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

TitleExome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.
Publication TypeJournal Article
Year of Publication2018
AuthorsPrins BP, Mead TJ, Brody JA, et al.
Secondary AuthorsJamshidi Y
JournalGenome Biol
Volume19
Issue1
Pagination87
Date Published2018 07 17
ISSN1474-760X
KeywordsADAMTS Proteins, African Continental Ancestry Group, Animals, Connexin 43, Electrocardiography, European Continental Ancestry Group, Exome, Female, Gene Expression, Gene Expression Profiling, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mice, Middle Aged, Myocardium, Open Reading Frames, Polymorphism, Single Nucleotide, Whole Exome Sequencing
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.

DOI10.1186/s13059-018-1457-6
Alternate JournalGenome Biol
PubMed ID30012220
PubMed Central IDPMC6048820
Grant ListR01 HL139731 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
F32 AR063548 / AR / NIAMS NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
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MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
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R01 HL116747 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
K23 NS059774 / NS / NINDS NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
MR/N025083/1 / MRC_ / Medical Research Council / United Kingdom
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
P01 HL107147 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
R01 HL104156 / HL / NHLBI NIH HHS / United States
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R01 HL092577 / HL / NHLBI NIH HHS / United States
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
R01 HL068986 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
U01 HL120393 / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
PG/12/38/29615 / BHF_ / British Heart Foundation / United Kingdom
HHSN268201300048C / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
R01 HL128914 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201300049C / HL / NHLBI NIH HHS / United States
U01 HL098180 / HL / NHLBI NIH HHS / United States
R01 NS059727 / NS / NINDS NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
HHSN268201300047C / HL / NHLBI NIH HHS / United States
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MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
HHSN268201100009C / HL / NHLBI NIH HHS / United States
R01 NS073344 / NS / NINDS NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
HHSN268201300046C / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
U54 GM115428 / GM / NIGMS NIH HHS / United States
K23 HL114724 / HL / NHLBI NIH HHS / United States