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Author (up) Helgeland, O.; Hertel, J.K.; Molven, A.; Raeder, H.; Platou, C.G.P.; Midthjell, K.; Hveem, K.; Nygard, O.; Njolstad, P.R.; Johansson, S. url  doi
  Title The Chromosome 9p21 CVD- and T2D-Associated Regions in a Norwegian Population (The HUNT2 Survey) Type Journal Article
  Year 2015 Publication International Journal of Endocrinology Abbreviated Journal Int J Endocrinol  
  Volume 2015 Issue Pages 164652  
  Keywords HUNT2  
  Abstract Background. Two adjacent regions upstream CDKN2B on chromosome 9p21 have been associated with type 2 diabetes (T2D) and progression of cardiovascular disease (CVD). The precise location and number of risk variants have not been completely delineated and a possible synergistic relationship between the adjacent regions is not fully addressed. By a population based cross-sectional case-control design, we genotyped 18 SNPs upstream of CDKN2B tagging 138 kb in and around two LD-blocks associated with CVD and T2D and investigated associations with T2D, angina pectoris (AP), myocardial infarction (MI), coronary heart disease (CHD; AP or AMI), and stroke using 5,564 subjects from HUNT2. Results. Single point and haplotype analysis showed evidence for only one common T2D risk haplotype (rs10757282mid R:rs10811661: OR = 1.19, P = 2.0 x 10(-3)) in the region. We confirmed the strong association between SNPs in the 60 kb CVD region with AP, MI, and CHD (P < 0.01). Conditioning on the lead SNPs in the region, we observed two suggestive independent single SNP association signals for MI, rs2065501 (P = 0.03) and rs3217986 (P = 0.04). Conclusions. We confirmed the association of known variants within the 9p21 interval with T2D and CHD. Our results further suggest that additional CHD susceptibility variants exist in this region.  
  Address KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway ; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1687-8337 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:26089876; PMC4451520 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1714  
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Author (up) Marouli, E.; Graff, M.; Medina-Gomez, C.; Lo, K.S.; Wood, A.R.; Kjaer, T.R.; Fine, R.S.; Lu, Y.; Schurmann, C.; Highland, H.M.; Rueger, S.; Thorleifsson, G.; Justice, A.E.; Lamparter, D.; Stirrups, K.E.; Turcot, V.; Young, K.L.; Winkler, T.W.; Esko, T.; Karaderi, T.; Locke, A.E.; Masca, N.G.D.; Ng, M.C.Y.; Mudgal, P.; Rivas, M.A.; Vedantam, S.; Mahajan, A.; Guo, X.; Abecasis, G.; Aben, K.K.; Adair, L.S.; Alam, D.S.; Albrecht, E.; Allin, K.H.; Allison, M.; Amouyel, P.; Appel, E.V.; Arveiler, D.; Asselbergs, F.W.; Auer, P.L.; Balkau, B.; Banas, B.; Bang, L.E.; Benn, M.; Bergmann, S.; Bielak, L.F.; Bluher, M.; Boeing, H.; Boerwinkle, E.; Boger, C.A.; Bonnycastle, L.L.; Bork-Jensen, J.; Bots, M.L.; Bottinger, E.P.; Bowden, D.W.; Brandslund, I.; Breen, G.; Brilliant, M.H.; Broer, L.; Burt, A.A.; Butterworth, A.S.; Carey, D.J.; Caulfield, M.J.; Chambers, J.C.; Chasman, D.I.; Chen, Y.