Browsing by Author "Reppe, Sjur"

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    Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus
    (Nature Publishing Group, 2017-07-25) Medina-Gomez, Carolina; Kemp, John P.; Dimou, Niki L.; Kreiner, Eskil; Chesi, Alessandra; Zemel, Babette S.; Bønnelykke, Klaus; Boer, Cindy G.; Ahluwalia, Tarunveer S.; Bisgaard, Hans; Evangelou, Evangelos; Heppe, Denise H.M.; Bonewald, Lynda F.; Gorski, Jeffrey P.; Ghanbari, Mohsen; Demissie, Serkalem; Duque, Gustavo; Maurano, Matthew T.; Kiel, Douglas P.; Hsu, Yi-Hsiang; Eerden, Bram C.J. van der; Ackert-Bicknell, Cheryl; Reppe, Sjur; Gautvik, Kaare M.; Raastad, Truls; Karasik, David; Peppel, Jeroen van de; Jaddoe, Vincent W.V.; Uitterlinden, André G.; Tobias, Jonathan H.; Grant, Struan F.A.; Bagos, Pantelis G.; Evans, David M.; Rivadeneira, Fernando; Anatomy and Cell Biology, School of Medicine
    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% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). 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.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.
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    Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry
    (Wiley, 2019-07) Hsu, Yi-Hsiang; Estrada, Karol; Evangelou, Evangelos; Ackert-Bicknell, Cheryl; Akesson, Kristina; Beck, Thomas; Brown, Suzanne J.; Capellini, Terence; Carbone, Laura; Cauley, Jane; Cheung, Ching-Lung; Cummings, Steven R.; Czerwinski, Stefan; Demissie, Serkalem; Econs, Michael; Evans, Daniel; Farber, Charles; Gautvik, Kaare; Harris, Tamara; Kammerer, Candace; Kemp, John; Koller, Daniel L.; Kung, Annie; Lawlor, Debbie; Lee, Miryoung; Lorentzon, Mattias; McGuigan, Fiona; Medina-Gomez, Carolina; Mitchell, Braxton; Newman, Anne; Nielson, Carrie; Ohlsson, Claes; Peacock, Munro; Reppe, Sjur; Richards, J. Brent; Robbins, John; Sigurdsson, Gunnar; Spector, Timothy D.; Stefansson, Kari; Streeten, Elizabeth; Styrkarsdottir, Unnur; Tobias, Jonathan; Trajanoska, Katerina; Uitterlinden, André; Vandenput, Liesbeth; Wilson, Scott G.; Yerges-Armstrong, Laura; Young, Mariel; Zillikens, Carola; Rivadeneira, Fernando; Kiel, Douglas P.; Karasik, David; Medicine, School of Medicine
    Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility.