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1. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Author

Ntalla I, Weng LC, Cartwright JH, Hall AW, Sveinbjornsson G, Tucker NR, Choi SH, Chaffin MD, Roselli C, Barnes MR, Mifsud B, Warren HR, Hayward C, Marten J, Cranley JJ, Concas MP, Gasparini P, Boutin T, Kolcic I, Polasek O, Rudan I, Araujo NM, Lima-Costa MF, Ribeiro ALP, Souza RP, Tarazona-Santos E, Giedraitis V, Ingelsson E, Mahajan A, Morris AP, Del Greco M F, Foco L, Gögele M, Hicks AA, Cook JP, Lind L, Lindgren CM, Sundström J, Nelson CP, Riaz MB, Samani NJ, Sinagra G, Ulivi S, Kähönen M, Mishra PP, Mononen N, Nikus K, Caulfield MJ, Dominiczak A, Padmanabhan S, Montasser ME, O'Connell JR, Ryan K, Shuldiner AR, Aeschbacher S, Conen D, Risch L, Thériault S, Hutri-Kähönen N, Lehtimäki T, Lyytikäinen LP, Raitakari OT, Barnes CLK, Campbell H, Joshi PK, Wilson JF, Isaacs A, Kors JA, van Duijn CM, Huang PL, Gudnason V, Harris TB, Launer LJ, Smith AV, Bottinger EP, Loos RJF, Nadkarni GN, Preuss MH, Correa A, Mei H, Wilson J, Meitinger T, Müller-Nurasyid M, Peters A, Waldenberger M, Mangino M, Spector TD, Rienstra M, van de Vegte YJ, van der Harst P, Verweij N, Kääb S, Schramm K, Sinner MF, Strauch K, Cutler MJ, Fatkin D, London B, Olesen M, Roden DM, Benjamin Shoemaker M, Gustav Smith J, Biggs ML, Bis JC, Brody JA, Psaty BM, Rice K, Sotoodehnia N, De Grandi A, Fuchsberger C, Pattaro C, Pramstaller PP, Ford I, Wouter Jukema J, Macfarlane PW, Trompet S, Dörr M, Felix SB, Völker U, Weiss S, Havulinna AS, Jula A, Sääksjärvi K, Salomaa V, Guo X, Heckbert SR, Lin HJ, Rotter JI, Taylor KD, Yao J, de Mutsert R, Maan AC, Mook-Kanamori DO, Noordam R, Cucca F, Ding J, Lakatta EG, Qian Y, Tarasov KV, Levy D, Lin H, Newton-Cheh CH, Lunetta KL, Murray AD, Porteous DJ, Smith BH, Stricker BH, Uitterlinden A, van den Berg ME, Haessler J, Jackson RD, Kooperberg C, Peters U, Reiner AP, Whitsel EA, Alonso A, Arking DE, Boerwinkle E, Ehret GB, Soliman EZ, Avery CL, Gogarten SM, Kerr KF, Laurie CC, Seyerle AA, Stilp A, Assa S, Abdullah Said M, Yldau van der Ende M, Lambiase PD, Orini M, Ramirez J, Van Duijvenboden S, Arnar DO, Gudbjartsson DF, Holm H, Sulem P, Thorleifsson G, Thorolfsdottir RB, Thorsteinsdottir U, Benjamin EJ, Tinker A, Stefansson K, Ellinor PT, Jamshidi Y, Lubitz SA, and Munroe PB

Subjects
Arrhythmias, Cardiac physiopathology, Cardiovascular Diseases genetics, Cardiovascular Diseases physiopathology, Endophenotypes, Female, Gene Expression, Genetic Variation, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Quantitative Trait Loci genetics, Arrhythmias, Cardiac genetics, Electrocardiography, Genetic Loci genetics, Genetic Predisposition to Disease genetics
Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Published
2020
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2. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Author

