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1. Genetic basis of falling risk susceptibility in the UK Biobank Study

Author

Trajanoska, K., Seppala, L.J., Medina-Gomez, M.C. (Carolina), Hsu, Y.-H. (Yi-Hsiang), Zhou, S.R., Schoor, N.M., Groot, L., Karasik, D. (David), Richards, J.B. (Brent), Kiel, D.P. (Douglas), Uitterlinden, A.G. (André), Perry, J.R. (James), van der Velde, N., Day, F.R. (Felix), Rivadeneira Ramirez, F. (Fernando), Trajanoska, K., Seppala, L.J., Medina-Gomez, M.C. (Carolina), Hsu, Y.-H. (Yi-Hsiang), Zhou, S.R., Schoor, N.M., Groot, L., Karasik, D. (David), Richards, J.B. (Brent), Kiel, D.P. (Douglas), Uitterlinden, A.G. (André), Perry, J.R. (James), van der Velde, N., Day, F.R. (Felix), and Rivadeneira Ramirez, F. (Fernando)

Published
2020
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2. Bivariate genome-wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression

Author

Amare, AT, Vaez, A. (Ahmad), Hsu, Y.-H. (Yi-Hsiang), Direk, N., Kamali, Z., Howard, D.M., Mcintosh, A.M. (Andrew), Tiemeier, H.W. (Henning), B?ltmann, U., Snieder, H. (Harold), Hartman, C. (Corina), Amare, AT, Vaez, A. (Ahmad), Hsu, Y.-H. (Yi-Hsiang), Direk, N., Kamali, Z., Howard, D.M., Mcintosh, A.M. (Andrew), Tiemeier, H.W. (Henning), B?ltmann, U., Snieder, H. (Harold), and Hartman, C. (Corina)

Abstract

Although a genetic basis of depression has been well established in twin studies, identification of genome-wide significant loci has been difficult. We hypothesized that bivariate analyses of findings from a meta-analysis of genome-wide association studies (meta-GWASs) of the broad depression phenotype with those from meta-GWASs of self-reported and recurrent major depressive disorder (MDD), bipolar disorder and schizophrenia would enhance statistical power to identify novel genetic loci for depression. LD score regression analyses were first used to estimate the genetic correlations of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia. Then, we performed four bivariate GWAS analyses. The genetic correlations (rg ± SE) of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia were 0.79 ± 0.07, 0.24 ± 0.08, 0.53 ±

Published
2020
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3. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, X. (Xia), O'Reilly, P. F. (Paul F.), Aschard, H. (Hugues), Hsu, Y.-H. (Yi-Hsiang), Richards, J. B. (J. Brent), Dupuis, J. (Josee), Ingelsson, E. (Erik), Karasik, D. (David), Pilz, S. (Stefan), Berry, D. (Diane), Kestenbaum, B. (Bryan), Zheng, J. (Jusheng), Luan, J. (Jianan), Sofianopoulou, E. (Eleni), Streeten, E. A. (Elizabeth A.), Albanes, D. (Demetrius), Lutsey, P. L. (Pamela L.), Yao, L. (Lu), Tang, W. (Weihong), Econs, M. J. (Michael J.), Wallaschofski, H. (Henri), Voelzke, H. (Henry), Zhou, A. (Ang), Power, C. (Chris), McCarthy, M. I. (Mark I.), Michos, E. D. (Erin D.), Boerwinkle, E. (Eric), Weinstein, S. J. (Stephanie J.), Freedman, N. D. (Neal D.), Huang, W.-Y. (Wen-Yi), Van Schoor, N. M. (Natasja M.), van der Velde, N. (Nathalie), de Groot, L. C. (Lisette C. P. G. M.), Enneman, A. (Anke), Cupples, L. A. (L. Adrienne), Booth, S. L. (Sarah L.), Vasan, R. S. (Ramachandran S.), Liu, C.-T. (Ching-Ti), Zhou, Y. (Yanhua), Ripatti, S. (Samuli), Ohlsson, C. (Claes), Vandenput, L. (Liesbeth), Lorentzon, M. (Mattias), Eriksson, J. G. (Johan G.), Shea, M. K. (M. Kyla), Houston, D. K. (Denise K.), Kritchevsky, S. B. (Stephen B.), Liu, Y. (Yongmei), Lohman, K. K. (Kurt K.), Ferrucci, L. (Luigi), Peacock, M. (Munro), Gieger, C. (Christian), Beekman, M. (Marian), Slagboom, E. (Eline), Deelen, J. (Joris), van Heemst, D. (Diana), Kleber, M. E. (Marcus E.), Maerz, W. (Winfried), de Boer, I. H. (Ian H.), Wood, A. C. (Alexis C.), Rotter, J. I. (Jerome I.), Rich, S. S. (Stephen S.), Robinson-Cohen, C. (Cassianne), den Heijer, M. (Martin), Järvelin, M.-R. (Marjo-Riitta), Cavadino, A. (Alana), Joshi, P. K. (Peter K.), Wilson, J. F. (James F.), Hayward, C. (Caroline), Lind, L. (Lars), Michaelsson, K. (Karl), Trompet, S. (Stella), Zillikens, M. C. (M. Carola), Uitterlinden, A. G. (Andre G.), Rivadeneira, F. (Fernando), Broer, L. (Linda), Zgaga, L. (Lina), Campbell, H. (Harry), Theodoratou, E. (Evropi), Farrington, S. M. (Susan M.), Timofeeva, M. (Maria), Dunlop, M. G. (Malcolm G.), Valdes, A. M. (Ana M.), Tikkanen, E. (Emmi), Lehtimaki, T. (Terho), Lyytikainen, L.-P. (Leo-Pekka), Kahonen, M. (Mika), Raitakari, O. T. (Olli T.), Mikkila, V. (Vera), Ikram, M. A. (M. Arfan), Sattar, N. (Naveed), Jukema, J. W. (J. Wouter), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Forouhi, N. G. (Nita G.), Gundersen, T. E. (Thomas E.), Khaw, K.-T. (Kay-Tee), Butterworth, A. S. (Adam S.), Danesh, J. (John), Spector, T. (Timothy), Wang, T. J. (Thomas J.), Hypponen, E. (Elina), Kraft, P. (Peter), and Kiel, D. P. (Douglas P.)

