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Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

Wednesday,2015-03-04 13:51 America/Los_Angeles — zdrager
TitleSequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
Publication TypeJournal Article
Year of Publication2014
AuthorsMagnani, JW, Brody, JA, Prins, BP, Arking, DE, Lin, H, Yin, X, Liu, C-T, Morrison, AC, Zhang, F, Spector, TD, Alonso, A, Bis, JC, Heckbert, SR, Lumley, T, Sitlani, CM, Cupples, AL, Lubitz, SA, Soliman, EZ, Pulit, SL, Newton-Cheh, C, O'Donnell, CJ, Ellinor, PT, Benjamin, EJ, Muzny, DM, Gibbs, RA, Santibanez, J, Taylor, HA, Rotter, JI, Lange, LA, Psaty, BM, Jackson, R, Rich, SS, Boerwinkle, E, Jamshidi, Y, Sotoodehnia, N
Corporate/Institutional AuthorsCHARGE Consortium,, NHLBI Exome Sequencing Project (ESP), UK10K
JournalCirc Cardiovasc Genet
Volume7
Issue3
Pagination365-73
Date Published2014 Jun
ISSN1942-3268
KeywordsAdult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Conduction System, Heart Diseases, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sequence Analysis, DNA
Abstract<p><b>BACKGROUND: </b>The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.</p><p><b>METHODS AND RESULTS: </b>In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).</p><p><b>CONCLUSIONS: </b>By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.</p>
DOI10.1161/CIRCGENETICS.113.000098
Alternate JournalCirc Cardiovasc Genet
PubMed ID24951663
PubMed Central IDPMC4177904
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
N01HC55222 / HC / NHLBI NIH HHS / United States
HHSN268201000010C / HL / NHLBI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
K23HL11472 / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
R21 DA027021 / DA / NIDA NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
1R01HL104156 / HL / NHLBI NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
1RC1HL101056 / HL / NHLBI NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
HHSN2682011000010C / / PHS HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HEALTH-F4-2007-201413 / / Wellcome Trust / United Kingdom
HHSN268201100005G / HL / NHLBI NIH HHS / United States
R01 HL104156 / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
N02 HL64278 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
RC1 HL101056 / HL / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
6R01-NS 17950NIH / NS / NINDS NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R03 AG045075 / AG / NIA NIH HHS / United States
N01HC85081 / HC / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
1R03AG045075 / AG / NIA NIH HHS / United States
R01 HL102214 / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
1K24HL105780 / HL / NHLBI NIH HHS / United States
N01HC85086 / HC / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
HHSN2682011000012C / / PHS HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
HHSN268200800007C / / PHS HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
WT091310 / / Wellcome Trust / United Kingdom
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
1R01 HL102214L / HL / NHLBI NIH HHS / United States
HHSN268201200036C / / PHS HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
HHSN268201000012C / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
1R01HL092577 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
100140 / / Wellcome Trust / United Kingdom
N01HC85080 / HL / NHLBI NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
K23 HL114724 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
UC2 HL102925 / HL / NHLBI NIH HHS / United States
R01 HL111089 / HL / NHLBI NIH HHS / United States
R01 HL116747 / HL / NHLBI NIH HHS / United States
PG/12/38/29615 / / British Heart Foundation / United Kingdom
N01HC85081 / HL / NHLBI NIH HHS / United States
5R21DA027021 / DA / NIDA NIH HHS / United States
HHSN2682011000011C / / PHS HHS / United States

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