Franceschini N, Giambartolomei C, de Vries PS, Finan C, Bis JC, Huntley RP, Lovering RC, Tajuddin SM, Winkler TW, Graff M, Kavousi M, Dale C, Smith AV, Hofer E, van Leeuwen EM, Nolte IM, Lu L, Scholz M, Sargurupremraj M, Pitkänen N, Franzén O, Joshi PK, Noordam R, Marioni RE, Hwang SJ, Musani SK, Schminke U, Palmas W, Isaacs A, Correa A, Zonderman AB, Hofman A, Teumer A, Cox AJ, Uitterlinden AG, Wong A, Smit AJ, Newman AB, Britton A, Ruusalepp A, Sennblad B, Hedblad B, Pasaniuc B, Penninx BW, Langefeld CD, Wassel CL, Tzourio C, Fava C, Baldassarre D, O'Leary DH, Teupser D, Kuh D, Tremoli E, Mannarino E, Grossi E, Boerwinkle E, Schadt EE, Ingelsson E, Veglia F, Rivadeneira F, Beutner F, Chauhan G, Heiss G, Snieder H, Campbell H, Völzke H, Markus HS, Deary IJ, Jukema JW, de Graaf J, Price J, Pott J, Hopewell JC, Liang J, Thiery J, Engmann J, Gertow K, Rice K, Taylor KD, Dhana K, Kiemeney LALM, Lind L, Raffield LM, Launer LJ, Holdt LM, Dörr M, Dichgans M, Traylor M, Sitzer M, Kumari M, Kivimaki M, Nalls MA, Melander O, Raitakari O, Franco OH, Rueda-Ochoa OL, Roussos P, Whincup PH, Amouyel P, Giral P, Anugu P, Wong Q, Malik R, Rauramaa R, Burkhardt R, Hardy R, Schmidt R, de Mutsert R, Morris RW, Strawbridge RJ, Wannamethee SG, Hägg S, Shah S, McLachlan S, Trompet S, Seshadri S, Kurl S, Heckbert SR, Ring S, Harris TB, Lehtimäki T, Galesloot TE, Shah T, de Faire U, Plagnol V, Rosamond WD, Post W, Zhu X, Zhang X, Guo X, Saba Y, Dehghan A, Seldenrijk A, Morrison AC, Hamsten A, Psaty BM, van Duijn CM, Lawlor DA, Mook-Kanamori DO, Bowden DW, Schmidt H, Wilson JF, Wilson JG, Rotter JI, Wardlaw JM, Deanfield J, Halcox J, Lyytikäinen LP, Loeffler M, Evans MK, Debette S, Humphries SE, Völker U, Gudnason V, Hingorani AD, Björkegren JLM, Casas JP, and O'Donnell CJ

Subjects
ADAMTS9 Protein genetics, Amino Acid Oxidoreductases genetics, Coronary Disease pathology, Humans, Lod Score, Plaque, Atherosclerotic pathology, Polymorphism, Single Nucleotide, Protein-Lysine 6-Oxidase, Quantitative Trait Loci genetics, Risk Factors, Carotid Intima-Media Thickness, Coronary Disease genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Plaque, Atherosclerotic genetics
Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Published
2018
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3. Heritability in a SCN5A-mutation founder population with increased female susceptibility to non-nocturnal ventricular tachyarrhythmia and sudden cardiac death.

Author

Ter Bekke RMA, Isaacs A, Barysenka A, Hoos MB, Jongbloed JDH, Hoorntje JCA, Patelski ASM, Helderman-van den Enden ATJM, van den Wijngaard A, Stoll M, and Volders PGA

Subjects
DNA genetics, DNA Mutational Analysis, Female, Follow-Up Studies, Heterozygote, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel metabolism, Pedigree, Phenotype, Retrospective Studies, Tachycardia, Ventricular metabolism, Tachycardia, Ventricular physiopathology, Death, Sudden, Cardiac etiology, Electrocardiography, Genetic Predisposition to Disease, Heart Conduction System physiopathology, Mutation, NAV1.5 Voltage-Gated Sodium Channel genetics, Tachycardia, Ventricular genetics
Abstract

Background: Heritable cardiac-sodium channel dysfunction is associated with various arrhythmia syndromes, some predisposing to ventricular fibrillation. Phenotypic diversity among carriers of identical-by-descent mutations is often remarkable, suggesting influences of genetic modifiers., Objective: The purpose of this study was to identify a unique SCN5A-mutation founder population with mixed clinical phenotypes and sudden cardiac death, and to investigate the heritability of electromechanical traits besides the SCN5A-mutation effect., Methods: The 16-generation founder population segregating SCN5A c.4850&#95;4852delTCT, p.(Phe1617del), was comprehensively phenotyped. Variance component analysis was used to evaluate the mutation's effects and assess heritability., Results: In 45 p.(Phe1617del) positives, the mutation associated strongly with QTc prolongation (472 ± 60 ms vs 423 ± 35 ms in 26 mutation negatives; P <.001; odds ratio for long-QT syndrome 22.4; 95% confidence interval 4.5-224.2; P <.001) and electromechanical window (EMW) negativity (-29 ± 47 ms vs 34 ± 26 ms; P <.001). Overlapping phenotypes including conduction delay and Brugada syndrome were noted in 19. Polymorphic ventricular tachyarrhythmias occurred mostly in the daytime, after arousal-evoked heart-rate acceleration and repolarization prolongation. Cox proportional hazards regression analysis revealed female gender as an independent risk factor for cardiac events (hazard ratio 5.1; 95% confidence interval 1.6-16.3; P = .006). p.(Phe1617del) was an important determinant of QTc baseline , QTc max , and EMW, explaining 18%, 28%, and 37%, respectively, of the trait's variance. Significant heritability was observed for PQ interval (P = .003) after accounting for the p.(Phe1617del) effect., Conclusion: This SCN5A-p.(Phe1617del) founder population with phenotypic divergence and overlap reveals long-QT syndrome-related and arousal-evoked ventricular tachyarrhythmias with a female preponderance. Variance component analysis indicates additional genetic variance for PQ interval hidden in the genome, besides a dominant p.(Phe1617del) effect on QTc and EMW., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Published
2017
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4. Identification of context-dependent expression quantitative trait loci in whole blood.

