadeneira, Fernando / Williams, Frances M / Cherkas, Lynn / Deloukas, Panos / Soranzo, Nicole / de Keyzer, Jules J / Pop, Victor J M / Lips, Paul / Lebrun, Corinne E I / van der Schouw, Yvonne T / Grobbee, Diederick E / Witteman, Jacqueline / Hofman, Albert / Pols, Huibert A P / Laven, Joop S E / Spector, Tim D / Uitterlinden, André G. ·Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. ·Nat Genet · Pubmed #19448619.

ABSTRACT: We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; -0.4 year per T allele (39%); P = 6.3 × 10(-11)), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10(-11)) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10(-8)). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

8 Article Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study. 2008

Liu, Yao-Zhong / Wilson, Scott G / Wang, Liang / Liu, Xiao-Gang / Guo, Yan-Fang / Li, Jian / Yan, Han / Deloukas, Panos / Soranzo, Nicole / Chinappen-Horsley, Usha / Cervino, Alessandra / Williams, Frances M / Xiong, Dong-Hai / Zhang, Yin-Ping / Jin, Tian-Bo / Levy, Shawn / Papasian, Christopher J / Drees, Betty M / Hamilton, James J / Recker, Robert R / Spector, Tim D / Deng, Hong-Wen. ·School of Medicine, University of Missouri - Kansas City, Kansas City, Missouri, United States of America. ·PLoS One · Pubmed #18776929.

ABSTRACT: Osteoporosis, the most prevalent metabolic bone disease among older people, increases risk for low trauma hip fractures (HF) that are associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of the key measurable risk factors for HF. Although hip BS is highly genetically determined, genetic factors underlying the trait are still poorly defined. Here, we performed the first genome-wide association study (GWAS) of hip BS interrogating approximately 380,000 SNPs on the Affymetrix platform in 1,000 homogeneous unrelated Caucasian subjects, including 501 females and 499 males. We identified a gene, PLCL1 (phospholipase c-like 1), that had four SNPs associated with hip BS at, or approaching, a genome-wide significance level in our female subjects; the most significant SNP, rs7595412, achieved a p value of 3.72x10(-7). The gene's importance to hip BS was replicated using the Illumina genotyping platform in an independent UK cohort containing 1,216 Caucasian females. Two SNPs of the PLCL1 gene, rs892515 and rs9789480, surrounded by the four SNPs identified in our GWAS, achieved p values of 8.62x10(-3) and 2.44x10(-3), respectively, for association with hip BS. Imputation analyses on our GWAS and the UK samples further confirmed the replication signals; eight SNPs of the gene achieved combined imputed p values<10(-5) in the two samples. The PLCL1 gene's relevance to HF was also observed in a Chinese sample containing 403 females, including 266 with HF and 177 control subjects. A SNP of the PLCL1 gene, rs3771362 that is only approximately 0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66x10(-3) (odds ratio = 0.26) for association with HF. Additional biological support for the role of PLCL1 in BS comes from previous demonstrations that the PLCL1 protein inhibits IP3 (inositol 1,4,5-trisphosphate)-mediated calcium signaling, an important pathway regulating mechanical sensing of bone cells. Our findings suggest that PLCL1 is a novel gene associated with variation in hip BS, and provide new insights into the pathogenesis of HF.