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Author (up) Ferreira, M.A.; Vonk, J.M.; Baurecht, H.; Marenholz, I.; Tian, C.; Hoffman, J.D.; Helmer, Q.; Tillander, A.; Ullemar, V.; van Dongen, J.; Lu, Y.; Ruschendorf, F.; Esparza-Gordillo, J.; Medway, C.W.; Mountjoy, E.; Burrows, K.; Hummel, O.; Grosche, S.; Brumpton, B.M.; Witte, J.S.; Hottenga, J.-J.; Willemsen, G.; Zheng, J.; Rodriguez, E.; Hotze, M.; Franke, A.; Revez, J.A.; Beesley, J.; Matheson, M.C.; Dharmage, S.C.; Bain, L.M.; Fritsche, L.G.; Gabrielsen, M.E.; Balliu, B.; Nielsen, J.B.; Zhou, W.; Hveem, K.; Langhammer, A.; Holmen, O.L.; Loset, M.; Abecasis, G.R.; Willer, C.J.; Arnold, A.; Homuth, G.; Schmidt, C.O.; Thompson, P.J.; Martin, N.G.; Duffy, D.L.; Novak, N.; Schulz, H.; Karrasch, S.; Gieger, C.; Strauch, K.; Melles, R.B.; Hinds, D.A.; Hubner, N.; Weidinger, S.; Magnusson, P.K.E.; Jansen, R.; Jorgenson, E.; Lee, Y.-A.; Boomsma, D.I.; Almqvist, C.; Karlsson, R.; Koppelman, G.H.; Paternoster, L. url  doi
  Title Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology Type Meta-Analysis
  Year 2017 Publication Nature Genetics Abbreviated Journal Nat Genet  
  Volume 49 Issue 12 Pages 1752-1757  
  Keywords Asthma/*genetics; Eczema/*genetics; Genetic Predisposition to Disease/*genetics; Genome-Wide Association Study/methods; Humans; Hypersensitivity/*genetics; Phenotype; Polymorphism, Single Nucleotide; Rhinitis, Allergic, Seasonal/*genetics; Risk Factors  
  Abstract Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 x 10(-8)), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.  
  Address MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK  
  Corporate Author LifeLines Cohort Study 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 1061-4036 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:29083406 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1903  
Permanent link to this record
 

 
Author (up) Gusarova, V.; O'Dushlaine, C.; Teslovich, T.M.; Benotti, P.N.; Mirshahi, T.; Gottesman, O.; Van Hout, C.V.; Murray, M.F.; Mahajan, A.; Nielsen, J.B.; Fritsche, L.; Wulff, A.B.; Gudbjartsson, D.F.; Sjogren, M.; Emdin, C.A.; Scott, R.A.; Lee, W.-J.; Small, A.; Kwee, L.C.; Dwivedi, O.P.; Prasad, R.B.; Bruse, S.; Lopez, A.E.; Penn, J.; Marcketta, A.; Leader, J.B.; Still, C.D.; Kirchner, H.L.; Mirshahi, U.L.; Wardeh, A.H.; Hartle, C.M.; Habegger, L.; Fetterolf, S.N.; Tusie-Luna, T.; Morris, A.P.; Holm, H.; Steinthorsdottir, V.; Sulem, P.; Thorsteinsdottir, U.; Rotter, J.I.; Chuang, L.-M.; Damrauer, S.; Birtwell, D.; Brummett, C.M.; Khera, A.V.; Natarajan, P.; Orho-Melander, M.; Flannick, J.; Lotta, L.A.; Willer, C.J.; Holmen, O.L.; Ritchie, M.D.; Ledbetter, D.H.; Murphy, A.J.; Borecki, I.B.; Reid, J.G.; Overton, J.D.; Hansson, O.; Groop, L.; Shah, S.H.; Kraus, W.E.; Rader, D.J.; Chen, Y.-D.I.; Hveem, K.; Wareham, N.J.; Kathiresan, S.; Melander, O.; Stefansson, K.; Nordestgaard, B.G.; Tybjaerg-Hansen, A.; Abecasis, G.R.; Altshuler, D.; Florez, J.C.; Boehnke, M.; McCarthy, M.I.; Yancopoulos, G.D.; Carey, D.J.; Shuldiner, A.R.; Baras, A.; Dewey, F.E.; Gromada, J. url  doi
  Title Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes Type Journal Article
  Year 2018 Publication Nature Communications Abbreviated Journal Nat Commun  
  Volume 9 Issue 1 Pages 2252  
  Keywords Amino Acid Substitution; Angiopoietin-like 4 Protein/*deficiency/*genetics/metabolism; Animals; Blood Glucose/metabolism; Case-Control Studies; Diabetes Mellitus, Type 2/etiology/*genetics/*metabolism; Female; Gene Silencing; Genetic Association Studies; Genetic Variation; Heterozygote; Homeostasis; Humans; Insulin Resistance/genetics; Lipoprotein Lipase/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Risk Factors; Whole Exome Sequencing  
  Abstract Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 x 10(-10)), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.  
