title: Integration of genetics into a systems model of electrocardiographic traits using HumanCVD BeadChip.
abstract: BACKGROUND
  Electrocardiographic traits are important, substantially heritable determinants of risk of arrhythmias and sudden cardiac death.
  
  
  RESULTS
  In this study, 3 population-based cohorts (n=10,526) genotyped with the Illumina HumanCVD Beadchip and 4 quantitative electrocardiographic traits (PR interval, QRS axis, QRS duration, and QTc interval) were evaluated for single-nucleotide polymorphism associations. Six gene regions contained single nucleotide polymorphisms associated with these traits at P<10(-6), including SCN5A (PR interval and QRS duration), CAV1-CAV2 locus (PR interval), CDKN1A (QRS duration), NOS1AP, KCNH2, and KCNQ1 (QTc interval). Expression quantitative trait loci analyses of top associated single-nucleotide polymorphisms were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9, and CAV1 showed evidence of differential allelic expression. We modeled the effects of ion channel activity on electrocardiographic parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and expression quantitative trait loci data to a systems model of the ECG.
  
  
  CONCLUSIONS
  These association results replicate and refine the mapping of previous genome-wide association study findings for electrocardiographic traits, while the expression analysis and modeling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, UK.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.forename: Ismail
authors.initials: I
authors.lastname: Adeniran
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Juan-Pablo
authors.initials: JP
authors.lastname: Casas
authors.forename: Antoinette
authors.initials: A
authors.lastname: Amuzu
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
authors.forename: Paul R
authors.initials: PR
authors.lastname: Burton
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Peter W
authors.initials: PW
authors.lastname: Macfarlane
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
mesh_terms: D000368:Aged; D015331:Cohort Studies; D003710:Demography; D004562:Electrocardiography; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D019655:Quantitative Trait, Heritable; D006113:United Kingdom