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1. Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis.

Author: Scholz M, Horn K, Pott J, Gross A, Kleber ME, Delgado GE, Mishra PP, Kirsten H, Gieger C, Müller-Nurasyid M, Tönjes A, Kovacs P, Lehtimäki T, Raitakari O, Kähönen M, Gylling H, Baber R, Isermann B, Stumvoll M, Loeffler M, März W, Meitinger T, Peters A, Thiery J, Teupser D, and Ceglarek U
Subjects: ABO Blood-Group System blood, ABO Blood-Group System genetics, ATP Binding Cassette Transporter, Subfamily G, Member 5 blood, ATP Binding Cassette Transporter, Subfamily G, Member 5 genetics, ATP Binding Cassette Transporter, Subfamily G, Member 8 blood, ATP Binding Cassette Transporter, Subfamily G, Member 8 genetics, Adult, Apolipoproteins E blood, Apolipoproteins E genetics, Coronary Artery Disease blood, Coronary Artery Disease pathology, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl CoA Reductases blood, Hydroxymethylglutaryl CoA Reductases genetics, Lipase blood, Lipase genetics, Lipoproteins blood, Lipoproteins genetics, Male, Membrane Transport Proteins blood, Membrane Transport Proteins genetics, Mendelian Randomization Analysis, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Scavenger Receptors, Class B blood, Scavenger Receptors, Class B genetics, Cholesterol blood, Coronary Artery Disease genetics, Genetic Loci, Lipid Metabolism genetics, Phytosterols blood
Abstract: Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD., (© 2022. The Author(s).)
Published: 2022
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2. Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.

Author: Sabater-Lleal M, Huffman JE, de Vries PS, Marten J, Mastrangelo MA, Song C, Pankratz N, Ward-Caviness CK, Yanek LR, Trompet S, Delgado GE, Guo X, Bartz TM, Martinez-Perez A, Germain M, de Haan HG, Ozel AB, Polasek O, Smith AV, Eicher JD, Reiner AP, Tang W, Davies NM, Stott DJ, Rotter JI, Tofler GH, Boerwinkle E, de Maat MPM, Kleber ME, Welsh P, Brody JA, Chen MH, Vaidya D, Soria JM, Suchon P, van Hylckama Vlieg A, Desch KC, Kolcic I, Joshi PK, Launer LJ, Harris TB, Campbell H, Rudan I, Becker DM, Li JZ, Rivadeneira F, Uitterlinden AG, Hofman A, Franco OH, Cushman M, Psaty BM, Morange PE, McKnight B, Chong MR, Fernandez-Cadenas I, Rosand J, Lindgren A, Gudnason V, Wilson JF, Hayward C, Ginsburg D, Fornage M, Rosendaal FR, Souto JC, Becker LC, Jenny NS, März W, Jukema JW, Dehghan A, Trégouët DA, Morrison AC, Johnson AD, O'Donnell CJ, Strachan DP, Lowenstein CJ, and Smith NL
Subjects: Arterial Occlusive Diseases blood, Arterial Occlusive Diseases ethnology, Biomarkers blood, Blood Coagulation Disorders, Inherited blood, Blood Coagulation Disorders, Inherited ethnology, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Phenotype, Ribosomal Protein L3, Risk Factors, Venous Thrombosis blood, Venous Thrombosis ethnology, Arterial Occlusive Diseases genetics, Blood Coagulation genetics, Blood Coagulation Disorders, Inherited genetics, Factor VIII analysis, Genetic Loci, Venous Thrombosis genetics, von Willebrand Factor analysis
Abstract: Background: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF., Methods: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events., Results: We identified 13 novel genome-wide significant ( P≤2.5×10 -8 ) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk., Conclusions: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
Published: 2019
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3. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Author: Ligthart S, Vaez A, Võsa U, Stathopoulou MG, de Vries PS, Prins BP, Van der Most PJ, Tanaka T, Naderi E, Rose LM, Wu Y, Karlsson R, Barbalic M, Lin H, Pool R, Zhu G, Macé A, Sidore C, Trompet S, Mangino M, Sabater-Lleal M, Kemp JP, Abbasi A, Kacprowski T, Verweij N, Smith AV, Huang T, Marzi C, Feitosa MF, Lohman KK, Kleber ME, Milaneschi Y, Mueller C, Huq M, Vlachopoulou E, Lyytikäinen LP, Oldmeadow C, Deelen J, Perola M, Zhao JH, Feenstra B, Amini M, Lahti J, Schraut KE, Fornage M, Suktitipat B, Chen WM, Li X, Nutile T, Malerba G, Luan J, Bak T, Schork N, Del Greco M F, Thiering E, Mahajan A, Marioni RE, Mihailov E, Eriksson J, Ozel AB, Zhang W, Nethander M, Cheng YC, Aslibekyan S, Ang W, Gandin I, Yengo L, Portas L, Kooperberg C, Hofer E, Rajan KB, Schurmann C, den Hollander W, Ahluwalia TS, Zhao J, Draisma HHM, Ford I, Timpson N, Teumer A, Huang H, Wahl S, Liu Y, Huang J, Uh HW, Geller F, Joshi PK, Yanek LR, Trabetti E, Lehne B, Vozzi D, Verbanck M, Biino G, Saba Y, Meulenbelt I, O'Connell JR, Laakso M, Giulianini F, Magnusson PKE, Ballantyne CM, Hottenga JJ, Montgomery GW, Rivadineira F, Rueedi R, Steri M, Herzig KH, Stott DJ, Menni C, Frånberg M, St Pourcain B, Felix SB, Pers TH, Bakker SJL, Kraft P, Peters A, Vaidya D, Delgado G, Smit JH, Großmann V, Sinisalo J, Seppälä I, Williams SR, Holliday EG, Moed M, Langenberg C, Räikkönen K, Ding J, Campbell H, Sale MM, Chen YI, James AL, Ruggiero D, Soranzo N, Hartman CA, Smith EN, Berenson GS, Fuchsberger C, Hernandez D, Tiesler CMT, Giedraitis V, Liewald D, Fischer K, Mellström D, Larsson A, Wang Y, Scott WR, Lorentzon M, Beilby J, Ryan KA, Pennell CE, Vuckovic D, Balkau B, Concas MP, Schmidt R, Mendes de Leon CF, Bottinger EP, Kloppenburg M, Paternoster L, Boehnke M, Musk AW, Willemsen G, Evans DM, Madden PAF, Kähönen M, Kutalik Z, Zoledziewska M, Karhunen V, Kritchevsky SB, Sattar N, Lachance G, Clarke R, Harris TB, Raitakari OT, Attia JR, van Heemst D, Kajantie E, Sorice R, Gambaro G, Scott RA, Hicks AA, Ferrucci L, Standl M, Lindgren CM, Starr JM, Karlsson M, Lind L, Li JZ, Chambers JC, Mori TA, de Geus EJCN, Heath AC, Martin NG, Auvinen J, Buckley BM, de Craen AJM, Waldenberger M, Strauch K, Meitinger T, Scott RJ, McEvoy M, Beekman M, Bombieri C, Ridker PM, Mohlke KL, Pedersen NL, Morrison AC, Boomsma DI, Whitfield JB, Strachan DP, Hofman A, Vollenweider P, Cucca F, Jarvelin MR, Jukema JW, Spector TD, Hamsten A, Zeller T, Uitterlinden AG, Nauck M, Gudnason V, Qi L, Grallert H, Borecki IB, Rotter JI, März W, Wild PS, Lokki ML, Boyle M, Salomaa V, Melbye M, Eriksson JG, Wilson JF, Penninx BWJH, Becker DM, Worrall BB, Gibson G, Krauss RM, Ciullo M, Zaza G, Wareham NJ, Oldehinkel AJ, Palmer LJ, Murray SS, Pramstaller PP, Bandinelli S, Heinrich J, Ingelsson E, Deary IJ, Mägi R, Vandenput L, van der Harst P, Desch KC, Kooner JS, Ohlsson C, Hayward C, Lehtimäki T, Shuldiner AR, Arnett DK, Beilin LJ, Robino A, Froguel P, Pirastu M, Jess T, Koenig W, Loos RJF, Evans DA, Schmidt H, Smith GD, Slagboom PE, Eiriksdottir G, Morris AP, Psaty BM, Tracy RP, Nolte IM, Boerwinkle E, Visvikis-Siest S, Reiner AP, Gross M, Bis JC, Franke L, Franco OH, Benjamin EJ, Chasman DI, Dupuis J, Snieder H, Dehghan A, and Alizadeh BZ
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers metabolism, Bipolar Disorder genetics, Bipolar Disorder metabolism, Body Mass Index, C-Reactive Protein genetics, Child, Female, Genome-Wide Association Study methods, Humans, Inflammation metabolism, Liver metabolism, Liver pathology, Male, Mendelian Randomization Analysis methods, Middle Aged, Schizophrenia genetics, Schizophrenia metabolism, Young Adult, Genetic Loci genetics, Inflammation genetics, Metabolic Networks and Pathways genetics
Abstract: C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10 -8 ). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)
Published: 2018
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4. NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality.

Author: Böger CA, Gorski M, McMahon GM, Xu H, Chang YC, van der Most PJ, Navis G, Nolte IM, de Borst MH, Zhang W, Lehne B, Loh M, Tan ST, Boerwinkle E, Grams ME, Sekula P, Li M, Wilmot B, Moon JG, Scheet P, Cucca F, Xiao X, Lyytikäinen LP, Delgado G, Grammer TB, Kleber ME, Sedaghat S, Rivadeneira F, Corre T, Kutalik Z, Bergmann S, Nielson CM, Srikanth P, Teumer A, Müller-Nurasyid M, Brockhaus AC, Pfeufer A, Rathmann W, Peters A, Matsumoto M, de Andrade M, Atkinson EJ, Robinson-Cohen C, de Boer IH, Hwang SJ, Heid IM, Gögele M, Concas MP, Tanaka T, Bandinelli S, Nalls MA, Singleton A, Tajuddin SM, Adeyemo A, Zhou J, Doumatey A, McWeeney S, Murabito J, Franceschini N, Flessner M, Shlipak M, Wilson JG, Chen G, Rotimi CN, Zonderman AB, Evans MK, Ferrucci L, Devuyst O, Pirastu M, Shuldiner A, Hicks AA, Pramstaller PP, Kestenbaum B, Kardia SLR, Turner ST, Study LC, Briske TE, Gieger C, Strauch K, Meisinger C, Meitinger T, Völker U, Nauck M, Völzke H, Vollenweider P, Bochud M, Waeber G, Kähönen M, Lehtimäki T, März W, Dehghan A, Franco OH, Uitterlinden AG, Hofman A, Taylor HA, Chambers JC, Kooner JS, Fox CS, Hitzemann R, Orwoll ES, Pattaro C, Schlessinger D, Köttgen A, Snieder H, Parsa A, and Cohen DM
Subjects: Aged, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Osmolar Concentration, Racial Groups, Genetic Loci, Plasma chemistry, Sodium analysis, Sodium-Bicarbonate Symporters genetics, Transcription Factors genetics, Water-Electrolyte Imbalance blood, Water-Electrolyte Imbalance genetics
Abstract: Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P <5.0 × 10 -6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis ( P =3.1 × 10 -5 ), with combined stages 1 and 2 genome-wide significance of P =5.6 × 10 -10 Transethnic meta-analysis further supported the association at rs9980 ( P =5.9 × 10 -12 ). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis ( P =6.7 × 10 -8 ). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance., (Copyright © 2017 by the American Society of Nephrology.)
Published: 2017
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5. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