-D.I.; Chowdhury, R.; Christensen, C.; Chu, A.Y.; Cocca, M.; Collins, F.S.; Cook, J.P.; Corley, J.; Galbany, J.C.; Cox, A.J.; Cuellar-Partida, G.; Danesh, J.; Davies, G.; de Bakker, P.I.W.; de Borst, G.J.; de Denus, S.; de Groot, M.C.H.; de Mutsert, R.; Deary, I.J.; Dedoussis, G.; Demerath, E.W.; den Hollander, A.I.; Dennis, J.G.; Di Angelantonio, E.; Drenos, F.; Du, M.; Dunning, A.M.; Easton, D.F.; Ebeling, T.; Edwards, T.L.; Ellinor, P.T.; Elliott, P.; Evangelou, E.; Farmaki, A.-E.; Faul, J.D.; Feitosa, M.F.; Feng, S.; Ferrannini, E.; Ferrario, M.M.; Ferrieres, J.; Florez, J.C.; Ford, I.; Fornage, M.; Franks, P.W.; Frikke-Schmidt, R.; Galesloot, T.E.; Gan, W.; Gandin, I.; Gasparini, P.; Giedraitis, V.; Giri, A.; Girotto, G.; Gordon, S.D.; Gordon-Larsen, P.; Gorski, M.; Grarup, N.; Grove, M.L.; Gudnason, V.; Gustafsson, S.; Hansen, T.; Harris, K.M.; Harris, T.B.; Hattersley, A.T.; Hayward, C.; He, L.; Heid, I.M.; Heikkila, K.; Helgeland, O.; Hernesniemi, J.; Hewitt, A.W.; Hocking, L.J.; Hollensted, M.; Holmen, O.L.; Hovingh, G.K.; Howson, J.M.M.; Hoyng, C.B.; Huang, P.L.; Hveem, K.; Ikram, M.A.; Ingelsson, E.; Jackson, A.U.; Jansson, J.-H.; Jarvik, G.P.; Jensen, G.B.; Jhun, M.A.; Jia, Y.; Jiang, X.; Johansson, S.; Jorgensen, M.E.; Jorgensen, T.; Jousilahti, P.; Jukema, J.W.; Kahali, B.; Kahn, R.S.; Kahonen, M.; Kamstrup, P.R.; Kanoni, S.; Kaprio, J.; Karaleftheri, M.; Kardia, S.L.R.; Karpe, F.; Kee, F.; Keeman, R.; Kiemeney, L.A.; Kitajima, H.; Kluivers, K.B.; Kocher, T.; Komulainen, P.; Kontto, J.; Kooner, J.S.; Kooperberg, C.; Kovacs, P.; Kriebel, J.; Kuivaniemi, H.; Kury, S.; Kuusisto, J.; La Bianca, M.; Laakso, M.; Lakka, T.A.; Lange, E.M.; Lange, L.A.; Langefeld, C.D.; Langenberg, C.; Larson, E.B.; Lee, I.-T.; Lehtimaki, T.; Lewis, C.E.; Li, H.; Li, J.; Li-Gao, R.; Lin, H.; Lin, L.-A.; Lin, X.; Lind, L.; Lindstrom, J.; Linneberg, A.; Liu, Y.; Liu, Y.; Lophatananon, A.; Luan, J.'an; Lubitz, S.A.; Lyytikainen, L.-P.; Mackey, D.A.; Madden, P.A.F.; Manning, A.K.; Mannisto, S.; Marenne, G.; Marten, J.; Martin, N.G.; Mazul, A.L.; Meidtner, K.; Metspalu, A.; Mitchell, P.; Mohlke, K.L.; Mook-Kanamori, D.O.; Morgan, A.; Morris, A.D.; Morris, A.P.; Muller-Nurasyid, M.; Munroe, P.B.; Nalls, M.A.; Nauck, M.; Nelson, C.P.; Neville, M.; Nielsen, S.F.; Nikus, K.; Njolstad, P.R.; Nordestgaard, B.G.; Ntalla, I.; O'Connel, J.R.; Oksa, H.; Loohuis, L.M.O.; Ophoff, R.A.; Owen, K.R.; Packard, C.J.; Padmanabhan, S.; Palmer, C.N.A.; Pasterkamp, G.; Patel, A.P.; Pattie, A.; Pedersen, O.; Peissig, P.L.; Peloso, G.M.; Pennell, C.E.; Perola, M.; Perry, J.A.; Perry, J.R.B.; Person, T.N.; Pirie, A.; Polasek, O.; Posthuma, D.; Raitakari, O.T.; Rasheed, A.; Rauramaa, R.; Reilly, D.F.; Reiner, A.P.; Renstrom, F.; Ridker, P.M.; Rioux, J.D.; Robertson, N.; Robino, A.; Rolandsson, O.; Rudan, I.; Ruth, K.S.; Saleheen, D.; Salomaa, V.; Samani, N.J.; Sandow, K.; Sapkota, Y.; Sattar, N.; Schmidt, M.K.; Schreiner, P.J.; Schulze, M.B.; Scott, R.A.; Segura-Lepe, M.P.; Shah, S.; Sim, X.; Sivapalaratnam, S.; Small, K.S.; Smith, A.V.; Smith, J.A.; Southam, L.; Spector, T.D.; Speliotes, E.K.; Starr, J.M.; Steinthorsdottir, V.; Stringham, H.M.; Stumvoll, M.; Surendran, P.; 