title: Cumulative effects of common genetic variants on risk of sudden cardiac death.
abstract: BACKGROUND
  Genome-wide association studies and candidate-gene based approaches have identified multiple common variants associated with increased risk of sudden cardiac death (SCD). However, the independent contribution of these individual loci to disease risk is modest.
  
  
  OBJECTIVE
  To investigate the cumulative effects of genetic variants previously associated with SCD risk.
  
  
  METHODS
  A total of 966 SCD cases from the Oregon-Sudden Unexpected Death Study and 1,926 coronary artery disease controls from the Wellcome Trust Case-Control Consortium were investigated. We generated genetic risk scores (GRS) for each trait composed of variants previously associated with SCD or with abnormalities in specific electrocardiographic traits such as QRS duration, QTc interval and heart rate. GRSs were calculated using a weighted approach based on the number of risk alleles weighted by the beta coefficients derived from the original studies. We also compared the highest and lowest quintiles for the GRS composed of SCD SNPs.
  
  
  RESULTS
  Increased cumulative risk was observed for a GRS composed of 14 SCD-SNPs (OR=1.17 [1.05-1.29], P = 0.002). The risk for SCD was 1.5 fold higher in the highest quintile when compared to the lowest quintile (OR = 1.46[1.11-1.92]). We did not observe significant associations with SCD for SNPs that determine electrocardiographic traits.
  
  
  CONCLUSIONS
  A modest but significant effect on SCD risk was identified for a GRS composed of 14 previously associated SCD SNPs. While next generation sequencing methodology will continue to identify additional novel variants, these findings represent proof of concept for the additive effects of gene variants on SCD risk.
authors.affiliation: The Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Huertas-Vazquez
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester ; NIHR Leicester Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: Department of Biomathematics and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.affiliation: The Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA.
authors.forename: Kyndaron
authors.initials: K
authors.lastname: Reinier
authors.affiliation: The Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Uy-Evanado
authors.affiliation: The Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Teodorescu
authors.affiliation: The Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA.
authors.forename: Jo
authors.initials: J
authors.lastname: Ayala
authors.affiliation: University of Leeds, Leeds.
authors.forename: Alistair S
authors.initials: AS
authors.lastname: Hall
authors.affiliation: Pathology, Oregon Health & Science University, Portland, OR.
authors.forename: Karen
authors.initials: K
authors.lastname: Gunson
authors.affiliation: Emergency Medicine, Oregon Health & Science University, Portland, OR.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jui
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester ; NIHR Leicester Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: The Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA.
authors.forename: Sumeet S
authors.initials: SS
authors.lastname: Chugh
keywords: coronary artery disease; genetics; sudden cardiac death