Author: Christophersen IE, Rienstra M, Roselli C, Yin X, Geelhoed B, Barnard J, Lin H, Arking DE, Smith AV, Albert CM, Chaffin M, Tucker NR, Li M, Klarin D, Bihlmeyer NA, Low SK, Weeke PE, Müller-Nurasyid M, Smith JG, Brody JA, Niemeijer MN, Dörr M, Trompet S, Huffman J, Gustafsson S, Schurmann C, Kleber ME, Lyytikäinen LP, Seppälä I, Malik R, Horimoto ARVR, Perez M, Sinisalo J, Aeschbacher S, Thériault S, Yao J, Radmanesh F, Weiss S, Teumer A, Choi SH, Weng LC, Clauss S, Deo R, Rader DJ, Shah SH, Sun A, Hopewell JC, Debette S, Chauhan G, Yang Q, Worrall BB, Paré G, Kamatani Y, Hagemeijer YP, Verweij N, Siland JE, Kubo M, Smith JD, Van Wagoner DR, Bis JC, Perz S, Psaty BM, Ridker PM, Magnani JW, Harris TB, Launer LJ, Shoemaker MB, Padmanabhan S, Haessler J, Bartz TM, Waldenberger M, Lichtner P, Arendt M, Krieger JE, Kähönen M, Risch L, Mansur AJ, Peters A, Smith BH, Lind L, Scott SA, Lu Y, Bottinger EB, Hernesniemi J, Lindgren CM, Wong JA, Huang J, Eskola M, Morris AP, Ford I, Reiner AP, Delgado G, Chen LY, Chen YI, Sandhu RK, Li M, Boerwinkle E, Eisele L, Lannfelt L, Rost N, Anderson CD, Taylor KD, Campbell A, Magnusson PK, Porteous D, Hocking LJ, Vlachopoulou E, Pedersen NL, Nikus K, Orho-Melander M, Hamsten A, Heeringa J, Denny JC, Kriebel J, Darbar D, Newton-Cheh C, Shaffer C, Macfarlane PW, Heilmann-Heimbach S, Almgren P, Huang PL, Sotoodehnia N, Soliman EZ, Uitterlinden AG, Hofman A, Franco OH, Völker U, Jöckel KH, Sinner MF, Lin HJ, Guo X, Dichgans M, Ingelsson E, Kooperberg C, Melander O, Loos RJF, Laurikka J, Conen D, Rosand J, van der Harst P, Lokki ML, Kathiresan S, Pereira A, Jukema JW, Hayward C, Rotter JI, März W, Lehtimäki T, Stricker BH, Chung MK, Felix SB, Gudnason V, Alonso A, Roden DM, Kääb S, Chasman DI, Heckbert SR, Benjamin EJ, Tanaka T, Lunetta KL, Lubitz SA, and Ellinor PT
Subjects: Black or African American genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Quantitative Trait Loci, White People genetics, Atrial Fibrillation genetics, Genetic Loci
Abstract: Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.
Published: 2017
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6. Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.

Author: Wild PS, Felix JF, Schillert A, Teumer A, Chen MH, Leening MJG, Völker U, Großmann V, Brody JA, Irvin MR, Shah SJ, Pramana S, Lieb W, Schmidt R, Stanton AV, Malzahn D, Smith AV, Sundström J, Minelli C, Ruggiero D, Lyytikäinen LP, Tiller D, Smith JG, Monnereau C, Di Tullio MR, Musani SK, Morrison AC, Pers TH, Morley M, Kleber ME, Aragam J, Benjamin EJ, Bis JC, Bisping E, Broeckel U, Cheng S, Deckers JW, Del Greco M F, Edelmann F, Fornage M, Franke L, Friedrich N, Harris TB, Hofer E, Hofman A, Huang J, Hughes AD, Kähönen M, Investigators K, Kruppa J, Lackner KJ, Lannfelt L, Laskowski R, Launer LJ, Leosdottir M, Lin H, Lindgren CM, Loley C, MacRae CA, Mascalzoni D, Mayet J, Medenwald D, Morris AP, Müller C, Müller-Nurasyid M, Nappo S, Nilsson PM, Nuding S, Nutile T, Peters A, Pfeufer A, Pietzner D, Pramstaller PP, Raitakari OT, Rice KM, Rivadeneira F, Rotter JI, Ruohonen ST, Sacco RL, Samdarshi TE, Schmidt H, Sharp ASP, Shields DC, Sorice R, Sotoodehnia N, Stricker BH, Surendran P, Thom S, Töglhofer AM, Uitterlinden AG, Wachter R, Völzke H, Ziegler A, Münzel T, März W, Cappola TP, Hirschhorn JN, Mitchell GF, Smith NL, Fox ER, Dueker ND, Jaddoe VWV, Melander O, Russ M, Lehtimäki T, Ciullo M, Hicks AA, Lind L, Gudnason V, Pieske B, Barron AJ, Zweiker R, Schunkert H, Ingelsson E, Liu K, Arnett DK, Psaty BM, Blankenberg S, Larson MG, Felix SB, Franco OH, Zeller T, Vasan RS, and Dörr M
Subjects: Female, Humans, Male, Genetic Loci, Genome-Wide Association Study, Heart Diseases genetics, Heart Diseases metabolism, Heart Diseases physiopathology, Myocardium, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable
Abstract: Background: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function., Methods: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function., Results: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue., Conclusion: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies., Funding: For detailed information per study, see Acknowledgments.
Published: 2017
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7. Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

Author: Iotchkova V, Huang J, Morris JA, Jain D, Barbieri C, Walter K, Min JL, Chen L, Astle W, Cocca M, Deelen P, Elding H, Farmaki AE, Franklin CS, Franberg M, Gaunt TR, Hofman A, Jiang T, Kleber ME, Lachance G, Luan J, Malerba G, Matchan A, Mead D, Memari Y, Ntalla I, Panoutsopoulou K, Pazoki R, Perry JRB, Rivadeneira F, Sabater-Lleal M, Sennblad B, Shin SY, Southam L, Traglia M, van Dijk F, van Leeuwen EM, Zaza G, Zhang W, Amin N, Butterworth A, Chambers JC, Dedoussis G, Dehghan A, Franco OH, Franke L, Frontini M, Gambaro G, Gasparini P, Hamsten A, Issacs A, Kooner JS, Kooperberg C, Langenberg C, Marz W, Scott RA, Swertz MA, Toniolo D, Uitterlinden AG, van Duijn CM, Watkins H, Zeggini E, Maurano MT, Timpson NJ, Reiner AP, Auer PL, and Soranzo N
Subjects: Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Quantitative Trait Loci, Sequence Analysis, DNA, Genetic Loci, Genome, Human, Genome-Wide Association Study, Heart Diseases genetics, Hematologic Diseases genetics
Abstract: Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.
Published: 2016
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8. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.

Author: de Vries PS, Chasman DI, Sabater-Lleal M, Chen MH, Huffman JE, Steri M, Tang W, Teumer A, Marioni RE, Grossmann V, Hottenga JJ, Trompet S, Müller-Nurasyid M, Zhao JH, Brody JA, Kleber ME, Guo X, Wang JJ, Auer PL, Attia JR, Yanek LR, Ahluwalia TS, Lahti J, Venturini C, Tanaka T, Bielak LF, Joshi PK, Rocanin-Arjo A, Kolcic I, Navarro P, Rose LM, Oldmeadow C, Riess H, Mazur J, Basu S, Goel A, Yang Q, Ghanbari M, Willemsen G, Rumley A, Fiorillo E, de Craen AJ, Grotevendt A, Scott R, Taylor KD, Delgado GE, Yao J, Kifley A, Kooperberg C, Qayyum R, Lopez LM, Berentzen TL, Räikkönen K, Mangino M, Bandinelli S, Peyser PA, Wild S, Trégouët DA, Wright AF, Marten J, Zemunik T, Morrison AC, Sennblad B, Tofler G, de Maat MP, de Geus EJ, Lowe GD, Zoledziewska M, Sattar N, Binder H, Völker U, Waldenberger M, Khaw KT, Mcknight B, Huang J, Jenny NS, Holliday EG, Qi L, Mcevoy MG, Becker DM, Starr JM, Sarin AP, Hysi PG, Hernandez DG, Jhun MA, Campbell H, Hamsten A, Rivadeneira F, Mcardle WL, Slagboom PE, Zeller T, Koenig W, Psaty BM, Haritunians T, Liu J, Palotie A, Uitterlinden AG, Stott DJ, Hofman A, Franco OH, Polasek O, Rudan I, Morange PE, Wilson JF, Kardia SL, Ferrucci L, Spector TD, Eriksson JG, Hansen T, Deary IJ, Becker LC, Scott RJ, Mitchell P, März W, Wareham NJ, Peters A, Greinacher A, Wild PS, Jukema JW, Boomsma DI, Hayward C, Cucca F, Tracy R, Watkins H, Reiner AP, Folsom AR, Ridker PM, O'Donnell CJ, Smith NL, Strachan DP, and Dehghan A
Subjects: Adult, Aged, Aged, 80 and over, Female, Fibrinogen genetics, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Middle Aged, White People genetics, Fibrinogen analysis, Genetic Loci, Polymorphism, Single Nucleotide
Abstract: Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2016
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9. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