't Hart, L.M.; Tansey, K.E.; Tardif, J.-C.; Taylor, K.D.; Teumer, A.; Thompson, D.J.; Thorsteinsdottir, U.; Thuesen, B.H.; Tonjes, A.; Tromp, G.; Trompet, S.; Tsafantakis, E.; Tuomilehto, J.; Tybjaerg-Hansen, A.; Tyrer, J.P.; Uher, R.; Uitterlinden, A.G.; Ulivi, S.; van der Laan, S.W.; Van Der Leij, A.R.; van Duijn, C.M.; van Schoor, N.M.; van Setten, J.; Varbo, A.; Varga, T.V.; Varma, R.; Edwards, D.R.V.; Vermeulen, S.H.; Vestergaard, H.; Vitart, V.; Vogt, T.F.; Vozzi, D.; Walker, M.; Wang, F.; Wang, C.A.; Wang, S.; Wang, Y.; Wareham, N.J.; Warren, H.R.; Wessel, J.; Willems, S.M.; Wilson, J.G.; Witte, D.R.; Woods, M.O.; Wu, Y.; Yaghootkar, H.; Yao, J.; Yao, P.; Yerges-Armstrong, L.M.; Young, R.; Zeggini, E.; Zhan, X.; Zhang, W.; Zhao, J.H.; Zhao, W.; Zhao, W.; Zheng, H.; Zhou, W.; Rotter, J.I.; Boehnke, M.; Kathiresan, S.; McCarthy, M.I.; Willer, C.J.; Stefansson, K.; Borecki, I.B.; Liu, D.J.; North, K.E.; Heard-Costa, N.L.; Pers, T.H.; Lindgren, C.M.; Oxvig, C.; Kutalik, Z.; Rivadeneira, F.; Loos, R.J.F.; Frayling, T.M.; Hirschhorn, J.N.; Deloukas, P.; Lettre, G. url  doi
  Title Rare and low-frequency coding variants alter human adult height Type Journal Article
  Year 2017 Publication Nature Abbreviated Journal Nature  
  Volume 542 Issue 7640 Pages 186-190  
  Keywords ADAMTS Proteins/genetics; Adult; Alleles; Body Height/*genetics; Cell Adhesion Molecules/genetics; Female; Gene Frequency/*genetics; Genetic Variation/*genetics; Genome, Human/genetics; Glycoproteins/genetics/metabolism; Glycosaminoglycans/biosynthesis; Hedgehog Proteins/genetics; Humans; Intercellular Signaling Peptides and Proteins/genetics/metabolism; Interferon Regulatory Factors/genetics; Interleukin-11 Receptor alpha Subunit/genetics; Male; Multifactorial Inheritance/genetics; NADPH Oxidase 4; NADPH Oxidases/genetics; Phenotype; Pregnancy-Associated Plasma Protein-A/metabolism; Procollagen N-Endopeptidase/genetics; Proteoglycans/biosynthesis; Proteolysis; Receptors, Androgen/genetics; Somatomedins/metabolism  
  Abstract Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.  
  Address Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal, Quebec, H3T 1J4, Canada  
  Corporate Author MAGIC Investigators Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0028-0836 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28146470; PMCID:PMC5302847 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1953  
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