Author

Zhernakova DV, Deelen P, Vermaat M, van Iterson M, van Galen M, Arindrarto W, van 't Hof P, Mei H, van Dijk F, Westra HJ, Bonder MJ, van Rooij J, Verkerk M, Jhamai PM, Moed M, Kielbasa SM, Bot J, Nooren I, Pool R, van Dongen J, Hottenga JJ, Stehouwer CD, van der Kallen CJ, Schalkwijk CG, Zhernakova A, Li Y, Tigchelaar EF, de Klein N, Beekman M, Deelen J, van Heemst D, van den Berg LH, Hofman A, Uitterlinden AG, van Greevenbroek MM, Veldink JH, Boomsma DI, van Duijn CM, Wijmenga C, Slagboom PE, Swertz MA, Isaacs A, van Meurs JB, Jansen R, Heijmans BT, 't Hoen PA, and Franke L

Subjects
Cohort Studies, Female, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, RNA, Messenger genetics, Blood Proteins genetics, Cell Lineage genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, RNA, Messenger blood, Regulatory Sequences, Nucleic Acid genetics
Abstract

Genetic risk factors often localize to noncoding regions of the genome with unknown effects on disease etiology. Expression quantitative trait loci (eQTLs) help to explain the regulatory mechanisms underlying these genetic associations. Knowledge of the context that determines the nature and strength of eQTLs may help identify cell types relevant to pathophysiology and the regulatory networks underlying disease. Here we generated peripheral blood RNA-seq data from 2,116 unrelated individuals and systematically identified context-dependent eQTLs using a hypothesis-free strategy that does not require previous knowledge of the identity of the modifiers. Of the 23,060 significant cis-regulated genes (false discovery rate (FDR) ≤ 0.05), 2,743 (12%) showed context-dependent eQTL effects. The majority of these effects were influenced by cell type composition. A set of 145 cis-eQTLs depended on type I interferon signaling. Others were modulated by specific transcription factors binding to the eQTL SNPs.

Published
2017
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5. Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram.

Author

Verweij N, Mateo Leach I, Isaacs A, Arking DE, Bis JC, Pers TH, Van Den Berg ME, Lyytikäinen LP, Barnett P, Wang X, Soliman EZ, Van Duijn CM, Kähönen M, Van Veldhuisen DJ, Kors JA, Raitakari OT, Silva CT, Lehtimäki T, Hillege HL, Hirschhorn JN, Boyer LA, Van Gilst WH, Alonso A, Sotoodehnia N, Eijgelsheim M, De Boer RA, De Bakker PI, Franke L, and Van Der Harst P

Subjects
Adaptor Proteins, Signal Transducing genetics, Arrhythmias, Cardiac physiopathology, Basic Helix-Loop-Helix Transcription Factors genetics, Brugada Syndrome physiopathology, Cardiac Conduction System Disease, Death, Sudden, Cardiac pathology, Female, Heart Conduction System physiopathology, Humans, Male, NAV1.5 Voltage-Gated Sodium Channel genetics, Polymorphism, Single Nucleotide genetics, Repressor Proteins genetics, Shab Potassium Channels genetics, Shal Potassium Channels genetics, Arrhythmias, Cardiac genetics, Brugada Syndrome genetics, Electrocardiography, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up., (© The Author 2016. Published by Oxford University Press.)

Published
2016
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6. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Author

