title: Genotype-informed estimation of risk of coronary heart disease based on genome-wide association data linked to the electronic medical record.
abstract: BACKGROUND
  Susceptibility variants identified by genome-wide association studies (GWAS) have modest effect sizes. Whether such variants provide incremental information in assessing risk for common 'complex' diseases is unclear. We investigated whether measured and imputed genotypes from a GWAS dataset linked to the electronic medical record alter estimates of coronary heart disease (CHD) risk.
  
  
  METHODS
  Study participants (n = 1243) had no known cardiovascular disease and were considered to be at high, intermediate, or low 10-year risk of CHD based on the Framingham risk score (FRS) which includes age, sex, total and HDL cholesterol, blood pressure, diabetes, and smoking status. Of twelve SNPs identified in prior GWAS to be associated with CHD, four were genotyped in the participants as part of a GWAS. Genotypes for seven SNPs were imputed from HapMap CEU population using the program MACH. We calculated a multiplex genetic risk score for each patient based on the odds ratios of the susceptibility SNPs and incorporated this into the FRS.
  
  
  RESULTS
  The mean (SD) number of risk alleles was 12.31 (1.95), range 6-18. The mean (SD) of the weighted genetic risk score was 12.64 (2.05), range 5.75-18.20. The CHD genetic risk score was not correlated with the FRS (P = 0.78). After incorporating the genetic risk score into the FRS, a total of 380 individuals (30.6%) were reclassified into higher-(188) or lower-risk groups (192).
  
  
  CONCLUSIONS
  A genetic risk score based on measured/imputed genotypes at 11 susceptibility SNPs, led to significant reclassification in the 10-y CHD risk categories. Additional prospective studies are needed to assess accuracy and clinical utility of such reclassification.
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.forename: Kent R
authors.initials: KR
authors.lastname: Bailey
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
mesh_terms: D000368:Aged; D015331:Cohort Studies; D003327:Coronary Disease / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D057286:Electronic Health Records; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors