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Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

ABSTRACT: BACKGROUND:Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS:Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS:Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

SUBMITTER: Prins BP

PROVIDER: S-EPMC6048820 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

Prins Bram P BP Mead Timothy J TJ Brody Jennifer A JA Sveinbjornsson Gardar G Ntalla Ioanna I Bihlmeyer Nathan A NA van den Berg Marten M Bork-Jensen Jette J Cappellani Stefania S Van Duijvenboden Stefan S Klena Nikolai T NT Gabriel George C GC Liu Xiaoqin X Gulec Cagri C Grarup Niels N Haessler Jeffrey J Hall Leanne M LM Iorio Annamaria A Isaacs Aaron A Li-Gao Ruifang R Lin Honghuang H Liu Ching-Ti CT Lyytikäinen Leo-Pekka LP Marten Jonathan J Mei Hao H Müller-Nurasyid Martina M Orini Michele M Padmanabhan Sandosh S Radmanesh Farid F Ramirez Julia J Robino Antonietta A Schwartz Molly M van Setten Jessica J Smith Albert V AV Verweij Niek N Warren Helen R HR Weiss Stefan S Alonso Alvaro A Arnar David O DO Bots Michiel L ML de Boer Rudolf A RA Dominiczak Anna F AF Eijgelsheim Mark M Ellinor Patrick T PT Guo Xiuqing X Felix Stephan B SB Harris Tamara B TB Hayward Caroline C Heckbert Susan R SR Huang Paul L PL Jukema J W JW Kähönen Mika M Kors Jan A JA Lambiase Pier D PD Launer Lenore J LJ Li Man M Linneberg Allan A Nelson Christopher P CP Pedersen Oluf O Perez Marco M Peters Annette A Polasek Ozren O Psaty Bruce M BM Raitakari Olli T OT Rice Kenneth M KM Rotter Jerome I JI Sinner Moritz F MF Soliman Elsayed Z EZ Spector Tim D TD Strauch Konstantin K Thorsteinsdottir Unnur U Tinker Andrew A Trompet Stella S Uitterlinden André A Vaartjes Ilonca I van der Meer Peter P Völker Uwe U Völzke Henry H Waldenberger Melanie M Wilson James G JG Xie Zhijun Z Asselbergs Folkert W FW Dörr Marcus M van Duijn Cornelia M CM Gasparini Paolo P Gudbjartsson Daniel F DF Gudnason Vilmundur V Hansen Torben T Kääb Stefan S Kanters Jørgen K JK Kooperberg Charles C Lehtimäki Terho T Lin Henry J HJ Lubitz Steven A SA Mook-Kanamori Dennis O DO Conti Francesco J FJ Newton-Cheh Christopher H CH Rosand Jonathan J Rudan Igor I Samani Nilesh J NJ Sinagra Gianfranco G Smith Blair H BH Holm Hilma H Stricker Bruno H BH Ulivi Sheila S Sotoodehnia Nona N Apte Suneel S SS van der Harst Pim P Stefansson Kari K Munroe Patricia B PB Arking Dan E DE Lo Cecilia W CW Jamshidi Yalda Y

Genome biology 20180717 1

<h4>Background</h4>Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.<h4>Results</h4>Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina Hu ...[more]

PMID: 30012220

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Project description:Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10-7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20-50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.

Dataset Information

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

Publications

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

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