A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6
Tekijät: Prins BP, Mead TJ, Brody JA, Sveinbjornsson G, Ntalla I, Bihlmeyer NA, van den Berg M, Bork-Jensen J, Cappellani S, Van Duijvenboden S, Klena NT, Gabriel GC, Liu XQ, Gulec C, Grarup N, Haessler J, Hall LM, Iorio A, Isaacs A, Li-Gao RF, Lin HH, Liu CT, Lyytikainen LP, Marten J, Mei H, Muller-Nurasyid M, Orini M, Padmanabhan S, Radmanesh F, Ramirez J, Robino A, Schwartz M, van Setten J, Smith AV, Verweij N, Warren HR, Weiss S, Alonso A, Arnar DO, Bots ML, de Boer RA, Dominiczak AF, Eijgelsheim M, Ellinor PT, Guo XQ, Felix SB, Harris TB, Hayward C, Heckbert SR, Huang PL, Jukema JW, Kahonen M, Kors JA, Lambiase PD, Launer LJ, Li M, Linneberg A, Nelson CP, Pedersen O, Perez M, Peters A, Polasek O, Psaty BM, Raitakari OT, Rice KM, Rotter JI, Sinner MF, Soliman EZ, Spector TD, Strauch K, Thorsteinsdottir U, Tinker A, Trompet S, Uitterlinden A, Vaartjes I, van der Meer P, Volker U, Volzke H, Waldenberger M, Wilson JG, Xie ZJ, Asselbergs FW, Dorr M, van Duijn CM, Gasparini P, Gudbjartsson DF, Gudnason V, Hansen T, Kaab S, Kanters JK, Kooperberg C, Lehtimaki T, Lin HJ, Lubitz SA, Mook-Kanamori DO, Conti FJ, Newton-Cheh CH, Rosand J, Rudan I, Samani NJ, Sinagra G, Smith BH, Holm H, Stricker BH, Ulivi S, Sotoodehnia N, Apte SS, van der Harst P, Stefansson K, Munroe PB, Arking DE, Lo CW, Jamshidi Y, Jamshidi Y
Kustantaja: BMC
Julkaisuvuosi: 2018
Journal: Genome Biology
Tietokannassa oleva lehden nimi: GENOME BIOLOGY
Lehden akronyymi: GENOME BIOL
Artikkelin numero: ARTN 87
Vuosikerta: 19
Sivujen määrä: 17
ISSN: 1474-760X
DOI: https://doi.org/10.1186/s13059-018-1457-6
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/35900429
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