Subjects
Risk factors, Epidemiology, Genetics research, Genome-wide association studies
Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Published
2018

4. Trans-ethnic polygenic analysis supports genetic overlaps of lumbar disc degeneration with height, body mass index, and bone mineral density

Author

Zhou, X. (Xueya), Cheung, C.-L. (Ching-Lung), Karasugi, T. (Tatsuki), Karppinen, J. (Jaro), Samartzis, D. (Dino), Hsu, Y.-H. (Yi-Hsiang), Mak, T. S. (Timothy Shin-Heng), Song, Y.-Q. (You-Qiang), Chiba, K. (Kazuhiro), Kawaguchi, Y. (Yoshiharu), Li, Y. (Yan), Chan, D. (Danny), Cheung, K. M. (Kenneth Man-Chee), Ikegawa, S. (Shiro), Cheah, K. S. (Kathryn Song-Eng), Sham, P. C. (Pak Chung), Zhou, X. (Xueya), Cheung, C.-L. (Ching-Lung), Karasugi, T. (Tatsuki), Karppinen, J. (Jaro), Samartzis, D. (Dino), Hsu, Y.-H. (Yi-Hsiang), Mak, T. S. (Timothy Shin-Heng), Song, Y.-Q. (You-Qiang), Chiba, K. (Kazuhiro), Kawaguchi, Y. (Yoshiharu), Li, Y. (Yan), Chan, D. (Danny), Cheung, K. M. (Kenneth Man-Chee), Ikegawa, S. (Shiro), Cheah, K. S. (Kathryn Song-Eng), and Sham, P. C. (Pak Chung)

Abstract

Lumbar disc degeneration (LDD) is age-related break-down in the fibrocartilaginous joints between lumbar vertebrae. It is a major cause of low back pain and is conventionally assessed by magnetic resonance imaging (MRI). Like most other complex traits, LDD is likely polygenic and influenced by both genetic and environmental factors. However, genome-wide association studies (GWASs) of LDD have uncovered few susceptibility loci due to the limited sample size. Previous epidemiology studies of LDD also reported multiple heritable risk factors, including height, body mass index (BMI), bone mineral density (BMD), lipid levels, etc. Genetics can help elucidate causality between traits and suggest loci with pleiotropic effects. One such approach is polygenic score (PGS) which summarizes the effect of multiple variants by the summation of alleles weighted by estimated effects from GWAS. To investigate genetic overlaps of LDD and related heritable risk factors, we calculated the PGS of height, BMI, BMD and lipid levels in a Chinese population-based cohort with spine MRI examination and a Japanese case-control cohort of lumbar disc herniation (LDH) requiring surgery. Because most large-scale GWASs were done in European populations, PGS of corresponding traits were created using weights from European GWASs. We calibrated their prediction performance in independent Chinese samples, then tested associations with MRI-derived LDD scores and LDH affection status. The PGS of height, BMI, BMD and lipid levels were strongly associated with respective phenotypes in Chinese, but phenotype variances explained were lower than in Europeans which would reduce the power to detect genetic overlaps. Despite of this, the PGS of BMI and lumbar spine BMD were significantly associated with LDD scores; and the PGS of height was associated with the increased the liability of LDH. Furthermore, linkage disequilibrium score regression suggested that, osteoarthritis, another degenerative disorde

Published
2018

5. Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density

Author

Morris, J.A. (John A.), Tsai, P.-C. (Pei-Chien), Joehanes, R. (Roby), Zheng, J. (Jie), Trajanoska, K. (Katerina), Soerensen, M. (Mette), Forgetta, V. (Vincenzo), Castillo-Fernandez, J.E. (Juan Edgar), Frost, M. (Morten), Spector, T.D. (Timothy), Christensen, K. (Kaare), Christiansen, L. (Lene), Rivadeneira Ramirez, F. (Fernando), Tobias, J.H. (Jon), Evans, D.M. (David M.), Kiel, D.P. (Douglas P.), Hsu, Y.-H. (Yi-Hsiang), Richards, J.B. (Brent), Bell, J.T. (Jordana T.), Morris, J.A. (John A.), Tsai, P.-C. (Pei-Chien), Joehanes, R. (Roby), Zheng, J. (Jie), Trajanoska, K. (Katerina), Soerensen, M. (Mette), Forgetta, V. (Vincenzo), Castillo-Fernandez, J.E. (Juan Edgar), Frost, M. (Morten), Spector, T.D. (Timothy), Christensen, K. (Kaare), Christiansen, L. (Lene), Rivadeneira Ramirez, F. (Fernando), Tobias, J.H. (Jon), Evans, D.M. (David M.), Kiel, D.P. (Douglas P.), Hsu, Y.-H. (Yi-Hsiang), Richards, J.B. (Brent), and Bell, J.T. (Jordana T.)