  Address Regeneron Pharmaceuticals, Tarrytown, 10591, NY, USA. jesper.gromada@regeneron.com  
  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 2041-1723 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:29899519; PMCID:PMC5997992 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 2086  
Permanent link to this record
 

 
Author (up) Helgadottir, A.; Thorleifsson, G.; Gretarsdottir, S.; Stefansson, O.A.; Tragante, V.; Thorolfsdottir, R.B.; Jonsdottir, I.; Bjornsson, T.; Steinthorsdottir, V.; Verweij, N.; Nielsen, J.B.; Zhou, W.; Folkersen, L.; Martinsson, A.; Heydarpour, M.; Prakash, S.; Oskarsson, G.; Gudbjartsson, T.; Geirsson, A.; Olafsson, I.; Sigurdsson, E.L.; Almgren, P.; Melander, O.; Franco-Cereceda, A.; Hamsten, A.; Fritsche, L.; Lin, M.; Yang, B.; Hornsby, W.; Guo, D.; Brummett, C.M.; Abecasis, G.; Mathis, M.; Milewicz, D.; Body, S.C.; Eriksson, P.; Willer, C.J.; Hveem, K.; Newton-Cheh, C.; Smith, J.G.; Danielsen, R.; Thorgeirsson, G.; Thorsteinsdottir, U.; Gudbjartsson, D.F.; Holm, H.; Stefansson, K. url  doi
  Title Genome-wide analysis yields new loci associating with aortic valve stenosis Type Journal Article
  Year 2018 Publication Nature Communications Abbreviated Journal Nat Commun  
  Volume 9 Issue 1 Pages 987  
  Keywords Aortic Valve Stenosis/*genetics; Case-Control Studies; Coronary Artery Disease/genetics; Genome-Wide Association Study; Humans; Phenotype; Risk Factors  
  Abstract Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 x 10(-22)) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 x 10(-13)). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 x 10(-10)) and aortic root diameter (P = 1.30 x 10(-8)), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 x 10(-3)) and coronary artery disease (OR = 1.05, P = 9.3 x 10(-5)). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.  