Author: Kato N, Loh M, Takeuchi F, Verweij N, Wang X, Zhang W, Kelly TN, Saleheen D, Lehne B, Leach IM, Drong AW, Abbott J, Wahl S, Tan ST, Scott WR, Campanella G, Chadeau-Hyam M, Afzal U, Ahluwalia TS, Bonder MJ, Chen P, Dehghan A, Edwards TL, Esko T, Go MJ, Harris SE, Hartiala J, Kasela S, Kasturiratne A, Khor CC, Kleber ME, Li H, Yu Mok Z, Nakatochi M, Sapari NS, Saxena R, Stewart AFR, Stolk L, Tabara Y, Teh AL, Wu Y, Wu JY, Zhang Y, Aits I, Da Silva Couto Alves A, Das S, Dorajoo R, Hopewell JC, Kim YK, Koivula RW, Luan J, Lyytikäinen LP, Nguyen QN, Pereira MA, Postmus I, Raitakari OT, Scannell Bryan M, Scott RA, Sorice R, Tragante V, Traglia M, White J, Yamamoto K, Zhang Y, Adair LS, Ahmed A, Akiyama K, Asif R, Aung T, Barroso I, Bjonnes A, Braun TR, Cai H, Chang LC, Chen CH, Cheng CY, Chong YS, Collins R, Courtney R, Davies G, Delgado G, Do LD, Doevendans PA, Gansevoort RT, Gao YT, Grammer TB, Grarup N, Grewal J, Gu D, Wander GS, Hartikainen AL, Hazen SL, He J, Heng CK, Hixson JE, Hofman A, Hsu C, Huang W, Husemoen LLN, Hwang JY, Ichihara S, Igase M, Isono M, Justesen JM, Katsuya T, Kibriya MG, Kim YJ, Kishimoto M, Koh WP, Kohara K, Kumari M, Kwek K, Lee NR, Lee J, Liao J, Lieb W, Liewald DCM, Matsubara T, Matsushita Y, Meitinger T, Mihailov E, Milani L, Mills R, Mononen N, Müller-Nurasyid M, Nabika T, Nakashima E, Ng HK, Nikus K, Nutile T, Ohkubo T, Ohnaka K, Parish S, Paternoster L, Peng H, Peters A, Pham ST, Pinidiyapathirage MJ, Rahman M, Rakugi H, Rolandsson O, Ann Rozario M, Ruggiero D, Sala CF, Sarju R, Shimokawa K, Snieder H, Sparsø T, Spiering W, Starr JM, Stott DJ, Stram DO, Sugiyama T, Szymczak S, Tang WHW, Tong L, Trompet S, Turjanmaa V, Ueshima H, Uitterlinden AG, Umemura S, Vaarasmaki M, van Dam RM, van Gilst WH, van Veldhuisen DJ, Viikari JS, Waldenberger M, Wang Y, Wang A, Wilson R, Wong TY, Xiang YB, Yamaguchi S, Ye X, Young RD, Young TL, Yuan JM, Zhou X, Asselbergs FW, Ciullo M, Clarke R, Deloukas P, Franke A, Franks PW, Franks S, Friedlander Y, Gross MD, Guo Z, Hansen T, Jarvelin MR, Jørgensen T, Jukema JW, Kähönen M, Kajio H, Kivimaki M, Lee JY, Lehtimäki T, Linneberg A, Miki T, Pedersen O, Samani NJ, Sørensen TIA, Takayanagi R, Toniolo D, Ahsan H, Allayee H, Chen YT, Danesh J, Deary IJ, Franco OH, Franke L, Heijman BT, Holbrook JD, Isaacs A, Kim BJ, Lin X, Liu J, März W, Metspalu A, Mohlke KL, Sanghera DK, Shu XO, van Meurs JBJ, Vithana E, Wickremasinghe AR, Wijmenga C, Wolffenbuttel BHW, Yokota M, Zheng W, Zhu D, Vineis P, Kyrtopoulos SA, Kleinjans JCS, McCarthy MI, Soong R, Gieger C, Scott J, Teo YY, He J, Elliott P, Tai ES, van der Harst P, Kooner JS, and Chambers JC
Subjects: Adult, Aged, Aged, 80 and over, Asian People genetics, Cardiovascular Diseases blood, Cardiovascular Diseases ethnology, Cardiovascular Diseases genetics, Female, Genetic Predisposition to Disease ethnology, Genetic Predisposition to Disease genetics, Genetic Variation, Genotype, Humans, Male, Middle Aged, Natriuretic Peptide, Brain blood, Peptide Fragments blood, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, White People genetics, Blood Pressure genetics, DNA Methylation, Genetic Loci genetics, Genome-Wide Association Study methods
Abstract: We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
Published: 2015
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10. Association between a gene variant near ataxia telangiectasia mutated and coronary artery disease in men.

Author: Schiekofer S, Bobak I, Kleber ME, Maerz W, Rudofsky G, Dugi KA, and Schneider JG
Subjects: Aged, Aged, 80 and over, Ataxia Telangiectasia Mutated Proteins metabolism, Blood Glucose analysis, Cohort Studies, Coronary Angiography, Coronary Artery Disease blood, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease metabolism, Coronary Vessels diagnostic imaging, Cross-Sectional Studies, Gene Frequency, Genetic Association Studies, Germany, Hospitals, University, Humans, Male, Middle Aged, Severity of Illness Index, Statistics as Topic, Ataxia Telangiectasia Mutated Proteins genetics, Coronary Artery Disease genetics, Genetic Loci, Polymorphism, Single Nucleotide
Abstract: Objective: Type 2 diabetes is accompanied by increased mortality from coronary artery disease (CAD), but the mechanisms linking these conditions remain elusive. Hence, treatment of hyperglycaemia alone is not sufficient to avoid CAD in diabetes. Alternative views suggest that metabolic and vascular diseases share unifying cellular defects that could serve as targets for novel therapeutic strategies. Recently, a variant [single-nucleotide polymorphism (SNP); rs11212617] near the gene for ataxia telangiectasia mutated (ATM) has been associated with glycaemic response to metformin., Materials and Methods: We determined rs11212617 in 240 male patients who underwent elective coronary angiography., Results: While the variant was not associated with glucose concentrations, the A allele was significantly associated with the presence of CAD (chi-square, p = 0.003), as well as with logarithmically transformed quantitative CAD indices [severe score (SS): 0.5 (0.4-0.6) vs 0.3 (0.2-0.5); extent score (ES): 2.63 (2.4-2.9) vs 1.94 (1.4-2.4), both p < 0.05, respectively]. Multivariate analysis revealed an independent association between the A allele with ES (β = 0.17, p < 0.01)., Conclusion: Our data suggest that ATM-dependent signalling might play a role in the development of atherosclerotic vascular disease, but larger studies are necessary to substantiate such a hypothesis.
Published: 2014
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11. Genome-wide association study identifies 3 genomic loci significantly associated with serum levels of homoarginine: the AtheroRemo Consortium.

Author: Kleber ME, Seppälä I, Pilz S, Hoffmann MM, Tomaschitz A, Oksala N, Raitoharju E, Lyytikäinen LP, Mäkelä KM, Laaksonen R, Kähönen M, Raitakari OT, Huang J, Kienreich K, Fahrleitner-Pammer A, Drechsler C, Krane V, Boehm BO, Koenig W, Wanner C, Lehtimäki T, März W, and Meinitzer A
Subjects: Adult, Aged, Arginine metabolism, Cardiovascular Diseases enzymology, Cardiovascular Diseases etiology, Cardiovascular Diseases mortality, Chromosomes, Human genetics, Enzymes genetics, Enzymes metabolism, Female, Genotype, Humans, Male, Middle Aged, Mitochondria metabolism, Polymorphism, Single Nucleotide, Cardiovascular Diseases genetics, Genetic Loci genetics, Genome-Wide Association Study, Homoarginine blood
Abstract: Background: Low serum levels of the amino acid derivative, homoarginine, have been associated with increased risk of total and cardiovascular mortality. Homoarginine deficiency may be related to renal and heart diseases, but the pathophysiologic role of homoarginine and the genetic regulation of its serum levels are largely unknown., Methods and Results: In 3041 patients of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study referred for coronary angiography and 2102 participants of the Young Finns Study (YFS), we performed a genome-wide association study to identify genomic loci associated with homoarginine serum levels and tested for associations of identified single-nucleotide polymorphisms with mortality in LURIC. We found genome-wide significant associations with homoarginine serum levels on chromosome 2 at the carbamoyl phosphate synthetase I locus, on chromosome 5 at the alanine-glyoxylate aminotransferase 2 locus, and on chromosome 15 at the glycine amidinotransferase locus, as well as a suggestive association on chromosome 6 at the Homo sapiens mediator complex subunit 23 gene/arginase I locus. All loci harbor enzymes located in the mitochondrium are involved in arginine metabolism. The strongest association was observed for rs1153858 at the glycine amidinotransferase locus with a P value of 1.25E-45 in the combined analysis and has been replicated in both the Die Deutsche Diabetes Dialyse Studie (4D study) and the Graz Endocrine Causes of Hypertension (GECOH) study., Conclusions: In our genome-wide association study, we identified 3 chromosomal regions significantly associated with serum homoarginine and another region with suggestive association, providing novel insights into the genetic regulation of homoarginine.
Published: 2013
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12. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.

Author: Köttgen A, Albrecht E, Teumer A, Vitart V, Krumsiek J, Hundertmark C, Pistis G, Ruggiero D, O'Seaghdha CM, Haller T, Yang Q, Tanaka T, Johnson AD, Kutalik Z, Smith AV, Shi J, Struchalin M, Middelberg RP, Brown MJ, Gaffo AL, Pirastu N, Li G, Hayward C, Zemunik T, Huffman J, Yengo L, Zhao JH, Demirkan A, Feitosa MF, Liu X, Malerba G, Lopez LM, van der Harst P, Li X, Kleber ME, Hicks AA, Nolte IM, Johansson A, Murgia F, Wild SH, Bakker SJ, Peden JF, Dehghan A, Steri M, Tenesa A, Lagou V, Salo P, Mangino M, Rose LM, Lehtimäki T, Woodward OM, Okada Y, Tin A, Müller C, Oldmeadow C, Putku M, Czamara D, Kraft P, Frogheri L, Thun GA, Grotevendt A, Gislason GK, Harris TB, Launer LJ, McArdle P, Shuldiner AR, Boerwinkle E, Coresh J, Schmidt H, Schallert M, Martin NG, Montgomery GW, Kubo M, Nakamura Y, Tanaka T, Munroe PB, Samani NJ, Jacobs DR Jr, Liu K, D'Adamo P, Ulivi S, Rotter JI, Psaty BM, Vollenweider P, Waeber G, Campbell S, Devuyst O, Navarro P, Kolcic I, Hastie N, Balkau B, Froguel P, Esko T, Salumets A, Khaw KT, Langenberg C, Wareham NJ, Isaacs A, Kraja A, Zhang Q, Wild PS, Scott RJ, Holliday EG, Org E, Viigimaa M, Bandinelli S, Metter JE, Lupo A, Trabetti E, Sorice R, Döring A, Lattka E, Strauch K, Theis F, Waldenberger M, Wichmann HE, Davies G, Gow AJ, Bruinenberg M, Stolk RP, Kooner JS, Zhang W, Winkelmann BR, Boehm BO, Lucae S, Penninx BW, Smit JH, Curhan G, Mudgal P, Plenge RM, Portas L, Persico I, Kirin M, Wilson JF, Mateo Leach I, van Gilst WH, Goel A, Ongen H, Hofman A, Rivadeneira F, Uitterlinden AG, Imboden M, von Eckardstein A, Cucca F, Nagaraja R, Piras MG, Nauck M, Schurmann C, Budde K, Ernst F, Farrington SM, Theodoratou E, Prokopenko I, Stumvoll M, Jula A, Perola M, Salomaa V, Shin SY, Spector TD, Sala C, Ridker PM, Kähönen M, Viikari J, Hengstenberg C, Nelson CP, Meschia JF, Nalls MA, Sharma P, Singleton AB, Kamatani N, Zeller T, Burnier M, Attia J, Laan M, Klopp N, Hillege HL, Kloiber S, Choi H, Pirastu M, Tore S, Probst-Hensch NM, Völzke H, Gudnason V, Parsa A, Schmidt R, Whitfield JB, Fornage M, Gasparini P, Siscovick DS, Polašek O, Campbell H, Rudan I, Bouatia-Naji N, Metspalu A, Loos RJ, van Duijn CM, Borecki IB, Ferrucci L, Gambaro G, Deary IJ, Wolffenbuttel BH, Chambers JC, März W, Pramstaller PP, Snieder H, Gyllensten U, Wright AF, Navis G, Watkins H, Witteman JC, Sanna S, Schipf S, Dunlop MG, Tönjes A, Ripatti S, Soranzo N, Toniolo D, Chasman DI, Raitakari O, Kao WH, Ciullo M, Fox CS, Caulfield M, Bochud M, and Gieger C
Subjects: Analysis of Variance, Gene Frequency, Genome-Wide Association Study, Glucose metabolism, Gout blood, Humans, Inhibins genetics, Inhibins metabolism, Polymorphism, Single Nucleotide genetics, White People, Genetic Loci genetics, Gout genetics, Signal Transduction genetics, Uric Acid blood
Abstract: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Published: 2013
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13. Seventy-five genetic loci influencing the human red blood cell.

