Dataset Information

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

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.

SUBMITTER: Ntalla I

PROVIDER: S-EPMC7242331 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Ntalla Ioanna I Weng Lu-Chen LC Cartwright James H JH Hall Amelia Weber AW Sveinbjornsson Gardar G Tucker Nathan R NR Choi Seung Hoan SH Chaffin Mark D MD Roselli Carolina C Barnes Michael R MR Mifsud Borbala B Warren Helen R HR Hayward Caroline C Marten Jonathan J Cranley James J JJ Concas Maria Pina MP Gasparini Paolo P Boutin Thibaud T Kolcic Ivana I Polasek Ozren O Rudan Igor I Araujo Nathalia M NM Lima-Costa Maria Fernanda MF Ribeiro Antonio Luiz P ALP Souza Renan P RP Tarazona-Santos Eduardo E Giedraitis Vilmantas V Ingelsson Erik E Mahajan Anubha A Morris Andrew P AP Del Greco M Fabiola F Foco Luisa L Gögele Martin M Hicks Andrew A AA Cook James P JP Lind Lars L Lindgren Cecilia M CM Sundström Johan J Nelson Christopher P CP Riaz Muhammad B MB Samani Nilesh J NJ Sinagra Gianfranco G Ulivi Sheila S Kähönen Mika M Mishra Pashupati P PP Mononen Nina N Nikus Kjell K Caulfield Mark J MJ Dominiczak Anna A Padmanabhan Sandosh S Montasser May E ME O'Connell Jeff R JR Ryan Kathleen K Shuldiner Alan R AR Aeschbacher Stefanie S Conen David D Risch Lorenz L Thériault Sébastien S Hutri-Kähönen Nina N Lehtimäki Terho T Lyytikäinen Leo-Pekka LP Raitakari Olli T OT Barnes Catriona L K CLK Campbell Harry H Joshi Peter K PK Wilson James F JF Isaacs Aaron A Kors Jan A JA van Duijn Cornelia M CM Huang Paul L PL Gudnason Vilmundur V Harris Tamara B TB Launer Lenore J LJ Smith Albert V AV Bottinger Erwin P EP Loos Ruth J F RJF Nadkarni Girish N GN Preuss Michael H MH Correa Adolfo A Mei Hao H Wilson James J Meitinger Thomas T Müller-Nurasyid Martina M Peters Annette A Waldenberger Melanie M Mangino Massimo M Spector Timothy D TD Rienstra Michiel M van de Vegte Yordi J YJ van der Harst Pim P Verweij Niek N Kääb Stefan S Schramm Katharina K Sinner Moritz F MF Strauch Konstantin K Cutler Michael J MJ Fatkin Diane D London Barry B Olesen Morten M Roden Dan M DM Benjamin Shoemaker M M Gustav Smith J J Biggs Mary L ML Bis Joshua C JC Brody Jennifer A JA Psaty Bruce M BM Rice Kenneth K Sotoodehnia Nona N De Grandi Alessandro A Fuchsberger Christian C Pattaro Cristian C Pramstaller Peter P PP Ford Ian I Wouter Jukema J J Macfarlane Peter W PW Trompet Stella S Dörr Marcus M Felix Stephan B SB Völker Uwe U Weiss Stefan S Havulinna Aki S AS Jula Antti A Sääksjärvi Katri K Salomaa Veikko V Guo Xiuqing X Heckbert Susan R SR Lin Henry J HJ Rotter Jerome I JI Taylor Kent D KD Yao Jie J de Mutsert Renée R Maan Arie C AC Mook-Kanamori Dennis O DO Noordam Raymond R Cucca Francesco F Ding Jun J Lakatta Edward G EG Qian Yong Y Tarasov Kirill V KV Levy Daniel D Lin Honghuang H Newton-Cheh Christopher H CH Lunetta Kathryn L KL Murray Alison D AD Porteous David J DJ Smith Blair H BH Stricker Bruno H BH Uitterlinden André A van den Berg Marten E ME Haessler Jeffrey J Jackson Rebecca D RD Kooperberg Charles C Peters Ulrike U Reiner Alexander P AP Whitsel Eric A EA Alonso Alvaro A Arking Dan E DE Boerwinkle Eric E Ehret Georg B GB Soliman Elsayed Z EZ Avery Christy L CL Gogarten Stephanie M SM Kerr Kathleen F KF Laurie Cathy C CC Seyerle Amanda A AA Stilp Adrienne A Assa Solmaz S Abdullah Said M M Yldau van der Ende M M Lambiase Pier D PD Orini Michele M Ramirez Julia J Van Duijvenboden Stefan S Arnar David O DO Gudbjartsson Daniel F DF Holm Hilma H Sulem Patrick P Thorleifsson Gudmar G Thorolfsdottir Rosa B RB Thorsteinsdottir Unnur U Benjamin Emelia J EJ Tinker Andrew A Stefansson Kari K Ellinor Patrick T PT Jamshidi Yalda Y Lubitz Steven A SA Munroe Patricia B PB

Nature communications 20200521 1

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 ...[more]

PMID: 32439900

Similar Datasets

Project description:While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets