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Author Notes:

Correspondence: yjamshid@sgul.ac.uk

See publication for full list of author contributions.

See publication for full list of acknowledgements.

See publication for full list of disclosures.

Subjects:

Research Funding:

This work was funded by a grant to YJ from the British Heart Foundation (PG/12/38/29615).

See publication for full funding statements from: AGES, ARIC, BRIGHT, CHS, ERF, FHS, Generation Scotland, GOCHA, GRAPHIC, INGI-FVG, INTER99, JHS, KORA, Korcula, LifeLines, UHP, MGH-CAMP, NEO, RS-I, SHIP, TWINSUK, UKBB, YFS, Cell culture and biochemistry, and Mutant mouse model.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biotechnology & Applied Microbiology
  • Genetics & Heredity
  • Exome chip
  • Conduction
  • ADAMTS6
  • Meta-analysis
  • GENOME-WIDE ASSOCIATION
  • WORSENING HEART-FAILURE
  • QRS DURATION
  • VENTRICULAR CONDUCTION
  • ELECTROCARDIOGRAPHIC PARAMETERS
  • ARRHYTHMIC DEATH
  • COMMON VARIANTS
  • PR INTERVAL
  • MORTALITY
  • POPULATION

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

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Journal Title:

Genome Biology

Volume:

Volume 19, Number 1

Publisher:

, Pages 87-87

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© The Author(s). 2018

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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