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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.    Electronic supplementary material  The online version of this article (10.1186/s13059-018-1457-6) contains supplementary material, which is available to authorized users.

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