Author: van der Harst P, Zhang W, Mateo Leach I, Rendon A, Verweij N, Sehmi J, Paul DS, Elling U, Allayee H, Li X, Radhakrishnan A, Tan ST, Voss K, Weichenberger CX, Albers CA, Al-Hussani A, Asselbergs FW, Ciullo M, Danjou F, Dina C, Esko T, Evans DM, Franke L, Gögele M, Hartiala J, Hersch M, Holm H, Hottenga JJ, Kanoni S, Kleber ME, Lagou V, Langenberg C, Lopez LM, Lyytikäinen LP, Melander O, Murgia F, Nolte IM, O'Reilly PF, Padmanabhan S, Parsa A, Pirastu N, Porcu E, Portas L, Prokopenko I, Ried JS, Shin SY, Tang CS, Teumer A, Traglia M, Ulivi S, Westra HJ, Yang J, Zhao JH, Anni F, Abdellaoui A, Attwood A, Balkau B, Bandinelli S, Bastardot F, Benyamin B, Boehm BO, Cookson WO, Das D, de Bakker PI, de Boer RA, de Geus EJ, de Moor MH, Dimitriou M, Domingues FS, Döring A, Engström G, Eyjolfsson GI, Ferrucci L, Fischer K, Galanello R, Garner SF, Genser B, Gibson QD, Girotto G, Gudbjartsson DF, Harris SE, Hartikainen AL, Hastie CE, Hedblad B, Illig T, Jolley J, Kähönen M, Kema IP, Kemp JP, Liang L, Lloyd-Jones H, Loos RJ, Meacham S, Medland SE, Meisinger C, Memari Y, Mihailov E, Miller K, Moffatt MF, Nauck M, Novatchkova M, Nutile T, Olafsson I, Onundarson PT, Parracciani D, Penninx BW, Perseu L, Piga A, Pistis G, Pouta A, Puc U, Raitakari O, Ring SM, Robino A, Ruggiero D, Ruokonen A, Saint-Pierre A, Sala C, Salumets A, Sambrook J, Schepers H, Schmidt CO, Silljé HH, Sladek R, Smit JH, Starr JM, Stephens J, Sulem P, Tanaka T, Thorsteinsdottir U, Tragante V, van Gilst WH, van Pelt LJ, van Veldhuisen DJ, Völker U, Whitfield JB, Willemsen G, Winkelmann BR, Wirnsberger G, Algra A, Cucca F, d'Adamo AP, Danesh J, Deary IJ, Dominiczak AF, Elliott P, Fortina P, Froguel P, Gasparini P, Greinacher A, Hazen SL, Jarvelin MR, Khaw KT, Lehtimäki T, Maerz W, Martin NG, Metspalu A, Mitchell BD, Montgomery GW, Moore C, Navis G, Pirastu M, Pramstaller PP, Ramirez-Solis R, Schadt E, Scott J, Shuldiner AR, Smith GD, Smith JG, Snieder H, Sorice R, Spector TD, Stefansson K, Stumvoll M, Tang WH, Toniolo D, Tönjes A, Visscher PM, Vollenweider P, Wareham NJ, Wolffenbuttel BH, Boomsma DI, Beckmann JS, Dedoussis GV, Deloukas P, Ferreira MA, Sanna S, Uda M, Hicks AA, Penninger JM, Gieger C, Kooner JS, Ouwehand WH, Soranzo N, and Chambers JC
Subjects: Animals, Cell Cycle genetics, Cytokines metabolism, Drosophila melanogaster genetics, Erythrocytes cytology, Female, Gene Expression Regulation genetics, Hematopoiesis genetics, Hemoglobins genetics, Humans, Male, Mice, Organ Specificity, Polymorphism, Single Nucleotide genetics, RNA Interference, Signal Transduction genetics, Erythrocytes metabolism, Genetic Loci, Genome-Wide Association Study, Phenotype
Abstract: Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
Published: 2012
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14. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

Author: Lanktree MB, Guo Y, Murtaza M, Glessner JT, Bailey SD, Onland-Moret NC, Lettre G, Ongen H, Rajagopalan R, Johnson T, Shen H, Nelson CP, Klopp N, Baumert J, Padmanabhan S, Pankratz N, Pankow JS, Shah S, Taylor K, Barnard J, Peters BJ, Maloney CM, Lobmeyer MT, Stanton A, Zafarmand MH, Romaine SP, Mehta A, van Iperen EP, Gong Y, Price TS, Smith EN, Kim CE, Li YR, Asselbergs FW, Atwood LD, Bailey KM, Bhatt D, Bauer F, Behr ER, Bhangale T, Boer JM, Boehm BO, Bradfield JP, Brown M, Braund PS, Burton PR, Carty C, Chandrupatla HR, Chen W, Connell J, Dalgeorgou C, Boer Ad, Drenos F, Elbers CC, Fang JC, Fox CS, Frackelton EC, Fuchs B, Furlong CE, Gibson Q, Gieger C, Goel A, Grobbee DE, Hastie C, Howard PJ, Huang GH, Johnson WC, Li Q, Kleber ME, Klein BE, Klein R, Kooperberg C, Ky B, Lacroix A, Lanken P, Lathrop M, Li M, Marshall V, Melander O, Mentch FD, Meyer NJ, Monda KL, Montpetit A, Murugesan G, Nakayama K, Nondahl D, Onipinla A, Rafelt S, Newhouse SJ, Otieno FG, Patel SR, Putt ME, Rodriguez S, Safa RN, Sawyer DB, Schreiner PJ, Simpson C, Sivapalaratnam S, Srinivasan SR, Suver C, Swergold G, Sweitzer NK, Thomas KA, Thorand B, Timpson NJ, Tischfield S, Tobin M, Tomaszewski M, Verschuren WM, Wallace C, Winkelmann B, Zhang H, Zheng D, Zhang L, Zmuda JM, Clarke R, Balmforth AJ, Danesh J, Day IN, Schork NJ, de Bakker PI, Delles C, Duggan D, Hingorani AD, Hirschhorn JN, Hofker MH, Humphries SE, Kivimaki M, Lawlor DA, Kottke-Marchant K, Mega JL, Mitchell BD, Morrow DA, Palmen J, Redline S, Shields DC, Shuldiner AR, Sleiman PM, Smith GD, Farrall M, Jamshidi Y, Christiani DC, Casas JP, Hall AS, Doevendans PA, Christie JD, Berenson GS, Murray SS, Illig T, Dorn GW 2nd, Cappola TP, Boerwinkle E, Sever P, Rader DJ, Reilly MP, Caulfield M, Talmud PJ, Topol E, Engert JC, Wang K, Dominiczak A, Hamsten A, Curtis SP, Silverstein RL, Lange LA, Sabatine MS, Trip M, Saleheen D, Peden JF, Cruickshanks KJ, März W, O'Connell JR, Klungel OH, Wijmenga C, Maitland-van der Zee AH, Schadt EE, Johnson JA, Jarvik GP, Papanicolaou GJ, Grant SF, Munroe PB, North KE, Samani NJ, Koenig W, Gaunt TR, Anand SS, van der Schouw YT, Soranzo N, Fitzgerald GA, Reiner A, Hegele RA, Hakonarson H, and Keating BJ
Subjects: Adult, Black or African American genetics, Asian People genetics, Female, Gene Frequency, Genome-Wide Association Study, Hispanic or Latino genetics, Humans, Interleukin-11 genetics, Male, Smad3 Protein genetics, White People genetics, Body Height genetics, Cardiovascular System, Genetic Heterogeneity, Genetic Loci, Polymorphism, Single Nucleotide
Abstract: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
Published: 2011
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15. A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology

Author: de Vries, PS, Sabater-Lleal, M, Huffman, JE, Marten, J, Song, C, Pankratz, N, Bartz, TM, de Haan, HG, Delgado, GE, Eicher, JD, Martinez-Perez, A, Ward-Caviness, CK, Brody, JA, Chen, MH, de Maat, MPM, Franberg, M, Gill, D, Kleber, ME, Rivadeneira, F, Soria, JM, Tang, WH, Tofler, GH, Uitterlinden, AG, Vlieg, AV, Seshadri, S, Boerwinkle, E, Davies, NM, Giese, AK, Ikram, MK, Kittner, SJ, McKnight, B, Psaty, BM, Reiner, AP, Sargurupremraj, M, Taylor, KD, Fornage, M, Hamsten, A, Marz, W, Rosendaal, FR, Souto, JC, Dehghan, A, Johnson, AD, Morrison, AC, O'Donnell, CJ, Smith, NL, INVENT Consortium, MEGASTROKE Consortium Intl, Epidemiology, Hematology, Internal Medicine, and Neurology
Subjects: 0301 basic medicine, Male, Candidate gene, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biochemistry, Brain Ischemia, Thrombosis and Hemostasis, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, Cardiac and Cardiovascular Systems, Genetics, education.field_of_study, Kardiologi, Factor VII, Mendelian Randomization Analysis, Hematology, Venous Thromboembolism, Middle Aged, Prognosis, Neoplasm Proteins, DNA-Binding Proteins, Stroke, Phenotype, Female, Co-Repressor Proteins, Immunology, Population, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Mendelian randomization, Gene silencing, Humans, Genetic Predisposition to Disease, cardiovascular diseases, education, Genetic association, Membrane Transport Proteins, Cell Biology, 030104 developmental biology, chemistry, Genetic Loci, Follow-Up Studies, Genome-Wide Association Study
Abstract: Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of nine genome-wide association studies of plasma FVII levels (seven FVII activity and two FVII antigen) among 27,495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the seven studies that measured FVII activity, and a secondary analysis included all nine studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using siRNA and then measuring F7 mRNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke, and venous thromboembolism. We identified two novel (REEP3 and JAZF1-AS1) and six known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, while silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of ischemic stroke. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of ischemic stroke in the general population.
Published: 2019

16. Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Author: Randall, JC, Winkler, TW, Kutalik, Z, Berndt, SI, Jackson, AU, Monda, KL, Kilpeläinen, TO, Esko, T, Mägi, R, Li, S, Workalemahu, T, Feitosa, MF, Croteau-Chonka, DC, Day, FR, Fall, T, Ferreira, T, Gustafsson, S, Locke, AE, Mathieson, I, Scherag, A, Vedantam, S, Wood, AR, Liang, L, Steinthorsdottir, V, Thorleifsson, G, Dermitzakis, ET, Dimas, AS, Karpe, F, Min, JL, Nicholson, G, Clegg, DJ, Person, T, Krohn, JP, Bauer, S, Buechler, C, Eisinger, K, DIAGRAM Consortium, Bonnefond, A, Froguel, P, MAGIC Investigators, Hottenga, JJ, Prokopenko, I, Waite, LL, Harris, TB, Smith, AV, Shuldiner, AR, McArdle, WL, Caulfield, MJ, Munroe, PB, Grönberg, H, Chen, YD, Li, G, Beckmann, JS, Johnson, T, Thorsteinsdottir, U, Teder-Laving, M, Khaw, KT, Wareham, NJ, Zhao, JH, Amin, N, Oostra, BA, Kraja, AT, Province, MA, Cupples, LA, Heard-Costa, NL, Kaprio, J, Ripatti, S, Surakka, I, Collins, FS, Saramies, J, Tuomilehto, J, Jula, A, Salomaa, V, Erdmann, J, Hengstenberg, C, Loley, C, Schunkert, H, Lamina, C, Wichmann, HE, Albrecht, E, Gieger, C, Hicks, AA, Johansson, A, Pramstaller, PP, Kathiresan, S, Speliotes, EK, Penninx, B, Hartikainen, AL, Jarvelin, MR, Gyllensten, U, Boomsma, DI, Campbell, H, Wilson, JF, Chanock, SJ, Farrall, M, Goel, A, Medina-Gomez, C, Rivadeneira, F, Estrada, K, Uitterlinden, AG, Hofman, A, Zillikens, MC, den Heijer, M, Kiemeney, LA, Maschio, A, Hall, P, Tyrer, J, Teumer, A, Völzke, H, Kovacs, P, Tönjes, A, Mangino, M, Spector, TD, Hayward, C, Rudan, I, Hall, AS, Samani, NJ, Attwood, AP, Sambrook, JG, Hung, J, Palmer, LJ, Lokki, ML, Sinisalo, J, Boucher, G, Huikuri, H, Lorentzon, M, Ohlsson, C, Eklund, N, Eriksson, JG, Barlassina, C, Rivolta, C, Nolte, IM, Snieder, H, Van der Klauw, MM, Van Vliet-Ostaptchouk, JV, Gejman, PV, Shi, J, Jacobs, KB, Wang, Z, Bakker, SJ, Mateo Leach, I, Navis, G, van der Harst, P, Martin, NG, Medland, SE, Montgomery, GW, Yang, J, Chasman, DI, Ridker, PM, Rose, LM, Lehtimäki, T, Raitakari, O, Absher, D, Iribarren, C, Basart, H, Hovingh, KG, Hyppönen, E, Power, C, Anderson, D, Beilby, JP, Hui, J, Jolley, J, Sager, H, Bornstein, SR, Schwarz, PE, Kristiansson, K, Perola, M, Lindström, J, Swift, AJ, Uusitupa, M, Atalay, M, Lakka, TA, Rauramaa, R, Bolton, JL, Fowkes, G, Fraser, RM, Price, JF, Fischer, K, Krjutå Kov, K, Metspalu, A, Mihailov, E, Langenberg, C, Luan, J, Ong, KK, Chines, PS, Keinanen-Kiukaanniemi, SM, Saaristo, TE, Edkins, S, Franks, PW, Hallmans, G, Shungin, D, Morris, AD, Palmer, CN, Erbel, R, Moebus, S, Nöthen, MM, Pechlivanis, S, Hveem, K, Narisu, N, Hamsten, A, Humphries, SE, Strawbridge, RJ, Tremoli, E, Grallert, H, Thorand, B, Illig, T, Koenig, W, Müller-Nurasyid, M, Peters, A, Boehm, BO, Kleber, ME, März, W, Winkelmann, BR, Kuusisto, J, Laakso, M, Arveiler, D, Cesana, G, Kuulasmaa, K, Virtamo, J, Yarnell, JW, Kuh, D, Wong, A, Lind, L, de Faire, U, Gigante, B, Magnusson, PK, Pedersen, NL, Dedoussis, G, Dimitriou, M, Kolovou, G, Kanoni, S, Stirrups, K, Bonnycastle, LL, Njølstad, I, Wilsgaard, T, Ganna, A, Rehnberg, E, Hingorani, A, Kivimaki, M, Kumari, M, Assimes, TL, Barroso, I, Boehnke, M, Borecki, IB, Deloukas, P, Fox, CS, Frayling, T, Groop, LC, Haritunians, T, Hunter, D, Ingelsson, E, Kaplan, R, Mohlke, KL, O'Connell, JR, Schlessinger, D, Strachan, DP, Stefansson, K, van Duijn, CM, Abecasis, GR, McCarthy, MI, Hirschhorn, JN, Qi, L, Loos, RJ, Lindgren, CM, North, KE, Heid, IM, Hjelt Institute (-2014), Department of Public Health, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Haartman Institute (-2014), Transplantation Laboratory, Kardiologian yksikkö, Department of Medicine, Clinicum, Department of General Practice and Primary Health Care, Diabetes and Obesity Research Program, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, DIAGRAM Consortium, MAGIC Investigators, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Epidemiology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Internal Medicine, Public Health, Surgery, Medical Research Council (MRC), and Dermitzakis, Emmanouil
Subjects: Male, Medicin och hälsovetenskap, Epidemiology, VARIANTS, Anthropometry/methods, Body Height/genetics, Body Mass Index, Body Weight/genetics, Body Weights and Measures, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Sex Characteristics, Waist Circumference/genetics, Waist-Hip Ratio, Medical and Health Sciences, ddc:576.5, GENETICS & HEREDITY, ADULT HEIGHT, RISK, Anthropometry, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, OBESITY, Genetic Epidemiology, Medicine, PPAR-GAMMA, Waist Circumference, Life Sciences & Biomedicine, Medical Genetics, Research Article, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, lcsh:QH426-470, 515 Psychology, education, DIAGRAM Consortium, Endocrinology and Diabetes, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714, MAGIC Investigators, ddc:610, ENZYME-ACTIVITIES, METAANALYSIS, Medicinsk genetik, 0604 Genetics, Science & Technology, Body Weight, FAT DISTRIBUTION, Body Height, BODY-MASS INDEX, lcsh:Genetics, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Developmental Biology
Abstract: Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR, Author Summary Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Published: 2013

17. Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

Author: Iotchkova, V, Huang, J, Morris, JA, Jain, D, Barbieri, C, Walter, K, Min, JL, Chen, L, Astle, W, Cocca, M, Deelen, P, Elding, H, Farmaki, A-E, Franklin, CS, Franberg, M, Gaunt, TR, Hofman, A, Jiang, T, Kleber, ME, Lachance, G, Luan, J, Malerba, G, Matchan, A, Mead, D, Memari, Y, Ntalla, I, Panoutsopoulou, K, Pazoki, R, Perry, JRB, Rivadeneira, F, Sabater-Lleal, M, Sennblad, B, Shin, S-Y, Southam, L, Traglia, M, Van Dijk, F, Van Leeuwen, EM, Zaza, G, Zhang, W, UK10K Consortium, Amin, N, Butterworth, A, Chambers, JC, Dedoussis, G, Dehghan, A, Franco, OH, Franke, L, Frontini, M, Gambaro, G, Gasparini, P, Hamsten, A, Issacs, A, Kooner, JS, Kooperberg, C, Langenberg, C, Marz, W, Scott, RA, Swertz, MA, Toniolo, D, Uitterlinden, AG, Van Duijn, CM, Watkins, H, Zeggini, E, Maurano, MT, Timpson, NJ, Reiner, AP, Auer, PL, and Soranzo, N
Subjects: Male, Heart Diseases, Genetic Loci, Genome, Human, Quantitative Trait Loci, Genetic Variation, Humans, Female, Genetic Predisposition to Disease, Sequence Analysis, DNA, Hematologic Diseases, 3. Good health, Genome-Wide Association Study
Abstract: Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.