Pattaro C, Teumer A, Gorski M, Chu AY, Li M, Mijatovic V, Garnaas M, Tin A, Sorice R, Li Y, Taliun D, Olden M, Foster M, Yang Q, Chen MH, Pers TH, Johnson AD, Ko YA, Fuchsberger C, Tayo B, Nalls M, Feitosa MF, Isaacs A, Dehghan A, d'Adamo P, Adeyemo A, Dieffenbach AK, Zonderman AB, Nolte IM, van der Most PJ, Wright AF, Shuldiner AR, Morrison AC, Hofman A, Smith AV, Dreisbach AW, Franke A, Uitterlinden AG, Metspalu A, Tonjes A, Lupo A, Robino A, Johansson Å, Demirkan A, Kollerits B, Freedman BI, Ponte B, Oostra BA, Paulweber B, Krämer BK, Mitchell BD, Buckley BM, Peralta CA, Hayward C, Helmer C, Rotimi CN, Shaffer CM, Müller C, Sala C, van Duijn CM, Saint-Pierre A, Ackermann D, Shriner D, Ruggiero D, Toniolo D, Lu Y, Cusi D, Czamara D, Ellinghaus D, Siscovick DS, Ruderfer D, Gieger C, Grallert H, Rochtchina E, Atkinson EJ, Holliday EG, Boerwinkle E, Salvi E, Bottinger EP, Murgia F, Rivadeneira F, Ernst F, Kronenberg F, Hu FB, Navis GJ, Curhan GC, Ehret GB, Homuth G, Coassin S, Thun GA, Pistis G, Gambaro G, Malerba G, Montgomery GW, Eiriksdottir G, Jacobs G, Li G, Wichmann HE, Campbell H, Schmidt H, Wallaschofski H, Völzke H, Brenner H, Kroemer HK, Kramer H, Lin H, Leach IM, Ford I, Guessous I, Rudan I, Prokopenko I, Borecki I, Heid IM, Kolcic I, Persico I, Jukema JW, Wilson JF, Felix JF, Divers J, Lambert JC, Stafford JM, Gaspoz JM, Smith JA, Faul JD, Wang JJ, Ding J, Hirschhorn JN, Attia J, Whitfield JB, Chalmers J, Viikari J, Coresh J, Denny JC, Karjalainen J, Fernandes JK, Endlich K, Butterbach K, Keene KL, Lohman K, Portas L, Launer LJ, Lyytikäinen LP, Yengo L, Franke L, Ferrucci L, Rose LM, Kedenko L, Rao M, Struchalin M, Kleber ME, Cavalieri M, Haun M, Cornelis MC, Ciullo M, Pirastu M, de Andrade M, McEvoy MA, Woodward M, Adam M, Cocca M, Nauck M, Imboden M, Waldenberger M, Pruijm M, Metzger M, Stumvoll M, Evans MK, Sale MM, Kähönen M, Boban M, Bochud M, Rheinberger M, Verweij N, Bouatia-Naji N, Martin NG, Hastie N, Probst-Hensch N, Soranzo N, Devuyst O, Raitakari O, Gottesman O, Franco OH, Polasek O, Gasparini P, Munroe PB, Ridker PM, Mitchell P, Muntner P, Meisinger C, Smit JH, Kovacs P, Wild PS, Froguel P, Rettig R, Mägi R, Biffar R, Schmidt R, Middelberg RP, Carroll RJ, Penninx BW, Scott RJ, Katz R, Sedaghat S, Wild SH, Kardia SL, Ulivi S, Hwang SJ, Enroth S, Kloiber S, Trompet S, Stengel B, Hancock SJ, Turner ST, Rosas SE, Stracke S, Harris TB, Zeller T, Zemunik T, Lehtimäki T, Illig T, Aspelund T, Nikopensius T, Esko T, Tanaka T, Gyllensten U, Völker U, Emilsson V, Vitart V, Aalto V, Gudnason V, Chouraki V, Chen WM, Igl W, März W, Koenig W, Lieb W, Loos RJ, Liu Y, Snieder H, Pramstaller PP, Parsa A, O'Connell JR, Susztak K, Hamet P, Tremblay J, de Boer IH, Böger CA, Goessling W, Chasman DI, Köttgen A, Kao WH, and Fox CS

Subjects
Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Chronic genetics
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Published
2016
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7. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.

Author

Horikoshi M, Mӓgi R, van de Bunt M, Surakka I, Sarin AP, Mahajan A, Marullo L, Thorleifsson G, Hӓgg S, Hottenga JJ, Ladenvall C, Ried JS, Winkler TW, Willems SM, Pervjakova N, Esko T, Beekman M, Nelson CP, Willenborg C, Wiltshire S, Ferreira T, Fernandez J, Gaulton KJ, Steinthorsdottir V, Hamsten A, Magnusson PK, Willemsen G, Milaneschi Y, Robertson NR, Groves CJ, Bennett AJ, Lehtimӓki T, Viikari JS, Rung J, Lyssenko V, Perola M, Heid IM, Herder C, Grallert H, Müller-Nurasyid M, Roden M, Hypponen E, Isaacs A, van Leeuwen EM, Karssen LC, Mihailov E, Houwing-Duistermaat JJ, de Craen AJ, Deelen J, Havulinna AS, Blades M, Hengstenberg C, Erdmann J, Schunkert H, Kaprio J, Tobin MD, Samani NJ, Lind L, Salomaa V, Lindgren CM, Slagboom PE, Metspalu A, van Duijn CM, Eriksson JG, Peters A, Gieger C, Jula A, Groop L, Raitakari OT, Power C, Penninx BW, de Geus E, Smit JH, Boomsma DI, Pedersen NL, Ingelsson E, Thorsteinsdottir U, Stefansson K, Ripatti S, Prokopenko I, McCarthy MI, and Morris AP