  Address Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. kstefans@decode.is  
  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 2041-1723 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:29511194; PMCID:PMC5840367 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 2093  
Permanent link to this record
 

 
Author (up) Liu, D.J.; Peloso, G.M.; Yu, H.; Butterworth, A.S.; Wang, X.; Mahajan, A.; Saleheen, D.; Emdin, C.; Alam, D.; Alves, A.C.; Amouyel, P.; Di Angelantonio, E.; Arveiler, D.; Assimes, T.L.; Auer, P.L.; Baber, U.; Ballantyne, C.M.; Bang, L.E.; Benn, M.; Bis, J.C.; Boehnke, M.; Boerwinkle, E.; Bork-Jensen, J.; Bottinger, E.P.; Brandslund, I.; Brown, M.; Busonero, F.; Caulfield, M.J.; Chambers, J.C.; Chasman, D.I.; Chen, Y.E.; Chen, Y.-D.I.; Chowdhury, R.; Christensen, C.; Chu, A.Y.; Connell, J.M.; Cucca, F.; Cupples, L.A.; Damrauer, S.M.; Davies, G.; Deary, I.J.; Dedoussis, G.; Denny, J.C.; Dominiczak, A.; Dube, M.-P.; Ebeling, T.; Eiriksdottir, G.; Esko, T.; Farmaki, A.-E.; Feitosa, M.F.; Ferrario, M.; Ferrieres, J.; Ford, I.; Fornage, M.; Franks, P.W.; Frayling, T.M.; Frikke-Schmidt, R.; Fritsche, L.G.; Frossard, P.; Fuster, V.; Ganesh, S.K.; Gao, W.; Garcia, M.E.; Gieger, C.; Giulianini, F.; Goodarzi, M.O.; Grallert, H.; Grarup, N.; Groop, L.; Grove, M.L.; Gudnason, V.; Hansen, T.; Harris, T.B.; Hayward, C.; Hirschhorn, J.N.; Holmen, O.L.; Huffman, J.; Huo, Y.; Hveem, K.; Jabeen, S.; Jackson, A.U.; Jakobsdottir, J.; Jarvelin, M.-R.; Jensen, G.B.; Jorgensen, M.E.; Jukema, J.W.; Justesen, J.M.; Kamstrup, P.R.; Kanoni, S.; Karpe, F.; Kee, F.; Khera, A.V.; Klarin, D.; Koistinen, H.A.; Kooner, J.S.; Kooperberg, C.; Kuulasmaa, K.; Kuusisto, J.; Laakso, M.; Lakka, T.; Langenberg, C.; Langsted, A.; Launer, L.J.; Lauritzen, T.; Liewald, D.C.M.; Lin, L.A.; Linneberg, A.; Loos, R.J.F.; Lu, Y.; Lu, X.; Magi, R.; Malarstig, A.; Manichaikul, A.; Manning, A.K.; Mantyselka, P.; Marouli, E.; Masca, N.G.D.; Maschio, A.; Meigs, J.B.; Melander, O.; Metspalu, A.; Morris, A.P.; Morrison, A.C.; Mulas, A.; Muller-Nurasyid, M.; Munroe, P.B.; Neville, M.J.; Nielsen, J.B.; Nielsen, S.F.; Nordestgaard, B.G.; Ordovas, J.M.; Mehran, R.; O'Donnell, C.J.; Orho-Melander, M.; Molony, C.M.; Muntendam, P.; Padmanabhan, S.; Palmer, C.N.A.; Pasko, D.; Patel, A.P.; Pedersen, O.; Perola, M.; Peters, A.; Pisinger, C.; Pistis, G.; Polasek, O.; Poulter, N.; Psaty, B.M.; Rader, D.J.; Rasheed, A.; Rauramaa, R.; Reilly, D.F.; Reiner, A.P.; Renstrom, F.; Rich, S.S.; Ridker, P.M.; Rioux, J.D.; Robertson, N.R.; Roden, D.M.; Rotter, J.I.; Rudan, I.; Salomaa, V.; Samani, N.J.; Sanna, S.; Sattar, N.; Schmidt, E.M.; Scott, R.A.; Sever, P.; Sevilla, R.S.; Shaffer, C.M.; Sim, X.; Sivapalaratnam, S.; Small, K.S.; Smith, A.V.; Smith, B.H.; Somayajula, S.; Southam, L.; Spector, T.D.; Speliotes, E.K.; Starr, J.M.; Stirrups, K.E.; Stitziel, N.; Strauch, K.; Stringham, H.M.; Surendran, P.; Tada, H.; Tall, A.R.; Tang, H.; Tardif, J.