title: Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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)).
  
  
  CONCLUSIONS
  By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Magnani
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.forename: Bram P
authors.initials: BP
authors.lastname: Prins
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yin
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alonso
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Sitlani
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lubitz
authors.forename: Elsayed Z
authors.initials: EZ
authors.lastname: Soliman
authors.forename: Sara L
authors.initials: SL
authors.lastname: Pulit
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Jireh
authors.initials: J
authors.lastname: Santibanez
authors.forename: Herman A
authors.initials: HA
authors.lastname: Taylor
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jackson
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Yalda
authors.initials: Y
authors.lastname: Jamshidi
authors.forename: Nona
authors.initials: N
authors.lastname: Sotoodehnia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D006329:Heart Conduction System / Q000503:physiopathology*; D006331:Heart Diseases / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: electrocardiography; genomics