Subjects
Body Mass Index, Gene Frequency genetics, Genome-Wide Association Study, Germinal Center Kinases, Glucose-6-Phosphatase genetics, Humans, Polymorphism, Single Nucleotide genetics, Protein Serine-Threonine Kinases genetics, Thrombospondins genetics, Chromosome Mapping, Genetic Predisposition to Disease, Glycemic Index genetics, Obesity genetics, Quantitative Trait Loci genetics
Abstract

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Published
2015
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8. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Author

Wessel J, Chu AY, Willems SM, Wang S, Yaghootkar H, Brody JA, Dauriz M, Hivert MF, Raghavan S, Lipovich L, Hidalgo B, Fox K, Huffman JE, An P, Lu Y, Rasmussen-Torvik LJ, Grarup N, Ehm MG, Li L, Baldridge AS, Stančáková A, Abrol R, Besse C, Boland A, Bork-Jensen J, Fornage M, Freitag DF, Garcia ME, Guo X, Hara K, Isaacs A, Jakobsdottir J, Lange LA, Layton JC, Li M, Hua Zhao J, Meidtner K, Morrison AC, Nalls MA, Peters MJ, Sabater-Lleal M, Schurmann C, Silveira A, Smith AV, Southam L, Stoiber MH, Strawbridge RJ, Taylor KD, Varga TV, Allin KH, Amin N, Aponte JL, Aung T, Barbieri C, Bihlmeyer NA, Boehnke M, Bombieri C, Bowden DW, Burns SM, Chen Y, Chen YD, Cheng CY, Correa A, Czajkowski J, Dehghan A, Ehret GB, Eiriksdottir G, Escher SA, Farmaki AE, Frånberg M, Gambaro G, Giulianini F, Goddard WA 3rd, Goel A, Gottesman O, Grove ML, Gustafsson S, Hai Y, Hallmans G, Heo J, Hoffmann P, Ikram MK, Jensen RA, Jørgensen ME, Jørgensen T, Karaleftheri M, Khor CC, Kirkpatrick A, Kraja AT, Kuusisto J, Lange EM, Lee IT, Lee WJ, Leong A, Liao J, Liu C, Liu Y, Lindgren CM, Linneberg A, Malerba G, Mamakou V, Marouli E, Maruthur NM, Matchan A, McKean-Cowdin R, McLeod O, Metcalf GA, Mohlke KL, Muzny DM, Ntalla I, Palmer ND, Pasko D, Peter A, Rayner NW, Renström F, Rice K, Sala CF, Sennblad B, Serafetinidis I, Smith JA, Soranzo N, Speliotes EK, Stahl EA, Stirrups K, Tentolouris N, Thanopoulou A, Torres M, Traglia M, Tsafantakis E, Javad S, Yanek LR, Zengini E, Becker DM, Bis JC, Brown JB, Cupples LA, Hansen T, Ingelsson E, Karter AJ, Lorenzo C, Mathias RA, Norris JM, Peloso GM, Sheu WH, Toniolo D, Vaidya D, Varma R, Wagenknecht LE, Boeing H, Bottinger EP, Dedoussis G, Deloukas P, Ferrannini E, Franco OH, Franks PW, Gibbs RA, Gudnason V, Hamsten A, Harris TB, Hattersley AT, Hayward C, Hofman A, Jansson JH, Langenberg C, Launer LJ, Levy D, Oostra BA, O'Donnell CJ, O'Rahilly S, Padmanabhan S, Pankow JS, Polasek O, Province MA, Rich SS, Ridker PM, Rudan I, Schulze MB, Smith BH, Uitterlinden AG, Walker M, Watkins H, Wong TY, Zeggini E, Laakso M, Borecki IB, Chasman DI, Pedersen O, Psaty BM, Tai ES, van Duijn CM, Wareham NJ, Waterworth DM, Boerwinkle E, Kao WH, Florez JC, Loos RJ, Wilson JG, Frayling TM, Siscovick DS, Dupuis J, Rotter JI, Meigs JB, Scott RA, and Goodarzi MO

Subjects
Black People genetics, Diabetes Mellitus, Type 2 blood, Genetic Association Studies, Genetic Loci, Glucagon-Like Peptide-1 Receptor genetics, Glucose-6-Phosphatase genetics, Humans, Insulin blood, Polymorphism, Single Nucleotide genetics, White People genetics, Blood Glucose metabolism, Diabetes Mellitus, Type 2 genetics, Exome genetics, Fasting blood, Genetic Predisposition to Disease, Genetic Variation, Mutation Rate, Oligonucleotide Array Sequence Analysis
Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

Published
2015
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9. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.

