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Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

ABSTRACT: Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency?

SUBMITTER: van Setten J

PROVIDER: S-EPMC6777533 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

van Setten Jessica J Verweij Niek N Mbarek Hamdi H Niemeijer Maartje N MN Trompet Stella S Arking Dan E DE Brody Jennifer A JA Gandin Ilaria I Grarup Niels N Hall Leanne M LM Hemerich Daiane D Lyytikäinen Leo-Pekka LP Mei Hao H Müller-Nurasyid Martina M Prins Bram P BP Robino Antonietta A Smith Albert V AV Warren Helen R HR Asselbergs Folkert W FW Boomsma Dorret I DI Caulfield Mark J MJ Eijgelsheim Mark M Ford Ian I Hansen Torben T Harris Tamara B TB Heckbert Susan R SR Hottenga Jouke-Jan JJ Iorio Annamaria A Kors Jan A JA Linneberg Allan A MacFarlane Peter W PW Meitinger Thomas T Nelson Christopher P CP Raitakari Olli T OT Silva Aldana Claudia T CT Sinagra Gianfranco G Sinner Moritz M Soliman Elsayed Z EZ Stoll Monika M Uitterlinden Andre A van Duijn Cornelia M CM Waldenberger Melanie M Alonso Alvaro A Gasparini Paolo P Gudnason Vilmundur V Jamshidi Yalda Y Kääb Stefan S Kanters Jørgen K JK Lehtimäki Terho T Munroe Patricia B PB Peters Annette A Samani Nilesh J NJ Sotoodehnia Nona N Ulivi Sheila S Wilson James G JG de Geus Eco J C EJC Jukema J Wouter JW Stricker Bruno B van der Harst Pim P de Bakker Paul I W PIW Isaacs Aaron A

European journal of human genetics : EJHG 20190124 6

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompas ...[more]

PMID: 30679814

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Project description:There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

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Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

Publications

Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

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