-C.; Taylor, K.D.; Trompet, S.; Tsao, P.S.; Tuomilehto, J.; Tybjaerg-Hansen, A.; van Zuydam, N.R.; Varbo, A.; Varga, T.V.; Virtamo, J.; Waldenberger, M.; Wang, N.; Wareham, N.J.; Warren, H.R.; Weeke, P.E.; Weinstock, J.; Wessel, J.; Wilson, J.G.; Wilson, P.W.F.; Xu, M.; Yaghootkar, H.; Young, R.; Zeggini, E.; Zhang, H.; Zheng, N.S.; Zhang, W.; Zhang, Y.; Zhou, W.; Zhou, Y.; Zoledziewska, M.; Howson, J.M.M.; Danesh, J.; McCarthy, M.I.; Cowan, C.A.; Abecasis, G.; Deloukas, P.; Musunuru, K.; Willer, C.J.; Kathiresan, S. url  doi
  Title Exome-wide association study of plasma lipids in >300,000 individuals Type Journal Article
  Year 2017 Publication Nature Genetics Abbreviated Journal Nat Genet  
  Volume 49 Issue 12 Pages 1758-1766  
  Keywords Coronary Artery Disease/blood/genetics; Diabetes Mellitus, Type 2/blood/genetics; Exome/*genetics; Genetic Association Studies/*methods; Genetic Predisposition to Disease/genetics; *Genetic Variation; Genotype; Humans; Lipids/*blood; Macular Degeneration/blood/genetics; Phenotype; Risk Factors  
  Abstract We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.  
  Address Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA  
  Corporate Author VA Million Veteran Program 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 1061-4036 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:29083408; PMCID:PMC5709146 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1943  
Permanent link to this record
 

 
Author (up) Lu, X.; Peloso, G.M.; Liu, D.J.; Wu, Y.; Zhang, H.; Zhou, W.; Li, J.; Tang, C.S.-M.; Dorajoo, R.; Li, H.; Long, J.; Guo, X.; Xu, M.; Spracklen, C.N.; Chen, Y.; Liu, X.; Zhang, Y.; Khor, C.C.; Liu, J.; Sun, L.; Wang, L.; Gao, Y.-T.; Hu, Y.; Yu, K.; Wang, Y.; Cheung, C.Y.Y.; Wang, F.; Huang, J.; Fan, Q.; Cai, Q.; Chen, S.; Shi, J.; Yang, X.; Zhao, W.; Sheu, W.H.-H.; Cherny, S.S.; He, M.; Feranil, A.B.; Adair, L.S.; Gordon-Larsen, P.; Du, S.; Varma, R.; Chen, Y.-D.I.; Shu, X.-O.; Lam, K.S.L.; Wong, T.Y.; Ganesh, S.K.; Mo, Z.; Hveem, K.; Fritsche, L.G.; Nielsen, J.B.; Tse, H.-F.; Huo, Y.; Cheng, C.-Y.; Chen, Y.E.; Zheng, W.; Tai, E.S.; Gao, W.; Lin, X.; Huang, W.; Abecasis, G.; Kathiresan, S.; Mohlke, K.L.; Wu, T.; Sham, P.C.; Gu, D.; Willer, C.J. url  doi
  Title Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease Type Meta-Analysis
  Year 2017 Publication Nature Genetics Abbreviated Journal Nat Genet  
  Volume 49 Issue 12 Pages 1722-1730  
  Keywords Asian Continental Ancestry Group/genetics; Coronary Artery Disease/ethnology/*genetics; Europe; European Continental Ancestry Group/genetics; Exome/*genetics; Far East; Gene Frequency; Genetic Predisposition to Disease/ethnology/*genetics; *Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Lipid Metabolism/*genetics; Lipids/analysis  
  Abstract Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.  