18. A catalog of genetic loci associated with kidney function from analyses of a million individuals

Author: Wuttke, Matthias, Li, Yong, Li, Man, Sieber, Karsten B., Feitosa, Mary F., Gorski, Mathias, Tin, Adrienne, Wang, Lihua, Chu, Audrey Y., Hoppmann, Anselm, Kirsten, Holger, Giri, Ayush, Chai, Jin-Fang, Sveinbjornsson, Gardar, Tayo, Bamidele O., Nutile, Teresa, Fuchsberger, Christian, Marten, Jonathan, Cocca, Massimiliano, Ghasemi, Sahar, Xu, Yizhe, Horn, Katrin, Noce, Damia, van der Most, Peter J., Sedaghat, Sanaz, Yu, Zhi, Akiyama, Masato, Afaq, Saima, Ahluwalia, Tarunveer S., Almgren, Peter, Amin, Najaf, Ärnlöv, Johan, Bakker, Stephan J. L., Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L., Biino, Ginevra, Boehnke, Michael, Boerwinkle, Eric, Boissel, Mathilde, Bottinger, Erwin P., Boutin, Thibaud S., Brenner, Hermann, Brumat, Marco, Burkhardt, Ralph, Butterworth, Adam S., Campana, Eric, Campbell, Archie, Campbell, Harry, Canouil, Mickaël, Carroll, Robert J., Catamo, Eulalia, Chambers, John C., Chee, Miao-Ling, Chee, Miao-Li, Chen, Xu, Cheng, Ching-Yu, Cheng, Yurong, Christensen, Kaare, Cifkova, Renata, Ciullo, Marina, Pina Concas, Maria, Cook, James P., Coresh, Josef, Corre, Tanguy, Sala, Cinzia Felicita, Cusi, Daniele, Danesh, John, Daw, E. Warwick, de Borst, Martin H., De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko P. J., Degenhardt, Frauke, Delgado, Graciela, Demirkan, Ayse, Di Angelantonio, Emanuele, Dittrich, Katalin, Divers, Jasmin, Dorajoo, Rajkumar, Eckardt, Kai-Uwe, Ehret, Georg, Elliott, Paul, Endlich, Karlhans, Evans, Michele K., Felix, Janine F., Foo, Valencia Hui Xian, Franco, Oscar H., Franke, Andre, Freedman, Barry I., Freitag-Wolf, Sandra, Friedlander, Yechiel, Froguel, Philippe, Gansevoort, Ron T., Gao, He, Gasparini, Paolo, Gaziano, J. Michael, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Giulianini, Franco, Gögele, Martin, Gordon, Scott D., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Haller, Toomas, Hamet, Pavel, Harris, Tamara B., Hartman, Catharina A., Hayward, Caroline, Hellwege, Jacklyn N., Heng, Chew-Kiat, Hickst, Andrew A., Hofer, Edith, Huang, Wei, Hutri-Kähönen, Nina, Hwang, Shih-Jen, ikram, M. Arfan, indridason, Olafur S., Ingelsson, Erik, ising, Marcus, Jaddoe, Vincent W. V., Jakobsdottir, Johanna, Jonas, Jost B, Joshi, Peter K., Shilpa Josyula, Navya, Jung, Bettina, Kähönen, Mika, Kamatani, Yoichiro, Kammerer, Candace M., Kanai, Masahiro, Kastarinen, Mika, Kerr, Shona M., Khor, Chiea-Chuen, Kiess, Wieland, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kraja, Aldi T., Krajcoviechova, Alena, Kramer, Holly, Krämer, Bernhard K., Kronenberg, Florian, Kubo, Michiaki, Kühnel, Brigitte, Kuokkanen, Mikko, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lange, Leslie A., Langefeld, Carl D., Jen-Mai Lee, Jeannette, Lehne, Benjamin, Lehtimäki, Terho, Lieb, Wolfgang, Cohort Study, Lifelines, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M., Liu, Jun, Liu, Jianjun, Loeffler, Markus, Loos, Ruth J. F., Lucae, Susanne, Ann Lukas, Mary, Lyytikäinen, Leo-Pekka, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Martins, Jade, März, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Christa Meisinger, Meitinger, Thomas, Melander, Olle, Metspalu, Andres, Mikaelsdottir, Evgenia K., Milaneschi, Yuri, Miliku, Kozeta, Mishra, Pashupati P., Veteran Program, V. A. Million, Mohlke, Karen L., Mononen, Nina, Montgomery, Grant W., Mook-Kanamori, Dennis O., Mychaleckyj, Josyf C., Nadkarni, Girish N, Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, ilja M., Noordam, Raymond, O’Connell, Jeffrey, O’Donoghue, Michelle L., Olafsson, Isleifur, Oldehinkel, Albertine J., Orho-Melander, Marju, Ouwehand, Willem H., Padmanabhan, Sandosh, Palmer, Nicholette D., Palsson, Runolfur, Penninx, Brenda W. J. H., Perls, Thomas, Perola, Markus, Pirastu, Mario, Pirastu, Nicola, Pistis, Giorgio, Podgornaia, Anna I., Polasek, Ozren, Ponte, Belen, Porteous, David J., Poulain, Tanja, Pramstaller, Peter P., Preuss, Michael H., Prins, Bram P., Province, Michael A., Rabelink, Ton J., Raffield, Laura M., Raitakari, Olli T., Reilly, Dermot F., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Ridker, Paul M., Rivadeneira, Fernando, Rizzi, Federica, Roberts, David J., Robino, Antonietta, Rossing, Peter, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Ryan, Kathleen A., Saba, Yasaman, Sabanayagam, Charumathi, Salomaa, Veikko, Salvi, Erika, Saum, Kai-Uwe, Schmidt, Helena, Schmidt, Reinhold, Schöttker, Ben, Schulz, Christina-Alexandra, Schupf, Nicole, Shaffer, Christian M., Shi, Yuan, Smith, Albert V., Smith, Blair H., Soranzo, Nicole, Spracklen, Cassandra N., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Svensson, Per O., Szymczak, Silke, Tai, E-Shyong, Tajuddin, Salman M., Tan, Nicholas Y. Q., Taylor, Kent D., Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris H. L., Thomsen, Hauke, Thorleifsson, Gudmar, Toniolo, Daniela, Tönjes, Anke, Tremblay, Johanne, Tzoulaki, Ioanna, Uitterlinden, André G., Vaccargiu, Simona, van Dam, Rob M., van der Harst, Pim, van Duijn, Cornelia M., Velez Edward, Digna R., Verweij, Niek, Vogelezang, suzanne, Völker, üwe, Vollenweider, Peter, Waeber, Gerard, Waldenberger, Melanie, Wallentin, Lars, Wang, Ya Xing, Wang, Chaolong, Waterworth, Dawn M., Bin Wei, Wen, White, Harvey, Whitfield, John B., Wild, Sarah H., Wilson, James F., Wojczynski, Mary K., Wong, Charlene, Wong, Tien-Yin, Xu, Liang, Yang, Qiong, Yasuda, Masayuki, Yerges-Armstrong, Laura M., Zhang, Weihua, Zonderman, Alan B., Rotter, Jerome I., Bochud, Murielle, Psaty, Bruce M., Vitart, Veronique, Wilson, James G., Dehghan, Abbas, Parsa, Afshin, Chasman, Daniel I., Ho, Kevin, Morris, Andrew P., Devuyst, Olivier, Akilesh, Shreeram, Pendergrass, Sarah A., Sim, Xueling, Böger, Carsten A., Okada, Yukinori, Edwards, Todd L., Snieder, Harold, Stefansson, Kari, Hung, Adriana M., Heid, Iris M., Markus Scholz, Teumer, Alexander, Köttgen, Anna, Pattaro, Cristian, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Internal Medicine, Epidemiology, Erasmus MC other, Pediatrics, Psychiatry, APH - Mental Health, APH - Digital Health, Wuttke, M, Li, Y, Li, M, Sieber, Kb, Feitosa, Mf, Gorski, M, Tin, A, Wang, L, Chu, Ay, Hoppmann, A, Kirsten, H, Giri, A, Chai, Jf, Sveinbjornsson, G, Tayo, Bo, Nutile, T, Fuchsberger, C, Marten, J, Cocca, M, Ghasemi, S, Xu, Y, Horn, K, Noce, D, van der Most, Pj, Sedaghat, S, Yu, Z, Akiyama, M, Afaq, S, Ahluwalia, T, Almgren, P, Amin, N, Ärnlöv, J, Bakker, Sjl, Bansal, N, Baptista, D, Bergmann, S, Biggs, Ml, Biino, G, Boehnke, M, Boerwinkle, E, Boissel, M, Bottinger, Ep, Boutin, T, Brenner, H, Brumat, M, Burkhardt, R, Butterworth, A, Campana, Eric, Campbell, A, Campbell, H, Canouil, M, Carroll, Rj, Catamo, E, Chambers, Jc, Chee, Ml, Chen, X, Cheng, Cy, Cheng, Y, Christensen, K, Cifkova, R, Ciullo, M, Concas, Mp, Cook, Jp, Coresh, J, Corre, T, Sala, Cf, Cusi, D, Danesh, J, Daw, Ew, de Borst, Mh, De Grandi, A, de Mutsert, R, de Vries, Apj, Degenhardt, F, Delgado, G, Demirkan, A, Di Angelantonio, E, Dittrich, K, Divers, J, Dorajoo, R, Eckardt, Ku, Ehret, G, Elliott, P, Endlich, K, Evans, Mk, Felix, Jf, Foo, Vhx, Franco, Oh, Franke, A, Freedman, Bi, Freitag-Wolf, S, Friedlander, Y, Froguel, P, Gansevoort, Rt, Gao, H, Gasparini, P, Gaziano, Jm, Giedraitis, V, Gieger, C, Girotto, G, Giulianini, F, Gögele, M, Gordon, Sd, Gudbjartsson, Df, Gudnason, V, Haller, T, Hamet, P, Harris, Tb, Hartman, Ca, Hayward, C, Hellwege, Jn, Heng, Ck, Hicks, Aa, Hofer, E, Huang, W, Hutri-Kähönen, N, Hwang, Sj, Ikram, Ma, Indridason, O, Ingelsson, E, Ising, M, Jaddoe, Vwv, Jakobsdottir, J, Jonas, Jb, Joshi, Pk, Josyula, N, Jung, B, Kähönen, M, Kamatani, Y, Kammerer, Cm, Kanai, M, Kastarinen, M, Kerr, Sm, Khor, Cc, Kiess, W, Kleber, Me, Koenig, W, Kooner, J, Körner, A, Kovacs, P, Kraja, At, Krajcoviechova, A, Kramer, H, Krämer, Bk, Kronenberg, F, Kubo, M, Kühnel, B, Kuokkanen, M, Kuusisto, J, La Bianca, M, Laakso, M, Lange, La, Langefeld, Cd, Lee, Jj, Lehne, B, Lehtimäki, T, Lieb, W, Lifelines Cohort, Study, Lim, Sc, Lind, L, Lindgren, Cm, Liu, J, Loeffler, M, Loos, Rjf, Lucae, S, Lukas, Ma, Lyytikäinen, Lp, Mägi, R, Magnusson, Pke, Mahajan, A, Martin, Ng, Martins, J, März, W, Mascalzoni, D, Matsuda, K, Meisinger, C, Meitinger, T, Melander, O, Metspalu, A, Mikaelsdottir, Ek, Milaneschi, Y, Miliku, K, Mishra, Pp, V. A., Million Veteran Program, Mohlke, Kl, Mononen, N, Montgomery, Gw, Mook-Kanamori, Do, Mychaleckyj, Jc, Nadkarni, Gn, Nalls, Ma, Nauck, M, Nikus, K, Ning, B, Nolte, Im, Noordam, R, O'Connell, J, O'Donoghue, Ml, Olafsson, I, Oldehinkel, Aj, Orho-Melander, M, Ouwehand, Wh, Padmanabhan, S, Palmer, Nd, Palsson, R, Penninx, Bwjh, Perls, T, Perola, M, Pirastu, M, Pirastu, N, Pistis, G, Podgornaia, Ai, Polasek, O, Ponte, B, Porteous, Dj, Poulain, T, Pramstaller, Pp, Preuss, Mh, Prins, Bp, Province, Ma, Rabelink, Tj, Raffield, Lm, Raitakari, Ot, Reilly, Df, Rettig, R, Rheinberger, M, Rice, Km, Ridker, Pm, Rivadeneira, F, Rizzi, F, Roberts, Dj, Robino, A, Rossing, P, Rudan, I, Rueedi, R, Ruggiero, D, Ryan, Ka, Saba, Y, Sabanayagam, C, Salomaa, V, Salvi, E, Saum, Ku, Schmidt, H, Schmidt, R, Schöttker, B, Schulz, Ca, Schupf, N, Shaffer, Cm, Shi, Y, Smith, Av, Smith, Bh, Soranzo, N, Spracklen, Cn, Strauch, K, Stringham, Hm, Stumvoll, M, Svensson, Po, Szymczak, S, Tai, E, Tajuddin, Sm, Tan, Nyq, Taylor, Kd, Teren, A, Tham, Yc, Thiery, J, Thio, Chl, Thomsen, H, Thorleifsson, G, Toniolo, D, Tönjes, A, Tremblay, J, Tzoulaki, I, Uitterlinden, Ag, Vaccargiu, S, van Dam, Rm, van der Harst, P, van Duijn, Cm, Velez Edward, Dr, Verweij, N, Vogelezang, S, Völker, U, Vollenweider, P, Waeber, G, Waldenberger, M, Wallentin, L, Wang, Yx, Wang, C, Waterworth, Dm, Bin Wei, W, White, H, Whitfield, Jb, Wild, Sh, Wilson, Jf, Wojczynski, Mk, Wong, C, Wong, Ty, Xu, L, Yang, Q, Yasuda, M, Yerges-Armstrong, Lm, Zhang, W, Zonderman, Ab, Rotter, Ji, Bochud, M, Psaty, Bm, Vitart, V, Wilson, Jg, Dehghan, A, Parsa, A, Chasman, Di, Ho, K, Morris, Ap, Devuyst, O, Akilesh, S, Pendergrass, Sa, Sim, X, Böger, Ca, Okada, Y, Edwards, Tl, Snieder, H, Stefansson, K, Hung, Am, Heid, Im, Scholz, M, Teumer, A, Köttgen, A, and Pattaro, C.
Subjects: catalog, Inheritance Patterns, Hasso-Plattner-Institut für Digital Engineering GmbH, Genome-wide association study, Disease, Kidney Function Tests, Bioinformatics, DISEASE, 0302 clinical medicine, Uromodulin/urine, kidney function, 11 Medical and Health Sciences, Genetics & Heredity, ddc:616, 0303 health sciences, Kidney, Genome-wide association, HERITABILITY, GENOME-WIDE ASSOCIATION, COMMON VARIANTS, RENAL-FUNCTION, TRANS-EQTLS, METAANALYSIS, TRANSPORTER, CLASSIFICATION, INTEGRATION, Chromosome Mapping, 3. Good health, Phenotype, medicine.anatomical_structure, Medical genetics, Common variants, Renal function, Trans-EQTLS, Metaanalysis, Heritability, Transporter, Life Sciences & Biomedicine, Glomerular Filtration Rate, Metaanalysi, medicine.medical_specialty, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Common variant, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, White People, V. A. Million Veteran Program, 03 medical and health sciences, Quantitative Trait, Heritable, Lifelines Cohort Study, Uromodulin, Genetics, medicine, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, Genetic Association Studies, 030304 developmental biology, Genetic association, Science & Technology, urogenital system, association, genetic loci, 06 Biological Sciences, medicine.disease, Renal Insufficiency, Chronic/genetics/physiopathology/urine, Genetic Association Studies/methods, ddc:000, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study, Kidney disease
Abstract: Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Published: 2019

19. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Author: Jacqueline C.M. Witteman, Nicole Probst-Hensch, Gail Davies, Anna Köttgen, Qunyuan Zhang, Pio D'Adamo, Nicholas G. Martin, Silvia Tore, Stephan J. L. Bakker, Gian Andri Thun, Cinzia Sala, Peter P. Pramstaller, Tamara B. Harris, Aaron Isaacs, Sheila Ulivi, Rossella Sorice, Xuan Liu, Andrew A. Hicks, Henry Völzke, Daniela Ruggiero, Arnold von Eckardstein, Yukinori Okada, Andres Metspalu, Jeffrey Metter, Serena Sanna, Jennifer E. Huffman, Philipp S. Wild, Florian Ernst, Eva Albrecht, Mary F. Feitosa, Claudia Schurmann, Kathrin Budde, Veikko Salomaa, Darina Czamara, Elizabeth G. Holliday, Marcel Bruinenberg, Laura Portas, Maris Laan, Alan J. Gow, Caroline Hayward, Tim D. Spector, Ozren Polasek, Ilja M. Nolte, Rodney J. Scott, Massimo Mangino, David S. Siscovick, Nilesh J. Samani, Toomas Haller, Laura Frogheri, A. Jula, Mika Kähönen, Bruce H. R. Wolffenbuttel, Caroline S. Fox, David R. Jacobs, Julia Shi, Yusuke Nakamura, Daniel I. Chasman, Fabian J. Theis, Alan F. Wright, Ayse Demirkan, Francesco Cucca, Paolo Gasparini, Paul M. Ridker, Olli T. Raitakari, Daniela Toniolo, Maristella Steri, Mario Pirastu, Susan Campbell, Maksim Struchalin, So-Youn Shin, Mark J. Caulfield, H.-Erich Wichmann, Grant W. Montgomery, Åsa Johansson, Alexander Teumer, Ulf Gyllensten, Robert M. Plenge, Michel Burnier, Michael Schallert, Jan Krumsiek, Jing Hua Zhao, Andres Salumets, Poorva Mudgal, Anke Tönjes, James F. Meschia, Gauti Kjartan Gislason, Perttu Salo, Angela Döring, Afshin Parsa, Vilmundur Gudnason, Patrick F. McArdle, Rita P. S. Middelberg, W. H. Linda Kao, Aldi Kraja, Christopher Oldmeadow, Adrienne Tin, Loic Yengo, Murielle Bochud, Gerjan Navis, Christian Gieger, Toshiko Tanaka, Cornelia M. van Duijn, Samuli Ripatti, Terho Lehtimäki, Claudia Langenberg, Bernhard O. Boehm, Conall M. O'Seaghdha, Eric Boerwinkle, Nicole Soranzo, Tõnu Esko, Susan M. Farrington, Mike A. Nalls, John F. Peden, Hyon K. Choi, Anuj Goel, Andrew D. Johnson, Norman Klopp, Anne Grotevendt, Halit Ongen, Marcus E. Kleber, Myriam Fornage, Malcolm G. Dunlop, Igor Rudan, Federico Murgia, Beverley Balkau, Jorma Viikari, Christopher P. Nelson, Gérard Waeber, Lenore J. Launer, Ivana Persico, Inga Prokopenko, Guo Li, Tatijana Zemunik, Elisabetta Trabetti, Tanja Zeller, Hugh Watkins, Qiong Yang, James F. Wilson, Peter Vollenweider, Veronique Vitart, Markus Perola, Nicola Pirastu, Olivier Devuyst, Irene Mateo Leach, John Attia, Bruce M. Psaty, Nicholas J. Wareham, Susanne Lucae, Josef Coresh, Ingrid B. Borecki, Claudia Hundertmark, Weihua Zhang, Luigi Ferrucci, Jaspal S. Kooner, Stefan Kloiber, Lynda M. Rose, Naoyuki Kamatani, Zoltán Kutalik, Giovanni Malerba, Ian J. Deary, Albert V. Smith, Helena Schmidt, Eva Lattka, Philippe Froguel, Harry Campbell, Medea Imboden, Antonio Lupo, Angelo L. Gaffo, Vasiliki Lagou, Alan R. Shuldiner, John Whitfield, Abbas Dehghan, Winfried März, Elin Org, Albert Hofman, Margus Viigimaa, Konstantin Strauch, Toshihiro Tanaka, Andrew B. Singleton, Stefania Bandinelli, Christian Hengstenberg, Xinzhong Li, Wiek H. van Gilst, Pim van der Harst, Giorgio Pistis, Jerome I. Rotter, Maria Grazia Piras, Gary C. Curhan, Brenda W.J.H. Penninx, Ramaiah Nagaraja, Nabila Bouatia-Naji, Christian Müller, Ronald P. Stolk, Pau Navarro, Lorna M. Lopez, Ruth J. F. Loos, Albert Tenesa, Johannes H. Smit, Peter Kraft, Giovanni Gambaro, Sarah H. Wild, Patricia B. Munroe, André G. Uitterlinden, Ivana Kolcic, Bernhard R. Winkelmann, Pankaj Sharma, John C. Chambers, Nicholas D. Hastie, Matthias Nauck, Harold Snieder, Michael Stumvoll, Reinhold Schmidt, Hans L. Hillege, Kiang Liu, Fernando Rivadeneira, Owen M. Woodward, Morris J. Brown, Margus Putku, Sabine Schipf, Mirna Kirin, Kay-Tee Khaw, Melanie Waldenberger, Evropi Theodoratou, Marina Ciullo, Michiaki Kubo, Köttgen, A, Albrecht, E, Teumer, A, Vitart, V, Krumsiek, J, Hundertmark, C, Pistis, G, Ruggiero, D, O'Seaghdha, Cm, Haller, T, Yang, Q, Tanaka, T, Johnson, Ad, Kutalik, Z, Smith, Av, Shi, J, Struchalin, M, Middelberg, Rp, Brown, Mj, Gaffo, Al, Pirastu, Nicola, Li, G, Hayward, C, Zemunik, T, Huffman, J, Yengo, L, Zhao, Jh, Demirkan, A, Feitosa, Mf, Liu, X, Malerba, G, Lopez, Lm, van der Harst, P, Li, X, Kleber, Me, Hicks, Aa, Nolte, Im, Johansson, A, Murgia, F, Wild, Sh, Bakker, Sj, Peden, Jf, Dehghan, A, Steri, M, Tenesa, A, Lagou, V, Salo, P, Mangino, M, Rose, Lm, Lehtimäki, T, Woodward, Om, Okada, Y, Tin, A, Müller, C, Oldmeadow, C, Putku, M, Czamara, D, Kraft, P, Frogheri, L, Thun, Ga, Grotevendt, A, Gislason, Gk, Harris, Tb, Launer, Lj, Mcardle, P, Shuldiner, Ar, Boerwinkle, E, Coresh, J, Schmidt, H, Schallert, M, Martin, Ng, Montgomery, Gw, Kubo, M, Nakamura, Y, Munroe, Pb, Samani, Nj, Jacobs DR, Jr, Liu, K, D'Adamo, ADAMO PIO, Ulivi, S, Rotter, Ji, Psaty, Bm, Vollenweider, P, Waeber, G, Campbell, S, Devuyst, O, Navarro, P, Kolcic, I, Hastie, N, Balkau, B, Froguel, P, Esko, T, Salumets, A, Khaw, Kt, Langenberg, C, Wareham, Nj, Isaacs, A, Kraja, A, Zhang, Q, Wild, P, Scott, Rj, Holliday, Eg, Org, E, Viigimaa, M, Bandinelli, S, Metter, Je, Lupo, A, Trabetti, E, Sorice, R, Döring, A, Lattka, E, Strauch, K, Theis, F, Waldenberger, M, Wichmann, He, Davies, G, Gow, Aj, Bruinenberg, M, Stolk, Rp, Kooner, J, Zhang, W, Winkelmann, Br, Boehm, Bo, Lucae, S, Penninx, Bw, Smit, Jh, Curhan, G, Mudgal, P, Plenge, Rm, Portas, L, Persico, I, Kirin, M, Wilson, Jf, Leach, Im, van Gilst, Wh, Goel, A, Ongen, H, Hofman, A, Rivadeneira, F, Uitterlinden, Ag, Imboden, M, von Eckardstein, A, Cucca, F, Nagaraja, R, Piras, Mg, Nauck, M, Schurmann, C, Budde, K, Ernst, F, Farrington, Sm, Theodoratou, E, Prokopenko, I, Stumvoll, M, Jula, A, Perola, M, Salomaa, V, Shin, Sy, Spector, Td, Sala, C, Ridker, Pm, Kähönen, M, Viikari, J, Hengstenberg, C, Nelson, Cp, Meschia, Jf, Nalls, Ma, Sharma, P, Singleton, Ab, Kamatani, N, Zeller, T, Burnier, M, Attia, J, Laan, M, Klopp, N, Hillege, Hl, Kloiber, S, Choi, H, Pirastu, M, Tore, S, Probst Hensch, Nm, Völzke, H, Gudnason, V, Parsa, A, Schmidt, R, Whitfield, Jb, Fornage, M, Gasparini, Paolo, Siscovick, D, Polašek, O, Campbell, H, Rudan, I, Bouatia Naji, N, Metspalu, A, Loos, Rj, van Duijn, Cm, Borecki, Ib, Ferrucci, L, Gambaro, G, Deary, Ij, Wolffenbuttel, Bh, Chambers, Jc, März, W, Pramstaller, Pp, Snieder, H, Gyllensten, U, Wright, Af, Navis, G, Watkins, H, Witteman, Jc, Sanna, S, Schipf, S, Dunlop, Mg, Tönjes, A, Ripatti, S, Soranzo, N, Toniolo, D, Chasman, Di, Raitakari, O, Kao, Wh, Ciullo, M, Fox, C, Caulfield, M, Bochud, M, Gieger, C, LifeLines Cohort, Study, Cardiogram, Consortium, Diagram, Consortium, Icbp, Consortium, Magic, Consortium, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Psychiatry, EMGO - Mental health, EMGO+ - Mental Health, LifeLines Cohort Study, CARDIoGRAM Consortium, DIAGRAM Consortium, ICBP Consortium, MAGIC Consortium, Epidemiology, Public Health, and Internal Medicine
Subjects: Candidate gene, Inhibins/genetics, Genome-wide association study, GENETIC-LOCI, chemistry.chemical_compound, 0302 clinical medicine, serum urate, Gene Frequency, Gout/blood, association analysis, serum urate, Glucose/metabolism, Settore MED/14 - NEFROLOGIA, Hyperuricemia, serum, urate, gene, POPULATION, METABOLIC SYNDROME, Genetics, 0303 health sciences, education.field_of_study, biology, Polymorphism, Single Nucleotide/genetics, 3. Good health, HYPERURICEMIA, Genetic Loci/genetics, SLC22A12, Single Nucleotide/genetics, SNPs, Signal Transduction, MOLECULAR PHYSIOLOGY, serum urate concentrations, gout, genome-wide meta-analysis, European Continental Ancestry Group, Population, Polymorphism, Single Nucleotide, White People, Uric Acid/blood, serum urate concentrations, genome-wide meta-analysis, 03 medical and health sciences, SDG 3 - Good Health and Well-being, uric acid, medicine, Humans, Inhibins, Polymorphism, education, 030304 developmental biology, 030203 arthritis & rheumatology, Analysis of Variance, GOUT, IDENTIFICATION, TRANSPORTER, CARDIOVASCULAR-DISEASE RISK, ta3121, medicine.disease, association analysis, Gout, meta-analysis, Glucose, chemistry, Genetic Loci, genome-wide association studies, biology.protein, Signal Transduction/genetics, Uric acid, URIC-ACID LEVELS, Genome-Wide Association Study, SLC2A9
Abstract: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout. © 2013 Nature America, Inc. All rights reserved.
Published: 2013