Abstract

Genetic and environmental determinants of skeletal phenotypes such as bone mineral density (BMD) may converge through the epigenome, providing a tool to better understand osteoporosis pathophysiology. Because the epigenetics of BMD have been largely unexplored in humans, we performed an epigenome-wide association study (EWAS) of BMD. We undertook a large-scale BMD EWAS using the Infinium HumanMethylation450 array to measure site-specific DNA methylation in up to 5515 European-descent individuals (NDiscovery= 4614, NValidation= 901). We associated methylation at multiple cytosine-phosphate-guanine (CpG) sites with dual-energy X-ray absorptiometry (DXA)-derived femoral neck and lumbar spine BMD. We performed sex-combined and stratified analyses, controlling for age, weight, smoking status, estimated white blood cell proportions, and random effects for relatedness and batch effects. A 5% false-discovery rate was used to identify CpGs associated with BMD. We identified one CpG site, cg23196985, significantly associated with femoral neck BMD in 3232 females (p = 7.9 × 10−11) and 4614 females and males (p = 3.0 × 10−8). cg23196985 was not associated with femoral neck BMD in an additional sample of 474 females (p = 0.64) and 901 males and females (p = 0.60). Lack of strong consistent association signal indicates that among the tested probes, no large-effect epigenetic changes in whole blood associated with BMD, suggesting future epigenomic studies of musculoskeletal traits measure DNA methylation in a different tissue with extended genome coverage.

Published
2017
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6. Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

Author

Manousaki, D. (Despoina), Dudding, T. (Tom), Haworth, S. (Simon), Hsu, Y.-H. (Yi-Hsiang), Liu, C.-T. (Ching-Ti), Medina-Gomez, M.C. (Carolina), Voortman, R.G. (Trudy), Velde, N. (Nathalie) van der, Melhus, H. (Håkan), Robinson-Cohen, C. (Cassianne), Cousminer, D.L. (Diana), Nethander, M. (Maria), Vandenput, L. (Liesbeth), Noordam, R., Forgetta, V. (Vincenzo), Greenwood, C.M.T. (Celia), Biggs, M.L. (M.), Psaty, B.M. (Bruce M.), Rotter, J.I. (Jerome I.), Zemel, B.S. (Babette S.), Mitchell, J.A. (Jonathan A.), Taylor, B. (Bruce), Lorentzon, M. (Mattias), Karlsson, M. (Magnus), Jaddoe, V.W.V. (Vincent), Tiemeier, H.W. (Henning), Campos Obando, N. (Natalia), Franco, O.H. (Oscar), Uitterlinden, A.G. (André), Broer, L. (Linda), Schoor, N.M. (Natasja) van, Ham, A.C. (Annelies), Ikram, M.K. (Kamran), Karasik, D. (David), Mutsert, R. (Reneé) de, Rosendaal, F.R. (Frits), Heijer, M. (Martin) den, Wang, T.J. (Thomas), Kao, W.H.L. (Wen), Orwoll, E.S. (Eric), Mook-Kanamori, D.O. (Dennis), Michaëlsson, K. (Karl), Kestenbaum, B. (Bryan), Ohlsson, C. (Claes), Mellström, D. (Dan), Groot, L.C.P.G.M. (Lisette) de, Grant, S.F.A. (Struan), Kiel, D.P. (Douglas P.), Zillikens, M.C. (Carola), Rivadeneira Ramirez, F. (Fernando), Sawcer, S.J. (Stephen), Timpson, N.J. (Nicholas), Richards, J.B. (Brent), Manousaki, D. (Despoina), Dudding, T. (Tom), Haworth, S. (Simon), Hsu, Y.-H. (Yi-Hsiang), Liu, C.-T. (Ching-Ti), Medina-Gomez, M.C. (Carolina), Voortman, R.G. (Trudy), Velde, N. (Nathalie) van der, Melhus, H. (Håkan), Robinson-Cohen, C. (Cassianne), Cousminer, D.L. (Diana), Nethander, M. (Maria), Vandenput, L. (Liesbeth), Noordam, R., Forgetta, V. (Vincenzo), Greenwood, C.M.T. (Celia), Biggs, M.L. (M.), Psaty, B.M. (Bruce M.), Rotter, J.I. (Jerome I.), Zemel, B.S. (Babette S.), Mitchell, J.A. (Jonathan A.), Taylor, B. (Bruce), Lorentzon, M. (Mattias), Karlsson, M. (Magnus), Jaddoe, V.W.V. (Vincent), Tiemeier, H.W. (Henning), Campos Obando, N. (Natalia), Franco, O.H. (Oscar), Uitterlinden, A.G. (André), Broer, L. (Linda), Schoor, N.M. (Natasja) van, Ham, A.C. (Annelies), Ikram, M.K. (Kamran), Karasik, D. (David), Mutsert, R. (Reneé) de, Rosendaal, F.R. (Frits), Heijer, M. (Martin) den, Wang, T.J. (Thomas), Kao, W.H.L. (Wen), Orwoll, E.S. (Eric), Mook-Kanamori, D.O. (Dennis), Michaëlsson, K. (Karl), Kestenbaum, B. (Bryan), Ohlsson, C. (Claes), Mellström, D. (Dan), Groot, L.C.P.G.M. (Lisette) de, Grant, S.F.A. (Struan), Kiel, D.P. (Douglas P.), Zillikens, M.C. (Carola), Rivadeneira Ramirez, F. (Fernando), Sawcer, S.J. (Stephen), Timpson, N.J. (Nicholas), and Richards, J.B. (Brent)

Abstract

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency synonymous coding variant g.14900931G>A, which conferred a large effect on 25-hydroxyvitamin D levels. The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency. Individuals carrying one copy of this variant also had increased odds of multiple sclerosis in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin

Published
2017
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7. Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Author

Medina-Gomez, M.C. (Carolina), Kemp, J.P. (John), Dimou, N.L. (Niki L.), Kreiner, E. (Eskil), Chesi, A. (Alessandra), Zemel, B.S. (Babette S.), Bønnelykke, K. (Klaus), Boer, C.G. (Cindy G.), Ahluwalia, T.S. (Tarunveer Singh), Bisgaard, H. (Hans), Evangelou, E. (Evangelos), Heppe, D.H.M. (Denise), Bonewald, L.F. (Lynda F.), Gorski, J.P. (Jeffrey P.), Ghanbari, M. (Mohsen), Demissie, S. (Serkalem), Duque, G. (Gustavo), Maurano, M.T. (Matthew T.), Kiel, D.P. (Douglas P.), Hsu, Y.-H. (Yi-Hsiang), Eerden, B.C.J. (Bram) van der, Ackert-Bicknell, C. (Cheryl), Reppe, S. (Sjur), Gautvik, K.M. (Kaare), Raastad, T. (Truls), Karasik, D. (David), Peppel, J. (Jeroen) van de, Jaddoe, V.W.V. (Vincent), Uitterlinden, A.G. (André), Tobias, J.H. (Jon), Grant, S.F.A. (Struan), Bagos, P.G. (Pantelis G.), Evans, D.M. (David), Rivadeneira Ramirez, F. (Fernando), Medina-Gomez, M.C. (Carolina), Kemp, J.P. (John), Dimou, N.L. (Niki L.), Kreiner, E. (Eskil), Chesi, A. (Alessandra), Zemel, B.S. (Babette S.), Bønnelykke, K. (Klaus), Boer, C.G. (Cindy G.), Ahluwalia, T.S. (Tarunveer Singh), Bisgaard, H. (Hans), Evangelou, E. (Evangelos), Heppe, D.H.M. (Denise), Bonewald, L.F. (Lynda F.), Gorski, J.P. (Jeffrey P.), Ghanbari, M. (Mohsen), Demissie, S. (Serkalem), Duque, G. (Gustavo), Maurano, M.T. (Matthew T.), Kiel, D.P. (Douglas P.), Hsu, Y.-H. (Yi-Hsiang), Eerden, B.C.J. (Bram) van der, Ackert-Bicknell, C. (Cheryl), Reppe, S. (Sjur), Gautvik, K.M. (Kaare), Raastad, T. (Truls), Karasik, D. (David), Peppel, J. (Jeroen) van de, Jaddoe, V.W.V. (Vincent), Uitterlinden, A.G. (André), Tobias, J.H. (Jon), Grant, S.F.A. (Struan), Bagos, P.G. (Pantelis G.), Evans, D.M. (David), and Rivadeneira Ramirez, F. (Fernando)

Abstract

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% for TBLH-BMD, and 39% for TB-LM, with a shared genetic component of 43%. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: _WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5_. Variants in the _TOM1L2/SREBF1_ locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that _SREBF1_ is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.

Published
2017
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8. Bivariate genome-wide association study identifies novel pleiotropic loci for lipids and inflammation

Author

Ligthart, S. (Symen), Vaez, A. (Ahmad), Hsu, Y.-H. (Yi-Hsiang), Stolk, R.P. (Ronald), Uitterlinden, A.G. (André), Hofman, A. (Albert), Alizadeh, B.Z. (Behrooz), Franco, O.H. (Oscar), Dehghan, A. (Abbas), Ligthart, S. (Symen), Vaez, A. (Ahmad), Hsu, Y.-H. (Yi-Hsiang), Stolk, R.P. (Ronald), Uitterlinden, A.G. (André), Hofman, A. (Albert), Alizadeh, B.Z. (Behrooz), Franco, O.H. (Oscar), and Dehghan, A. (Abbas)

Abstract

Background: Genome-wide association studies (GWAS) have identified multiple genetic loci for C-reactive protein (CRP) and lipids, of which some overlap. We aimed to identify genetic pleiotropy among CRP and lipids in order to better understand the shared biology of chronic inflammation and lipid metabolism. Results: In a bivariate GWAS, we combined summary statistics of published GWAS on CRP (n = 66,185) and lipids, including LDL-cholesterol, HDL-cholesterol, triglycerides, and total cholesterol (n = 100,184), using an empirical weighted linear-combined test statistic. We sought replication for novel CRP associations in an independent sample of 17,743 genotyped individuals, and performed in silico replication of novel lipid variants in 93,982 individuals. Fifty potentially pleiotropic SNPs were identified among CRP and lipids: 21 for LDL-cholesterol and CRP, 20 for HDL-cholesterol and CRP, 21 for triglycerides, and CRP and 20 for total cholesterol and CRP. We identified and significantly replicated three novel SNPs for CRP in or near CTSB/FDFT1 (rs10435719, Preplication: 2.6 × 10-5), STAG1/PCCB (rs7621025, Preplication: 1.4 × 10-3) and FTO (rs1558902, Preplication: 2.7 × 10-5). Seven pleiotropic lipid loci were replicated in the independent set of MetaboChip samples of the Global Lipids Genetics Consortium. Annotating the effect of replicated CRP SNPs to the expression of nearby genes, we observed an effect of rs10435719 on gene expression of FDFT1, and an effect of rs7621025 on PCCB. Conclusions: Our large scale combined GWAS analysis identified numerous pleiotropic loci for CRP and lipids providing further insight in the genetic interrelation between lipids and inflammation. In addition, we provide evidence for FDFT1, PCCB and FTO to be associated with CRP levels.