  Address Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA  
  Corporate Author GLGC Consortium 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 1061-4036 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:29083407 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1957  
Permanent link to this record
 

 
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  
Permanent link to this record
 

 
Author (up) Nielsen, J.B.; Fritsche, L.G.; Zhou, W.; Teslovich, T.M.; Holmen, O.L.; Gustafsson, S.; Gabrielsen, M.E.; Schmidt, E.M.; Beaumont, R.; Wolford, B.N.; Lin, M.; Brummett, C.M.; Preuss, M.H.; Refsgaard, L.; Bottinger, E.P.; Graham, S.E.; Surakka, I.; Chu, Y.; Skogholt, A.H.; Dalen, H.; Boyle, A.P.; Oral, H.; Herron, T.J.; Kitzman, J.; Jalife, J.; Svendsen, J.H.; Olesen, M.S.; Njolstad, I.; Lochen, M.-L.; Baras, A.; Gottesman, O.; Marcketta, A.; O'Dushlaine, C.; Ritchie, M.D.; Wilsgaard, T.; Loos, R.J.F.; Frayling, T.M.; Boehnke, M.; Ingelsson, E.; Carey, D.J.; Dewey, F.E.; Kang, H.M.; Abecasis, G.R.; Hveem, K.; Willer, C.J. url  doi
  Title Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development Type Journal Article
  Year 2018 Publication American Journal of Human Genetics Abbreviated Journal Am J Hum Genet  
  Volume 102 Issue 1 Pages 103-115  
  Keywords Atrial Fibrillation/*genetics; *Genetic Loci; *Genetic Predisposition to Disease; *Genome-Wide Association Study; Heart/*embryology; Humans; Inheritance Patterns/genetics; Multifactorial Inheritance/genetics; Organ Specificity/genetics; Physical Chromosome Mapping; Quantitative Trait Loci/genetics; Regulatory Sequences, Nucleic Acid/*genetics; Reproducibility of Results; Risk Factors; *Cdkn2c; *Dmrta2; *Gwas; *Ttn; *atrial fibrillation; *cardiomyopathy; *fetal; *genetic risk score; *heart; *pathway  
  Abstract Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 x 10(-18)) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 x 10(-11)) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.  
  Address Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: cristen@umich.edu  
  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 0002-9297 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:29290336; PMCID:PMC5777936 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 2143  
Permanent link to this record
 

 
Author (up) Nielsen, J.B.; Thorolfsdottir, R.B.; Fritsche, L.G.; Zhou, W.; Skov, M.W.; Graham, S.E.; Herron, T.J.; McCarthy, S.; Schmidt, E.M.; Sveinbjornsson, G.; Surakka, I.; Mathis, M.R.; Yamazaki, M.; Crawford, R.D.; Gabrielsen, M.E.; Skogholt, A.H.; Holmen, O.L.; Lin, M.; Wolford, B.N.; Dey, R.; Dalen, H.; Sulem, P.; Chung, J.H.; Backman, J.D.; Arnar, D.O.; Thorsteinsdottir, U.; Baras, A.; O'Dushlaine, C.; Holst, A.G.; Wen, X.; Hornsby, W.; Dewey, F.E.; Boehnke, M.; Kheterpal, S.; Mukherjee, B.; Lee, S.; Kang, H.M.; Holm, H.; Kitzman, J.; Shavit, J.A.; Jalife, J.; Brummett, C.M.; Teslovich, T.M.; Carey, D.J.; Gudbjartsson, D.F.; Stefansson, K.; Abecasis, G.R.; Hveem, K.; Willer, C.J. url  doi
  Title Biobank-driven genomic discovery yields new insight into atrial fibrillation biology Type Journal Article
  Year 2018 Publication Nature Genetics Abbreviated Journal Nat Genet  
  Volume 50 Issue 9 Pages 1234-1239  
  Keywords  
  Abstract To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5)(1), or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an 'atrial cardiomyopathy'(2), either during fetal heart development or as a response to stress in the adult heart.  