20. Seventy-five genetic loci influencing the human red blood cell

Author: Teresa Nutile, Anna-Liisa Hartikainen, Stavroula Kanoni, Johannes H. Smit, Harm-Jan Westra, Beben Benyamin, Gonneke Willemsen, Clara S. Tang, Maria Dimitriou, Peter Vollenweider, Olle Melander, Inga Prokopenko, W.H. Wilson Tang, John P. Kemp, Tim D. Spector, Evelin Mihailov, Paul F. O'Reilly, Eleonora Porcu, Marcus E. Kleber, Sheila Ulivi, George Dedoussis, Manuela Uda, Matthias Nauck, Brenda W.J.H. Penninx, Daniela Ruggiero, Xinzhong Li, Dirk S. Paul, Niek Verweij, Bernd Genser, Harold Snieder, Willem H. Ouwehand, Ido P. Kema, Miriam F. Moffatt, Carmel Moore, Hilma Holm, Nicola Pirastu, Adamo Pio D'Adamo, Michael Stumvoll, Rossella Sorice, Kay-Tee Khaw, Heather Lloyd-Jones, Federico Murgia, Stephen F. Garner, Jing Hua Zhao, Laura Portas, Abdel Abdellaoui, Ursula Puc, Andres Metspalu, Marleen H. M. de Moor, Isleifur Olafsson, Ruth J. F. Loos, Andres Salumets, François Bastardot, James Scott, Jian Yang, Braxton D. Mitchell, Debora Parracciani, Maria Novatchkova, Panos Deloukas, William O.C.M. Cookson, Lorna M. Lopez, Andrew A. Hicks, Aude Saint-Pierre, Daniel F. Gudbjartsson, Vinicius Tragante, Mario Pirastu, Jacques S. Beckmann, L. Joost van Pelt, Winfried Maerz, Hooman Allayee, Jouke-Jan Hottenga, Kari Stefansson, Debashish Das, Weihua Zhang, Anke Tönjes, Michela Traglia, Stuart Meacham, Antonio Piga, Cornelis A. Albers, Nicholas G. Martin, John C. Chambers, Christa Meisinger, Leo-Pekka Lyytikäinen, Nicole Soranzo, Mika Kähönen, Katrin Voss, Micha Hersch, Claudia Langenberg, Sian Tsung Tan, Sandosh Padmanabhan, Christian X. Weichenberger, J. Gustav Smith, Antony P. Attwood, Claire E. Hastie, Gunnar Engström, Janina S. Ried, Carsten Oliver Schmidt, Pall T. Onundarson, Kathy Miller, Francisco S. Domingues, Stefania Bandinelli, Ulrich Elling, Augusto Rendon, Paul Elliott, Quince Gibson, Tõnu Esko, Robert Sladek, Marina Ciullo, Gerald Wirnsberger, Franco Anni, Antonietta Robino, Serena Sanna, Hein Schepers, Jonathan Stephens, Joban Sehmi, Beverley Balkau, Jennifer G. Sambrook, Lucia Perseu, Ilja M. Nolte, Herman H W Silljé, John M. Starr, Cinzia Sala, Peter P. Pramstaller, David M. Evans, Renzo Galanello, Uwe Völker, Philippe Froguel, Dorret I. Boomsma, Vasiliki Lagou, Gerjan Navis, Christian Gieger, Susan M. Ring, Alexander Teumer, Angela Döring, Ale Algra, Toshiko Tanaka, Bo Hedblad, Anneli Pouta, Unnur Thorsteinsdottir, Bernhard R. Winkelmann, Liming Liang, John Danesh, Paolo Gasparini, Sarah E. Medland, Ian J. Deary, Martin Gögele, Pim van der Harst, Giorgia Girotto, Josef M. Penninger, Jaspal S. Kooner, Patrick Sulem, Thomas Illig, Yasin Memari, Sarah E. Harris, Wiek H. van Gilst, Francesco Cucca, Dirk J. van Veldhuisen, So-Youn Shin, Giorgio Pistis, Olli T. Raitakari, Lude Franke, Folkert W. Asselbergs, Abtehale Al-Hussani, Stanley L. Hazen, Manuel A. R. Ferreira, Aimo Ruokonen, Christian Dina, Aparna Radhakrishnan, Irene Mateo Leach, Nicholas J. Wareham, George Davey Smith, Eric E. Schadt, Alan R. Shuldiner, John Whitfield, Gudmundur I. Eyjolfsson, Eco J. C. de Geus, Grant W. Montgomery, Afshin Parsa, Terho Lehtimäki, Paolo Fortina, Luigi Ferrucci, Andreas Greinacher, Marjo-Riitta Järvelin, Krista Fischer, Fabrice Danjou, Rudolf A. de Boer, Paul I.W. de Bakker, Peter M. Visscher, Anna F. Dominiczak, Ramiro Ramirez-Solis, Jennifer Jolley, Bruce H. R. Wolffenbuttel, Jaana Hartiala, Daniela Toniolo, Bernhard O. Boehm, van der Harst, P, Zhang, W, Mateo Leach, I, Rendon, A, Verweij, N, Sehmi, J, Paul, D, Elling, U, Allayee, H, Li, X, Radhakrishnan, A, Tan, St, Voss, K, Weichenberger, Cx, Albers, Ca, Al Hussani, A, Asselbergs, Fw, Ciullo, M, Danjou, F, Dina, C, Esko, T, Evans, Dm, Franke, L, Gögele, M, Hartiala, J, Hersch, M, Holm, H, Hottenga, Jj, Kanoni, S, Kleber, Me, Lagou, V, Langenberg, C, Lopez, Lm, Lyytikäinen, Lp, Melander, O, Murgia, F, Nolte, Im, O'Reilly, Pf, Padmanabhan, S, Parsa, A, Pirastu, Nicola, Porcu, E, Portas, L, Prokopenko, I, Ried, J, Shin, Sy, Tang, C, Teumer, A, Traglia, Michela, Ulivi, S, Westra, Hj, Yang, J, Zhao, Jh, Anni, F, Abdellaoui, A, Attwood, A, Balkau, B, Bandinelli, S, Bastardot, F, Benyamin, B, Boehm, Bo, Cookson, Wo, Das, D, de Bakker, Pi, de Boer, Ra, de Geus, Ej, de Moor, Mh, Dimitriou, M, Domingues, F, Döring, A, Engström, G, Eyjolfsson, Gi, Ferrucci, L, Fischer, K, Galanello, R, Garner, Sf, Genser, B, Gibson, Qd, Girotto, Giorgia, Gudbjartsson, Df, Harris, Se, Hartikainen, Al, Hastie, Ce, Hedblad, B, Illig, T, Jolley, J, Kähönen, M, Kema, Ip, Kemp, Jp, Liang, L, Lloyd Jones, H, Loos, Rj, Meacham, S, Medland, Se, Meisinger, C, Memari, Y, Mihailov, E, Miller, K, Moffatt, Mf, Nauck, M, Novatchkova, M, Nutile, T, Olafsson, I, Onundarson, Pt, Parracciani, D, Penninx, Bw, Perseu, L, Piga, A, Pistis, G, Pouta, A, Puc, U, Raitakari, O, Ring, Sm, Robino, Antonietta, Ruggiero, D, Ruokonen, A, Saint Pierre, A, Sala, C, Salumets, A, Sambrook, J, Schepers, H, Schmidt, Co, Silljé, Hh, Sladek, R, Smit, Jh, Starr, Jm, Stephens, J, Sulem, P, Tanaka, T, Thorsteinsdottir, U, Tragante, V, van Gilst, Wh, van Pelt, Lj, van Veldhuisen, Dj, Völker, U, Whitfield, Jb, Willemsen, G, Winkelmann, Br, Wirnsberger, G, Algra, A, Cucca, F, D'Adamo, ADAMO PIO, Danesh, J, Deary, Ij, Dominiczak, Af, Elliott, P, Fortina, P, Froguel, P, Gasparini, Paolo, Greinacher, A, Hazen, Sl, Jarvelin, Mr, Khaw, Kt, Lehtimäki, T, Maerz, W, Martin, Ng, Metspalu, A, Mitchell, Bd, Montgomery, Gw, Moore, C, Navis, G, Pirastu, M, Pramstaller, Pp, Ramirez Solis, R, Schadt, E, Scott, J, Shuldiner, Ar, Smith, Gd, Smith, Jg, Snieder, H, Sorice, R, Spector, Td, Stefansson, K, Stumvoll, M, Tang, Wh, Toniolo, D, Tönjes, A, Visscher, Pm, Vollenweider, P, Wareham, Nj, Wolffenbuttel, Bh, Boomsma, Di, Beckmann, J, Dedoussis, Gv, Deloukas, P, Ferreira, Ma, Sanna, S, Uda, M, Hicks, Aa, Penninger, Jm, Gieger, C, Kooner, J, Ouwehand, Wh, Soranzo, N, Chambers, J. C., Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Van Der Harst, Pim, Zhang, Weihua, Mateo Leach, Irene, Rendon, Augusto, Benyamin, Beben, Chambers, John C, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Male, Netherlands Twin Register (NTR), Candidate gene, Erythrocytes, PROTEIN, Genome-wide association study, DISEASE, Hemoglobins, Mice, 0302 clinical medicine, Genetics, Genomics, blood, 0303 health sciences, Multidisciplinary, biology, Cell Cycle, COMMON VARIANTS, Genomics, Phenotype, anemia, 3. Good health, Haematopoiesis, DROSOPHILA, Drosophila melanogaster, medicine.anatomical_structure, HEMOGLOBIN LEVELS, Organ Specificity, 030220 oncology & carcinogenesis, Cytokines, Female, RNA Interference, TRAITS, Signal Transduction, EXPRESSION, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic, blood, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, RECEPTOR, CONSORTIUM, ta3121, hemoglobin, biology.organism_classification, Hematopoiesis, meta-analysis, Red blood cell, Gene Expression Regulation, Genetic Loci, Expression quantitative trait loci, genome-wide association studies, Genome-Wide Association Study
Abstract: Item does not contain fulltext Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
Published: 2012

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20 results on '"Kleber, ME."'

1. Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis.

2. Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.

3. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

4. NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality.

5. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

6. Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.

7. Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

8. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.

9. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

10. Association between a gene variant near ataxia telangiectasia mutated and coronary artery disease in men.

11. Genome-wide association study identifies 3 genomic loci significantly associated with serum levels of homoarginine: the AtheroRemo Consortium.

12. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.

13. Seventy-five genetic loci influencing the human red blood cell.

14. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

15. A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology

16. Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

17. Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

18. A catalog of genetic loci associated with kidney function from analyses of a million individuals

19. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

20. Seventy-five genetic loci influencing the human red blood cell

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20 results on '"Kleber, ME."'

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