Published
2016
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9. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, H.-F. (Hou-Feng), Forgetta, V. (Vincenzo), Hsu, Y.-H. (Yi-Hsiang), Estrada Gil, K. (Karol), Rosello-Diez, A. (Alberto), Leo, P.J. (Paul), Dahia, C.L. (Chitra L.), Park-Min, K.H. (Kyung Hyun), Tobias, J.H. (Jon), Kooperberg, C. (Charles), Kleinman, A. (Aaron), Styrkarsdottir, U. (Unnur), Liu, C.-T. (Ching-Ti), Uggla, C. (Charlotta), Evans, D.S. (Daniel), Nielson, C. (Carrie), Walter, K. (Klaudia), Pettersson-Kymmer, U. (Ulrika), McCarthy, S. (Shane), Eriksson, J. (Joel), Kwan, T. (Tony), Jhamai, M. (Mila), Trajanoska, K. (Katerina), Memari, Y. (Yasin), Min, J.L. (Josine L.), Huang, J. (Jie), Danecek, P. (Petr), Wilmot, B. (Beth), Li, R. (Rui), Chou, W.-C. (Wen-Chi), Mokry, L.E. (Lauren E.), Moayyeri, A. (Alireza), Claussnitzer, M. (Melina), Cheng, C.-H. (Chia-Ho), Cheung, W. (Warren), Medina-Gomez, M.C. (Carolina), Ge, B. (Bing), Chen, S.-H. (Shu-Huang), Choi, K. (Kunho), Oei, L. (Ling), Fraser, J. (James), Kraaij, R. (Robert), Hibbs, M.A. (Matthew A.), Gregson, C.L. (Celia L.), Paquette, D. (Denis), Hofman, A. (Albert), Wibom, C. (Carl), Tranah, G.J. (Gregory), Marshall, M. (Mhairi), Gardiner, B.B. (Brooke B.), Cremin, K. (Katie), Auer, P. (Paul), Hsu, L. (Li), Ring, S. (Susan), Tung, J.Y. (Joyce Y.), Thorleifsson, G. (Gudmar), Enneman, A.W. (Anke), Schoor, N.M. (Natasja) van, Groot, L.C.P.G.M. (Lisette) de, Velde, N. (Nathalie) van der, Melin, B. (Beatrice), Kemp, J.P. (John), Christiansen, C., Sayers, I. (Ian), Zhou, Y. (Yanhua), Calderari, S. (Sophie), Rooij, J.G.J. (Jeroen) van, Carlson, C. (Chris), Peters, U. (Ulrike), Berlivet, S. (Soizik), Dostie, J. (Josée), Uitterlinden, A.G. (André), Williams, S.R. (Stephen R.), Farber, C. (Charles), Grinberg, D. (Daniel), LaCroix, A.Z. (Andrea), Haessler, J. (Jeff), Chasman, D.I. (Daniel), Giulianini, F. (Franco), Rose, L.M. (Lynda M.), Ridker, P.M. (Paul), Eisman, J.A. (John), Nguyen, T.V. (Tuan), Center, J.R. (Jacqueline), Nogues, X. (Xavier), Garcia-Giralt, N. (Natàlia), Launer, L.J. (Lenore), Gudnason, V. (Vilmunder), Mellström, D. (Dan), Vandenput, L. (Liesbeth), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Karlsson, M. (Magnus), Ljunggren, O. (Östen), Svensson, O. (Olle), Hallmans, G. (Göran), Rousseau, M.F. (Francois), Giroux, S. (Sylvie), Bussière, J. (Johanne), Arp, P.P. (Pascal), Koromani, F. (Fjorda), Prince, R.L. (Richard L.), Lewis, J.R. (Joshua), Langdahl, B.L. (Bente), Hermann, A.P. (A. Pernille), Jensen, J.-E.B. (Jens-Erik B.), Kaptoge, S. (Stephen), Khaw, K.T., Reeve, J. (Jonathan), Formosa, M.M. (Melissa M.), Xuereb-Anastasi, A. (Angela), Åkesson, K. (Kristina), McGuigan, F.E., Garg, G. (Gaurav), Olmos, D. (David), Zarrabeitia, M.T. (María), Riancho, J.A. (José), Ralston, S.H. (Stuart), Alonso, N. (Nerea), Jiang, X. (Xi), Goltzman, D. (David), Pastinen, T. (Tomi), Grundberg, E. (Elin), Gauguier, D. (Dominique), Orwoll, E.S. (Eric), Karasik, D. (David), Smith, A.V. (Davey), Siggeirsdottir, K. (Kristin), Harris, T.B. (Tamara), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Thorsteinsdottir, U. (Unnur), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Soranzo, N. (Nicole), Durbin, R. (Richard), Wilson, S.G. (Scott), Ntzani, E.E. (Evangelia), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Hinds, D.A. (David A.), Spector, T.D. (Timothy), Cupples, L.A. (Adrienne), Ohlsson, C. (Claes), Greenwood, C.M.T. (Celia), Jackson, R.D. (Rebecca), Rowe, D.W. (David W.), Loomis, C.A. (Cynthia A.), Evans, D.M. (David M.), Ackert-Bicknell, C.L. (Cheryl), Joyner, A.L. (Alexandra L.), Duncan, E.L. (Emma), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), Richards, J.B. (Brent), Zheng, H.-F. (Hou-Feng), Forgetta, V. (Vincenzo), Hsu, Y.-H. (Yi-Hsiang), Estrada Gil, K. (Karol), Rosello-Diez, A. (Alberto), Leo, P.J. (Paul), Dahia, C.L. (Chitra L.), Park-Min, K.H. (Kyung Hyun), Tobias, J.H. (Jon), Kooperberg, C. (Charles), Kleinman, A. (Aaron), Styrkarsdottir, U. (Unnur), Liu, C.-T. (Ching-Ti), Uggla, C. (Charlotta), Evans, D.S. (Daniel), Nielson, C. (Carrie), Walter, K. (Klaudia), Pettersson-Kymmer, U. (Ulrika), McCarthy, S. (Shane), Eriksson, J. (Joel), Kwan, T. (Tony), Jhamai, M. (Mila), Trajanoska, K. (Katerina), Memari, Y. (Yasin), Min, J.L. (Josine L.), Huang, J. (Jie), Danecek, P. (Petr), Wilmot, B. (Beth), Li, R. (Rui), Chou, W.-C. (Wen-Chi), Mokry, L.E. (Lauren E.), Moayyeri, A. (Alireza), Claussnitzer, M. (Melina), Cheng, C.-H. (Chia-Ho), Cheung, W. (Warren), Medina-Gomez, M.C. (Carolina), Ge, B. (Bing), Chen, S.-H. (Shu-Huang), Choi, K. (Kunho), Oei, L. (Ling), Fraser, J. (James), Kraaij, R. (Robert), Hibbs, M.A. (Matthew A.), Gregson, C.L. (Celia L.), Paquette, D. (Denis), Hofman, A. (Albert), Wibom, C. (Carl), Tranah, G.J. (Gregory), Marshall, M. (Mhairi), Gardiner, B.B. (Brooke B.), Cremin, K. (Katie), Auer, P. (Paul), Hsu, L. (Li), Ring, S. (Susan), Tung, J.Y. (Joyce Y.), Thorleifsson, G. (Gudmar), Enneman, A.W. (Anke), Schoor, N.M. (Natasja) van, Groot, L.C.P.G.M. (Lisette) de, Velde, N. (Nathalie) van der, Melin, B. (Beatrice), Kemp, J.P. (John), Christiansen, C., Sayers, I. (Ian), Zhou, Y. (Yanhua), Calderari, S. (Sophie), Rooij, J.G.J. (Jeroen) van, Carlson, C. (Chris), Peters, U. (Ulrike), Berlivet, S. (Soizik), Dostie, J. (Josée), Uitterlinden, A.G. (André), Williams, S.R. (Stephen R.), Farber, C. (Charles), Grinberg, D. (Daniel), LaCroix, A.Z. (Andrea), Haessler, J. (Jeff), Chasman, D.I. (Daniel), Giulianini, F. (Franco), Rose, L.M. (Lynda M.), Ridker, P.M. (Paul), Eisman, J.A. (John), Nguyen, T.V. (Tuan), Center, J.R. (Jacqueline), Nogues, X. (Xavier), Garcia-Giralt, N. (Natàlia), Launer, L.J. (Lenore), Gudnason, V. (Vilmunder), Mellström, D. (Dan), Vandenput, L. (Liesbeth), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Karlsson, M. (Magnus), Ljunggren, O. (Östen), Svensson, O. (Olle), Hallmans, G. (Göran), Rousseau, M.F. (Francois), Giroux, S. (Sylvie), Bussière, J. (Johanne), Arp, P.P. (Pascal), Koromani, F. (Fjorda), Prince, R.L. (Richard L.), Lewis, J.R. (Joshua), Langdahl, B.L. (Bente), Hermann, A.P. (A. Pernille), Jensen, J.-E.B. (Jens-Erik B.), Kaptoge, S. (Stephen), Khaw, K.T., Reeve, J. (Jonathan), Formosa, M.M. (Melissa M.), Xuereb-Anastasi, A. (Angela), Åkesson, K. (Kristina), McGuigan, F.E., Garg, G. (Gaurav), Olmos, D. (David), Zarrabeitia, M.T. (María), Riancho, J.A. (José), Ralston, S.H. (Stuart), Alonso, N. (Nerea), Jiang, X. (Xi), Goltzman, D. (David), Pastinen, T. (Tomi), Grundberg, E. (Elin), Gauguier, D. (Dominique), Orwoll, E.S. (Eric), Karasik, D. (David), Smith, A.V. (Davey), Siggeirsdottir, K. (Kristin), Harris, T.B. (Tamara), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Thorsteinsdottir, U. (Unnur), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Soranzo, N. (Nicole), Durbin, R. (Richard), Wilson, S.G. (Scott), Ntzani, E.E. (Evangelia), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Hinds, D.A. (David A.), Spector, T.D. (Timothy), Cupples, L.A. (Adrienne), Ohlsson, C. (Claes), Greenwood, C.M.T. (Celia), Jackson, R.D. (Rebecca), Rowe, D.W. (David W.), Loomis, C.A. (Cynthia A.), Evans, D.M. (David M.), Ackert-Bicknell, C.L. (Cheryl), Joyner, A.L. (Alexandra L.), Duncan, E.L. (Emma), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), and Richards, J.B. (Brent)