  Address Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. cristen@umich.edu  
  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 1061-4036 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:30061737 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 2144  
Permanent link to this record
 

 
Author (up) Zhou, W.; Fritsche, L.G.; Das, S.; Zhang, H.; Nielsen, J.B.; Holmen, O.L.; Chen, J.; Lin, M.; Elvestad, M.B.; Hveem, K.; Abecasis, G.R.; Kang, H.M.; Willer, C.J. url  doi
  Title Improving power of association tests using multiple sets of imputed genotypes from distributed reference panels Type Journal Article
  Year 2017 Publication Genetic Epidemiology Abbreviated Journal Genet Epidemiol  
  Volume 41 Issue 8 Pages 744-755  
  Keywords Gwas; genotype imputation; multiple reference panels; population-specific; study power  
  Abstract The accuracy of genotype imputation depends upon two factors: the sample size of the reference panel and the genetic similarity between the reference panel and the target samples. When multiple reference panels are not consented to combine together, it is unclear how to combine the imputation results to optimize the power of genetic association studies. We compared the accuracy of 9,265 Norwegian genomes imputed from three reference panels-1000 Genomes phase 3 (1000G), Haplotype Reference Consortium (HRC), and a reference panel containing 2,201 Norwegian participants from the population-based Nord Trondelag Health Study (HUNT) from low-pass genome sequencing. We observed that the population-matched reference panel allowed for imputation of more population-specific variants with lower frequency (minor allele frequency (MAF) between 0.05% and 0.5%). The overall imputation accuracy from the population-specific panel was substantially higher than 1000G and was comparable with HRC, despite HRC being 15-fold larger. These results recapitulate the value of population-specific reference panels for genotype imputation. We also evaluated different strategies to utilize multiple sets of imputed genotypes to increase the power of association studies. We observed that testing association for all variants imputed from any panel results in higher power to detect association than the alternative strategy of including only one version of each genetic variant, selected for having the highest imputation quality metric. This was particularly true for lower frequency variants (MAF < 1%), even after adjusting for the additional multiple testing burden.  
  Address Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America  
  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 0741-0395 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28861891 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 2026  
Permanent link to this record
 

 
Author (up) Zhou, W.; Nielsen, J.B.; Fritsche, L.G.; Dey, R.; Gabrielsen, M.E.; Wolford, B.N.; LeFaive, J.; VandeHaar, P.; Gagliano, S.A.; Gifford, A.; Bastarache, L.A.; Wei, W.-Q.; Denny, J.C.; Lin, M.; Hveem, K.; Kang, H.M.; Abecasis, G.R.; Willer, C.J.; Lee, S. url  doi
  Title Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies Type Journal Article
  Year 2018 Publication Nature Genetics Abbreviated Journal Nat Genet  
  Volume 50 Issue 9 Pages 1335-1341  
  Keywords  
  Abstract In genome-wide association studies (GWAS) for thousands of phenotypes in large biobanks, most binary traits have substantially fewer cases than controls. Both of the widely used approaches, the linear mixed model and the recently proposed logistic mixed model, perform poorly; they produce large type I error rates when used to analyze unbalanced case-control phenotypes. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approximation to calibrate the distribution of score test statistics. This method, SAIGE (Scalable and Accurate Implementation of GEneralized mixed model), provides accurate P values even when case-control ratios are extremely unbalanced. SAIGE uses state-of-art optimization strategies to reduce computational costs; hence, it is applicable to GWAS for thousands of phenotypes by large biobanks. Through the analysis of UK Biobank data of 408,961 samples from white British participants with European ancestry for > 1,400 binary phenotypes, we show that SAIGE can efficiently analyze large sample data, controlling for unbalanced case-control ratios and sample relatedness.  
  Address Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA. leeshawn@umich.edu  
  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 1061-4036 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:30104761; PMCID:PMC6119127 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 2192  
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