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

Gasparini P

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Article number87
JournalGenome Biology
Volume19
Issue number1
DOIs
Publication statusPublished - Jul 17 2018

Fingerprint

Exome
Connexin 43
Genome-Wide Association Study
Gap Junctions
Sudden Cardiac Death
meta-analysis
Metalloproteases
ancestry
Meta-Analysis
Heart Failure
Genotype
loci
duration
secretion
Genes
connexins
genotype
gap junctions
genome
metalloproteinases

Keywords

  • ADAMTS6
  • Conduction
  • Exome chip
  • Meta-analysis

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

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

In: Genome Biology, Vol. 19, No. 1, 87, 17.07.2018.

Research output: Contribution to journalArticle

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title = "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.",
keywords = "ADAMTS6, Conduction, Exome chip, Meta-analysis",
author = "{Gasparini P} and Prins, {Bram P.} and Mead, {Timothy J.} and Brody, {Jennifer A.} and Gardar Sveinbjornsson and Ioanna Ntalla and Bihlmeyer, {Nathan A.} and {van den Berg}, Marten and Jette Bork-Jensen and Stefania Cappellani and {Van Duijvenboden}, Stefan and Klena, {Nikolai T.} and Gabriel, {George C.} and Xiaoqin Liu and Cagri Gulec and Niels Grarup and Jeffrey Haessler and Hall, {Leanne M.} and Annamaria Iorio and Aaron Isaacs and Ruifang Li-Gao and Honghuang Lin and Liu, {Ching Ti} and Lyytik{\"a}inen, {Leo Pekka} and Jonathan Marten and Hao Mei and Martina M{\"u}ller-Nurasyid and Michele Orini and Sandosh Padmanabhan and Farid Radmanesh and Julia Ramirez and Antonietta Robino and Molly Schwartz and {van Setten}, Jessica and Smith, {Albert V.} and Niek Verweij and Warren, {Helen R.} and Stefan Weiss and Alvaro Alonso and Arnar, {David O.} and Bots, {Michiel L.} and {de Boer}, {Rudolf A.} and Dominiczak, {Anna F.} and Mark Eijgelsheim and Ellinor, {Patrick T.} and Xiuqing Guo and Felix, {Stephan B.} and Harris, {Tamara B.} and Caroline Hayward and Paolo Gasparini and Sheila Ulivi",
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AU - Gasparini P

AU - Prins, Bram P.

AU - Mead, Timothy J.

AU - Brody, Jennifer A.

AU - Sveinbjornsson, Gardar

AU - Ntalla, Ioanna

AU - Bihlmeyer, Nathan A.

AU - van den Berg, Marten

AU - Bork-Jensen, Jette

AU - Cappellani, Stefania

AU - Van Duijvenboden, Stefan

AU - Klena, Nikolai T.

AU - Gabriel, George C.

AU - Liu, Xiaoqin

AU - Gulec, Cagri

AU - Grarup, Niels

AU - Haessler, Jeffrey

AU - Hall, Leanne M.

AU - Iorio, Annamaria

AU - Isaacs, Aaron

AU - Li-Gao, Ruifang

AU - Lin, Honghuang

AU - Liu, Ching Ti

AU - Lyytikäinen, Leo Pekka

AU - Marten, Jonathan

AU - Mei, Hao

AU - Müller-Nurasyid, Martina

AU - Orini, Michele

AU - Padmanabhan, Sandosh

AU - Radmanesh, Farid

AU - Ramirez, Julia

AU - Robino, Antonietta

AU - Schwartz, Molly

AU - van Setten, Jessica

AU - Smith, Albert V.

AU - Verweij, Niek

AU - Warren, Helen R.

AU - Weiss, Stefan

AU - Alonso, Alvaro

AU - Arnar, David O.

AU - Bots, Michiel L.

AU - de Boer, Rudolf A.

AU - Dominiczak, Anna F.

AU - Eijgelsheim, Mark

AU - Ellinor, Patrick T.

AU - Guo, Xiuqing

AU - Felix, Stephan B.

AU - Harris, Tamara B.

AU - Hayward, Caroline

AU - Gasparini, Paolo

AU - Ulivi, Sheila

PY - 2018/7/17

Y1 - 2018/7/17

N2 - 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.

AB - 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.

KW - ADAMTS6

KW - Conduction

KW - Exome chip

KW - Meta-analysis

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