Author

Benyamin B, Esko T, Ried JS, Radhakrishnan A, Vermeulen SH, Traglia M, Gögele M, Anderson D, Broer L, Podmore C, Luan J, Kutalik Z, Sanna S, van der Meer P, Tanaka T, Wang F, Westra HJ, Franke L, Mihailov E, Milani L, Hälldin J, Winkelmann J, Meitinger T, Thiery J, Peters A, Waldenberger M, Rendon A, Jolley J, Sambrook J, Kiemeney LA, Sweep FC, Sala CF, Schwienbacher C, Pichler I, Hui J, Demirkan A, Isaacs A, Amin N, Steri M, Waeber G, Verweij N, Powell JE, Nyholt DR, Heath AC, Madden PA, Visscher PM, Wright MJ, Montgomery GW, Martin NG, Hernandez D, Bandinelli S, van der Harst P, Uda M, Vollenweider P, Scott RA, Langenberg C, Wareham NJ, van Duijn C, Beilby J, Pramstaller PP, Hicks AA, Ouwehand WH, Oexle K, Gieger C, Metspalu A, Camaschella C, Toniolo D, Swinkels DW, and Whitfield JB

Subjects
Adult, Chromosomes, Human, Pair 7 genetics, Ferritins metabolism, Gene Expression Regulation, Genetic Association Studies, Hemochromatosis blood, Humans, Iron blood, Lipids blood, Phenotype, Polymorphism, Single Nucleotide genetics, Reproducibility of Results, Risk Factors, Transferrin metabolism, Genetic Loci, Genetic Predisposition to Disease, Hemochromatosis genetics, Homeostasis genetics, Iron metabolism
Abstract

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

Published
2014
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10. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Author

Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ, Pihur V, Vollenweider P, O'Reilly PF, Amin N, Bragg-Gresham JL, Teumer A, Glazer NL, Launer L, Zhao JH, Aulchenko Y, Heath S, Sõber S, Parsa A, Luan J, Arora P, Dehghan A, Zhang F, Lucas G, Hicks AA, Jackson AU, Peden JF, Tanaka T, Wild SH, Rudan I, Igl W, Milaneschi Y, Parker AN, Fava C, Chambers JC, Fox ER, Kumari M, Go MJ, van der Harst P, Kao WH, Sjögren M, Vinay DG, Alexander M, Tabara Y, Shaw-Hawkins S, Whincup PH, Liu Y, Shi G, Kuusisto J, Tayo B, Seielstad M, Sim X, Nguyen KD, Lehtimäki T, Matullo G, Wu Y, Gaunt TR, Onland-Moret NC, Cooper MN, Platou CG, Org E, Hardy R, Dahgam S, Palmen J, Vitart V, Braund PS, Kuznetsova T, Uiterwaal CS, Adeyemo A, Palmas W, Campbell H, Ludwig B, Tomaszewski M, Tzoulaki I, Palmer ND, Aspelund T, Garcia M, Chang YP, O'Connell JR, Steinle NI, Grobbee DE, Arking DE, Kardia SL, Morrison AC, Hernandez D, Najjar S, McArdle WL, Hadley D, Brown MJ, Connell JM, Hingorani AD, Day IN, Lawlor DA, Beilby JP, Lawrence RW, Clarke R, Hopewell JC, Ongen H, Dreisbach AW, Li Y, Young JH, Bis JC, Kähönen M, Viikari J, Adair LS, Lee NR, Chen MH, Olden M, Pattaro C, Bolton JA, Köttgen A, Bergmann S, Mooser V, Chaturvedi N, Frayling TM, Islam M, Jafar TH, Erdmann J, Kulkarni SR, Bornstein SR, Grässler J, Groop L, Voight BF, Kettunen J, Howard P, Taylor A, Guarrera S, Ricceri F, Emilsson V, Plump A, Barroso I, Khaw KT, Weder AB, Hunt SC, Sun YV, Bergman RN, Collins FS, Bonnycastle LL, Scott LJ, Stringham HM, Peltonen L, Perola M, Vartiainen E, Brand SM, Staessen JA, Wang TJ, Burton PR, Soler Artigas M, Dong Y, Snieder H, Wang X, Zhu H, Lohman KK, Rudock ME, Heckbert SR, Smith NL, Wiggins KL, Doumatey A, Shriner D, Veldre G, Viigimaa M, Kinra S, Prabhakaran D, Tripathy V, Langefeld CD, Rosengren A, Thelle DS, Corsi AM, Singleton A, Forrester T, Hilton G, McKenzie CA, Salako T, Iwai N, Kita Y, Ogihara T, Ohkubo T, Okamura T, Ueshima H, Umemura S, Eyheramendy S, Meitinger T, Wichmann HE, Cho YS, Kim HL, Lee JY, Scott J, Sehmi JS, Zhang W, Hedblad B, Nilsson P, Smith GD, Wong A, Narisu N, Stančáková A, Raffel LJ, Yao J, Kathiresan S, O'Donnell CJ, Schwartz SM, Ikram MA, Longstreth WT Jr, Mosley TH, Seshadri S, Shrine NR, Wain LV, Morken MA, Swift AJ, Laitinen J, Prokopenko I, Zitting P, Cooper JA, Humphries SE, Danesh J, Rasheed A, Goel A, Hamsten A, Watkins H, Bakker SJ, van Gilst WH, Janipalli CS, Mani KR, Yajnik CS, Hofman A, Mattace-Raso FU, Oostra BA, Demirkan A, Isaacs A, Rivadeneira F, Lakatta EG, Orru M, Scuteri A, Ala-Korpela M, Kangas AJ, Lyytikäinen LP, Soininen P, Tukiainen T, Würtz P, Ong RT, Dörr M, Kroemer HK, Völker U, Völzke H, Galan P, Hercberg S, Lathrop M, Zelenika D, Deloukas P, Mangino M, Spector TD, Zhai G, Meschia JF, Nalls MA, Sharma P, Terzic J, Kumar MV, Denniff M, Zukowska-Szczechowska E, Wagenknecht LE, Fowkes FG, Charchar FJ, Schwarz PE, Hayward C, Guo X, Rotimi C, Bots ML, Brand E, Samani NJ, Polasek O, Talmud PJ, Nyberg F, Kuh D, Laan M, Hveem K, Palmer LJ, van der Schouw YT, Casas JP, Mohlke KL, Vineis P, Raitakari O, Ganesh SK, Wong TY, Tai ES, Cooper RS, Laakso M, Rao DC, Harris TB, Morris RW, Dominiczak AF, Kivimaki M, Marmot MG, Miki T, Saleheen D, Chandak GR, Coresh J, Navis G, Salomaa V, Han BG, Zhu X, Kooner JS, Melander O, Ridker PM, Bandinelli S, Gyllensten UB, Wright AF, Wilson JF, Ferrucci L, Farrall M, Tuomilehto J, Pramstaller PP, Elosua R, Soranzo N, Sijbrands EJ, Altshuler D, Loos RJ, Shuldiner AR, Gieger C, Meneton P, Uitterlinden AG, Wareham NJ, Gudnason V, Rotter JI, Rettig R, Uda M, Strachan DP, Witteman JC, Hartikainen AL, Beckmann JS, Boerwinkle E, Vasan RS, Boehnke M, Larson MG, Järvelin MR, Psaty BM, Abecasis GR, Chakravarti A, Elliott P, van Duijn CM, Newton-Cheh C, Levy D, Caulfield MJ, and Johnson T

Subjects
Africa ethnology, Asia ethnology, Blood Pressure physiology, Coronary Artery Disease genetics, Europe ethnology, Genome-Wide Association Study, Humans, Hypertension genetics, Kidney Diseases genetics, Stroke genetics, Blood Pressure genetics, Cardiovascular Diseases genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide genetics
Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Published
2011
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11. A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14.

Author

Solouki AM, Verhoeven VJ, van Duijn CM, Verkerk AJ, Ikram MK, Hysi PG, Despriet DD, van Koolwijk LM, Ho L, Ramdas WD, Czudowska M, Kuijpers RW, Amin N, Struchalin M, Aulchenko YS, van Rij G, Riemslag FC, Young TL, Mackey DA, Spector TD, Gorgels TG, Willemse-Assink JJ, Isaacs A, Kramer R, Swagemakers SM, Bergen AA, van Oosterhout AA, Oostra BA, Rivadeneira F, Uitterlinden AG, Hofman A, de Jong PT, Hammond CJ, Vingerling JR, and Klaver CC

Subjects
Actins genetics, Adolescent, Adult, Aged, Case-Control Studies, Connexins genetics, Female, Genetic Variation genetics, Genotype, Humans, Male, Middle Aged, Young Adult, Gap Junction delta-2 Protein, Chromosomes, Human, Pair 15 genetics, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Myopia genetics
Abstract

Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10⁻¹⁴). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16-1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42-2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

Published
2010
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12. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.