Abstract

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and n controls = 409,511). Using an En1 cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation

Published
2015
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10. Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

Author

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

Abstract

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Published
2015
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11. Pleiotropic genes for metabolic syndrome and inflammation

Author

Kraja, A. (Aldi), Chasman, D.I. (Daniel), North, K.E. (Kari), Reiner, A. (Alexander), Yanek, L.R. (Lisa), Kilpeläinen, T.O. (Tuomas), Smith, J.A. (Jennifer), Dehghan, A. (Abbas), Dupuis, J. (Josée), Johnson, A.D. (Andrew), Feitosa, M.F. (Mary Furlan), Tekola-Ayele, F. (Fasil), Chu, A.Y. (Audrey), Nolte, I.M. (Ilja), Dastani, Z. (Zari), Morris, A.P. (Andrew), Pendergrass, S.A. (Sarah), Sun, Y.V. (Yan), Ritchie, M.D. (Marylyn), Vaez, A. (Ahmad), Lin, H. (Honghuang), Ligthart, S. (Symen), Marullo, L. (Letizia), Rohde, R. (Rebecca), Shao, Y. (Yaming), Ziegler, M.A. (Mark), Im, K.M. (Kate), Schnabel, R.B. (Renate), Jorgensen, T. (Torben), Jørgensen, M.E. (Marit), Hansen, T. (T.), Pedersen, O. (Oluf), Stolk, R.P. (Ronald), Snieder, H. (Harold), Hofman, A. (Albert), Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Ikram, M.A. (Arfan), Richards, J.B. (Brent), Rotimi, C. (Charles), Wilson, J.G. (James), Lange, L.A. (Leslie), Ganesh, S.K. (Santhi), Nalls, M.A. (Michael), Rasmussen-Torvik, L.J. (Laura), Pankow, J.S. (James), Coresh, J. (Josef), Tang, W. (Weihong), Kao, W.-H.L. (Linda), Boerwinkle, E.A. (Eric), Morrison, A.C. (Alanna), Ridker, P.M. (Paul), Becker, D.M. (Diane), Rotter, J.I. (Jerome), Kardia, S.L.R. (Sharon), Loos, R.J.F. (Ruth), Larson, M.G. (Martin), Hsu, Y.-H. (Yi-Hsiang), Province, M.A. (Mike), Tracy, R.P. (Russell), Voight, B.F. (Benjamin), Vaidya, D. (Dhananjay), O'Donnell, C.J. (Christopher), Benjamin, E.J. (Emelia), Alizadeh, B.Z. (Behrooz), Prokopenko, I. (Inga), Meigs, J.B. (James), Borecki, I.B. (Ingrid), Kraja, A. (Aldi), Chasman, D.I. (Daniel), North, K.E. (Kari), Reiner, A. (Alexander), Yanek, L.R. (Lisa), Kilpeläinen, T.O. (Tuomas), Smith, J.A. (Jennifer), Dehghan, A. (Abbas), Dupuis, J. (Josée), Johnson, A.D. (Andrew), Feitosa, M.F. (Mary Furlan), Tekola-Ayele, F. (Fasil), Chu, A.Y. (Audrey), Nolte, I.M. (Ilja), Dastani, Z. (Zari), Morris, A.P. (Andrew), Pendergrass, S.A. (Sarah), Sun, Y.V. (Yan), Ritchie, M.D. (Marylyn), Vaez, A. (Ahmad), Lin, H. (Honghuang), Ligthart, S. (Symen), Marullo, L. (Letizia), Rohde, R. (Rebecca), Shao, Y. (Yaming), Ziegler, M.A. (Mark), Im, K.M. (Kate), Schnabel, R.B. (Renate), Jorgensen, T. (Torben), Jørgensen, M.E. (Marit), Hansen, T. (T.), Pedersen, O. (Oluf), Stolk, R.P. (Ronald), Snieder, H. (Harold), Hofman, A. (Albert), Uitterlinden, A.G. (André), Franco, O.H. (Oscar), Ikram, M.A. (Arfan), Richards, J.B. (Brent), Rotimi, C. (Charles), Wilson, J.G. (James), Lange, L.A. (Leslie), Ganesh, S.K. (Santhi), Nalls, M.A. (Michael), Rasmussen-Torvik, L.J. (Laura), Pankow, J.S. (James), Coresh, J. (Josef), Tang, W. (Weihong), Kao, W.-H.L. (Linda), Boerwinkle, E.A. (Eric), Morrison, A.C. (Alanna), Ridker, P.M. (Paul), Becker, D.M. (Diane), Rotter, J.I. (Jerome), Kardia, S.L.R. (Sharon), Loos, R.J.F. (Ruth), Larson, M.G. (Martin), Hsu, Y.-H. (Yi-Hsiang), Province, M.A. (Mike), Tracy, R.P. (Russell), Voight, B.F. (Benjamin), Vaidya, D. (Dhananjay), O'Donnell, C.J. (Christopher), Benjamin, E.J. (Emelia), Alizadeh, B.Z. (Behrooz), Prokopenko, I. (Inga), Meigs, J.B. (James), and Borecki, I.B. (Ingrid)

Abstract

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up

Published
2014
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12. A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus

Author

Oei, L. (Ling), Hsu, Y.-H. (Yi-Hsiang), Styrkarsdottir, U. (Unnur), Eussen, H.J.F.M.M. (Bert), Klein, J.E.M.M. (Annelies) de, Peters, M.J. (Marjolein), Halldorsson, B.V. (Bjarni), Liu, C.-T. (Ching-Ti), Alonso, N. (Nerea), Kaptoge, S. (Stephen), Thorleifsson, G. (Gudmar), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Kingdom, M.K. (Marcin KrUnited), Lewis, J.R. (Joshua), Patel, M.S. (Millan), Scollen, S. (Serena), Svensson, O. (Olle), Trompet, S. (Stella), Schoor, N.M. (Natasja) van, Zhu, K. (Kun), Buckley, B.M. (Brendan M.), Cooper, C. (Charles), Ford, I. (Ian), Goltzman, D. (David), González-Macías, J. (Jesús), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Lorenc, R. (Roman), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Slagboom, P.E. (Eline), Garcia-Ibarbia, C. (Carmen), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Arp, P.P. (Pascal), Nandakumar, K. (Kannabiran), Palsson, S.T. (Stefan Th), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Zhou, Y. (Yanhua), Hofman, A. (Albert), Jukeme, J.W. (J. Wouter), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Cupples, L.A. (Adrienne), Marshall, C.R. (Christian), Pinto, D. (Duane), Sato, D.K. (DaisUnited Kingdome), Scherer, S.W. (Stephen), Reeve, J. (Jonathan), Thorsteinsdottir, U. (Unnur), Karasik, D. (David), Richards, J.B. (Brent), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Oei, L. (Ling), Hsu, Y.-H. (Yi-Hsiang), Styrkarsdottir, U. (Unnur), Eussen, H.J.F.M.M. (Bert), Klein, J.E.M.M. (Annelies) de, Peters, M.J. (Marjolein), Halldorsson, B.V. (Bjarni), Liu, C.-T. (Ching-Ti), Alonso, N. (Nerea), Kaptoge, S. (Stephen), Thorleifsson, G. (Gudmar), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Kingdom, M.K. (Marcin KrUnited), Lewis, J.R. (Joshua), Patel, M.S. (Millan), Scollen, S. (Serena), Svensson, O. (Olle), Trompet, S. (Stella), Schoor, N.M. (Natasja) van, Zhu, K. (Kun), Buckley, B.M. (Brendan M.), Cooper, C. (Charles), Ford, I. (Ian), Goltzman, D. (David), González-Macías, J. (Jesús), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Lorenc, R. (Roman), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Slagboom, P.E. (Eline), Garcia-Ibarbia, C. (Carmen), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Arp, P.P. (Pascal), Nandakumar, K. (Kannabiran), Palsson, S.T. (Stefan Th), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Zhou, Y. (Yanhua), Hofman, A. (Albert), Jukeme, J.W. (J. Wouter), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Cupples, L.A. (Adrienne), Marshall, C.R. (Christian), Pinto, D. (Duane), Sato, D.K. (DaisUnited Kingdome), Scherer, S.W. (Stephen), Reeve, J. (Jonathan), Thorsteinsdottir, U. (Unnur), Karasik, D. (David), Richards, J.B. (Brent), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), and Estrada Gil, K. (Karol)

Abstract

Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. Aim To identify CNVs associated with osteoporotic bone fracture risk. Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. Results A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10−5). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. Conclusions These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

Published
2014
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13. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Author

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

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.

Published
2012
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14. Large common deletions associate with mortality at old age

Author

Kuningas, M. (Maris), Estrada Gil, K. (Karol), Hsu, Y.-H. (Yi-Hsiang), Nandakumar, K. (Kannabiran), Uitterlinden, A.G. (André), Lunetta, K.L. (Kathryn), Tikka-Kleemola, P. (Päivi), Karasik, D. (David), Hofman, A. (Albert), Murabito, J. (Joanne), Rivadeneira Ramirez, F. (Fernando), Kiel, D.P. (Douglas), Tiemeier, H.W. (Henning), Kuningas, M. (Maris), Estrada Gil, K. (Karol), Hsu, Y.-H. (Yi-Hsiang), Nandakumar, K. (Kannabiran), Uitterlinden, A.G. (André), Lunetta, K.L. (Kathryn), Tikka-Kleemola, P. (Päivi), Karasik, D. (David), Hofman, A. (Albert), Murabito, J. (Joanne), Rivadeneira Ramirez, F. (Fernando), Kiel, D.P. (Douglas), and Tiemeier, H.W. (Henning)

Abstract

Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed the total burden of rare (frequency <1%) and common (frequency >1%) CNVs for association with mortality during follow-up. These analyses were repeated by stratifying CNVs by type and size. Secondly, we assessed individual comm

Published
2011
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