Author

Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, Falchi M, Willemsen G, Hottenga JJ, de Geus EJ, Montgomery GW, Whitfield J, Magnusson P, Saharinen J, Perola M, Silander K, Isaacs A, Sijbrands EJ, Uitterlinden AG, Witteman JC, Oostra BA, Elliott P, Ruokonen A, Sabatti C, Gieger C, Meitinger T, Kronenberg F, Döring A, Wichmann HE, Smit JH, McCarthy MI, van Duijn CM, and Peltonen L

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Body Mass Index, Cholesterol, HDL blood, Cohort Studies, Female, Genetic Testing, Genome, Human genetics, Humans, Male, Metabolic Networks and Pathways genetics, Middle Aged, Phenotype, Polymorphism, Single Nucleotide genetics, Sex Characteristics, Coronary Disease blood, Coronary Disease genetics, Genetic Predisposition to Disease, Lipids blood, Quantitative Trait Loci genetics, White People genetics
Abstract

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

Published
2009
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13. Cyclin-dependent kinase 5 is associated with risk for Alzheimer's disease in a Dutch population-based study.

Author

Arias-Vásquez A, Aulchenko YS, Isaacs A, van Oosterhout A, Sleegers K, Hofman A, van Broeckhoven C, Oostra BA, Breteler M, and van Duijn CM

Subjects
Aged, Alzheimer Disease enzymology, Alzheimer Disease epidemiology, Brain physiopathology, DNA Mutational Analysis, Female, Genetic Markers genetics, Genetic Testing, Genotype, Haplotypes genetics, Humans, Incidence, Male, Netherlands epidemiology, Prevalence, Risk Factors, Alzheimer Disease genetics, Brain enzymology, Cyclin-Dependent Kinase 5 genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide genetics
Abstract

Although the role of the Cdk5 protein in Alzheimer's disease (AD) is well recognized, there have been relatively few studies investigating genetic variants in the CDK5 gene in AD. In this study, we assessed the association between five previously described single nucleotide polymorphisms (SNPs) in the CDK5 gene and late onset AD by means of logistic regression and haplotype association analyses. Including all prevalent and incident AD cases, we found a significantly increased risk of AD for carriers of the GG genotype of SNP rs2069442 (OR = 1.79, 95 % CI 1.16-2.79, p = 0.001) in those without APOE*4. When limiting the analysis to incident cases without APOE*4, carriers of the GG genotype showed a 1.9-fold increased risk of AD (95 % CI 1.16-3.10, p = 0.003). Variations in the CDK5 gene can be described in 5 haplotype blocks. In our analysis, the haplotype tagged by the G allele of SNP rs2069442 was significantly associated with AD (p = 0.05). In conclusion, our study suggests that CDK5 may be associated with AD.

Published
2008
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14. Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function.

Author

Arias-Vásquez A, de Lau L, Pardo L, Liu F, Feng BJ, Bertoli-Avella A, Isaacs A, Aulchenko Y, Hofman A, Oostra B, Breteler M, and van Duijn C

Subjects
Adaptor Proteins, Signal Transducing, Age of Onset, Aged, Alzheimer Disease metabolism, Alzheimer Disease physiopathology, Autophagy-Related Proteins, Cognition Disorders metabolism, Cognition Disorders physiopathology, Cohort Studies, DNA Mutational Analysis, Female, Genetic Linkage genetics, Genetic Testing, Genotype, Heterozygote, Humans, Logistic Models, Male, Middle Aged, Netherlands, Parkinson Disease metabolism, Parkinson Disease physiopathology, Polymorphism, Single Nucleotide genetics, Alzheimer Disease genetics, Brain Chemistry genetics, Carrier Proteins genetics, Cell Cycle Proteins genetics, Cognition Disorders genetics, Genetic Predisposition to Disease genetics, Parkinson Disease genetics
Abstract

Ubiquilin 1 (UBQLN1) is involved in the ubiquitination machinery, which has been implicated in Alzheimer's disease (AD) as well as Parkinson's disease (PD). A polymorphism in the gene encoding for UBQLN1 has been previously associated with a higher risk of AD. We studied the role of the SNP rs12344615 on the UBQLN 1 gene in AD, PD and cognitive function in a population-based study, the Rotterdam Study, and a family-based study embedded in the genetic research in isolated population (GRIP) program. The Rotterdam Study includes 549 patients with AD and 157 patients with PD. The GRIP program includes a series of 123 patients with AD and a study of 1049 persons who are characterized for cognitive function. Data were analysed using logistic and multiple regression analysis. We found no significant difference in risk of AD or PD by the UBQLN1 SNP rs12344615 in our overall and stratified analyses in the Rotterdam Study. In our family-based study, we did not find evidence for linkage of AD to the region including the UBQLN1 gene. In the family-based study we also failed to detect an effect of this polymorphism on cognitive function. Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function.

Published
2007
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